A Memorandum Opinion And The Methods That Aren't There At All

You'd think that courts would be leery about dressing their Daubert gatekeeping opinions in the "differential etiology method". After all, as you can see for yourself by running the query on PubMed, the U.S. National Library of Medicine / National Institute of Health's massive database of scientific literature, apparently nobody has ever published a scientific paper containing the phrase "differential etiology method". Of the mere 22 articles ever to contain the sub-phrase "differential etiology" none use it in the sense - to rule in a heretofore unknown cause - meant by the most recent court to don its invisible raiment. Even mighty Google Scholar can manage to locate only 6 references to the "method" and all are law review articles resting not upon some explication and assessment of a scientific method known as differential etiology but rather on the courtroom assertions of paid experts who claimed to have used it.

You'd also hope courts would understand that scientific evidence is no different than any other kind of evidence. It must be still something that has been observed or detected albeit with techniques (e.g. nuclear magnetic resonance spectroscopy) or via analyses (e.g. epidemiology) beyond the ken of laymen. Yet, while they'd never allow into evidence (say in an automobile case) the testimony of someone who had witnessed neither the accident nor the driving habits of the Defendant but who was prepared to testify that he thought the Defendant was speeding at the time of the accident because Defendant looks like the sort of person would would speed and because he can't think of any other reason for the wreck to have occurred, some courts will allow that very sort of testimony so long it comes from a PhD or an M.D. who has used the "weight of the evidence method". Can you guess how many references to scientific papers using the "weight of the evidence method" PubMed yields? The same 0 as the "differential etiology method".

Nevertheless another (memorandum) opinion has joined the embarrassing procession of legal analyses bedecked in these ethereal methods; this time it's a radiation case styled  McMunn v. Babcock & Wilcox Power Generation Group, Inc. 

Plaintiffs suffering from a wide variety of cancers allegedly caused by releases of alpha particle emitting processed uranium from the Apollo, PA research and uranium fuel production facility sued Babcock and other operators of the site. Following battles over a Lone Pine order and extensive discovery the sides fired off motions to exclude each others' experts. The magistrate to whom the matter had been referred recommended that plaintiffs' general causation expert Dr. Howard Hu, specific causation expert Dr. James Melius, emissions and regulations expert Bernd Franke and nuclear safety standards expert Joseph Ring PhD be excluded. The plaintiffs filed objections to the magistrate's recommendations, the parties filed their briefs and the District Court rejected the magistrates recommendations and denied defendants' motions.

Dr. Hu had reasoned that since 1) ionizing radiation has been associated with lots of different kinds of cancer; 2) alpha particles ionize; and 3) IARC says alpha particles cause cancer it makes sense that the allegedly emitted alpha particles could cause any sort of cancer a plaintiff happened to come down with. It's not bad as hunches go though it's almost certainly the product of dogma -specifically the linear no-threshold dose model - rather than the wondering and questioning that so often leads to real scientific discoveries. But whether a hunch is the product of the paradigm you're trapped in or the "what ifs" of day dreaming it remains just that until it's tested. Unfortunately for Dr. Hu's hunch, it has been tested.

Thorotrast (containing thorium - one of the alpha emitters processed at the Apollo facility) was an X-ray contrast medium that was directly injected into numerous people over the course of decades. High levels of radon could be detected in the exhaled breath of those patients . So if Dr. Hu's hunch is correct you'd expect those patients to be at high risk for all sorts of cancer? They're not. They get liver cancer overwhelmingly and have a five fold increase in blood cancer risk but they're not at increased risk for lung cancer or the other big killers. Why? It's not clear though the fact that alpha particles can't penetrate paper or even skin suggests one reason. Look for yourself and you'll find no evidence (by which we mean that the result predicted by the hunch has actually been observed) to support the theory that alpha particles can cause all, most or even a significant fraction of the spectrum of malignancies whether they're eaten, injected or inhaled and whether at home or at work. Be sure to check out the studies of uranium miners.

But let's assume that alpha particles can produce the entire spectrum of malignancies, that the emissions from the facility into the community were sufficiently high, and that the citizenry managed to ingest the particles. What would you expect the cancer incidence to be for that community? Probably not what repeated epidemiological studies demonstrating that "living in municipalities near the former Apollo-Parks nuclear facilities is not associated with an increase in cancer occurrence" concluded.

Dr. Hu attacked the studies of uranium miners and of the communities around Apollo by pointing out their limitations. This one didn't have good dose information and that one had inadequate population data. Perfectly reasonable. It's like saying "I think you were looking through the wrong end of the telescope" or "I think you had it pointed in the wrong direction". He's saying "your evidence doesn't refute my hunch because your methods didn't test it in the first place."

Ok, but where's Dr. Hu's evidence? It's in his mind. His hunch is his evidence; and it's his only evidence. He weighed some unstated portion of what is known or suspected about alpha particles and cancer in the scales of his personal judgment and reported that CLANG! the result of his experiment was that the scale came down solidly on the side of causation for all of plaintiffs' cancers.

At the core of the real scientific method is the idea that anyone with enough time and money can attempt to reproduce a scientist's evidence; which is to say what he observed using the methods he employed. Since no one has access to Dr. Hu's observations and methods other than Dr. Hu his hunch is not science. Furthermore, there's no way to assess to what extent the heuristics that bias human decision-making impacted the "weighing it in my mind" approach of Dr. Hu.

Given that there's no way to reproduce Dr. Hu's experiment and given that none of the reproducible studies of people exposed to alpha particles demonstrate that they're at risk of developing the whole gamut of cancer Dr. Hu's argument boils down to that of the great Chico Marx: "Who are you going to believe, me or your own eyes?" Alas, the court believed Chico and held that "Dr. Hu's opinions have met the pedestrian standards required for reliability and fit, as they are based on scientifically sound methods and procedures, as opposed to 'subjective belief or unsupported speculation'".

Next, having already allowed plaintiffs to bootstrap alpha emitters into the set of possible causes of all of the plaintiffs' cancers, the court had no problem letting letting the specific causation expert, Dr. Melius, conclude that alpha emitters were the specific cause of each plaintiff's cancer merely because he couldn't think of any other cause that was more likely. At first that might seem sensible. It's anything but.

Don't you have to know how likely it is that the alpha emitters were the cause before you decide if some other factor is more likely? Obviously. And where does likelihood/risk information come from? Epidemiological studies in which dose is estimated. Of course the plaintiffs don't have any such studies (at least none that support their claim against alpha emitters) but couldn't they at least use the data for ionizing from say the atomic bomb or Chernobyl accident survivors? After all, the court decided to allow plaintiffs' experts to testify that "radiation is radiation".

Well, just giving a nod to those studies raises the embarrassing issue of dose and the one lesson we know plaintiffs' counsel have learned over the last several years of low-dose exposure cases is to never, ever, ever estimate a dose range unless they're ordered to do so. That's because dose is a measurement that can be assessed for accuracy and used to estimate likelihood of causation. Estimating a dose thus opens an avenue for cross examination but more devastatingly the argument that runs: "Plaintiff's own estimate places him in that category in which no excess risk has ever been detected."

Fortunately for plaintiffs the court held that Dr. Melius' differential diagnosis or differential etiology method does not require that he estimate the likelihood that radiation caused a particular cancer before he can conclude that radiation is the most likely cause among many (including those unknown).

First the court held that it was not its job to decide which method is the best among multiple methods so long as the method is reliable. For this it relies upon In re TMI Litigation. When In re TMI Litigation was decided (1999) the Nobel Prize in Physiology or Medicine for the discovery that Helicobacter pylori and not stress was the cause of most peptic ulcers was six years in the future. The method of observational epidemiology and application of the Hill causal criteria had generated the conclusion that peptic ulcers were caused by stress. The method of experimentation, observation and application of Koch's postulates established H. pylori (nee C. pyloridis) as the real cause; and, for the umpteenth time, experimentation as the best method. So could a court allow a jury to decide that the peptic ulcer in a plaintiff with a H. pylori infection was caused by stress at work? Apparently the answer is "Yes"; scientific knowledge be damned.

Second, citing In re Paoli and other Third Circuit cases, the court held that differential etiology (without knowledge of dose) has repeatedly been found to be a reliable method of determining causation in toxic tort cases. As we've written repeatedly this a claim wholly without support in the scientific literature. Are there studies of the reliability of differential diagnoses made by radiologists? You bet (here for example). Are there studies of immunohistochemical staining for the purpose differential diagnosis in the case of suspected mesothelioma? Yep. Here's a recent example. There are (as of today) 236,063 pages of citations to articles about differential diagnosis on PubMed and none of them (at least none I could find via key word searches) suggests that a methodology such as Dr. Melius' exists (outside the courtroom) and none represent an attempt to test the method to see if it is reliable.

Third, the court held that since Dr. Melius' opinions were the result of his "qualitative analysis" the fact that plaintiffs were living in proximity to the facility during the times of the alleged radiation releases and the fact that Babcock failed to monitor emissions and estimate process losses to the environment was enough to allow a jury to reasonably infer that plaintiffs were "regularly and frequently exposed to a substantial, though unquantifiable dose of iodized [ionized?] radiation emitted from the Apollo facility." How such reasoning can be anything other than argumentum ad ignorantiam is beyond our ability to understand.

Worse yet is this sentence appearing after the discussion about the absence of data: "A quantitative dose calculation, therefore, may in fact be far more speculative than a qualitative analysis." What would Galileo ("Measure what is measurable, and make measurable what is not so") the father of modern science make of that?  Yes an estimate could be wrong and a guess could be right but the scientist who comes up with an estimate makes plain for all to see her premises, facts, measurements, references and calculations whereas the expert peddling qualitative analyses hides his speculation behind his authority. Besides, dose is the only way to estimate the likelihood of causation when there are multiple, including unknown, alternate causes. Then again, in addition to everything else Galileo also proved that questioning authority can land you in hot water so we'll leave it at that.

Finally, in the last and lowest of the low hurdles set up for Dr. Melius, the court found that he had "adequately addressed other possible cause of Plaintiffs' cancers, both known and unknown." How? By taking looking for "any risk factor that would, on its own, account for Plaintiffs' cancers", reviewing medical records, questionnaires, depositions, work histories and interviewing a number of plaintiffs. Presumably this means he looked for rare things like angiosarcoma of the liver in a vinyl chloride monomer worker and mesothelioma in an insulator, commoner things like lung cancer in heavy smokers and liver cancer in hepatitis C carriers, and hereditary cancers (5% to 10% of all cancers) like acute lymphoblastic leukemia in people with Down syndrome or soft tissue sarcomas in kids with Li-Fraumeni Syndrome. You can make a long list of such cancers but they represent perhaps one fourth of all cases. Of those cancers that remain there will be no known risk factors so that once you're allowed to rule in alpha emitters as a possible cause ("radiation is radiation") and to then infer from both "qualitative analysis" and the absence of data that a "substantial" exposure occurred you've cleared the substantial factor causation hurdle (which at this point is just a pattern in the courtroom flooring). Having gotten to the jury all that remains is to make the argument plaintiffs' counsel made before Daubert: "X is a carcinogen, Plaintiff was exposed to X, Plaintiff got cancer; you know what to do."

We're living through an age not unlike Galileo's. People are questioning things we thought we knew and discovering that much of what the Grand Poohbahs have been telling us is false. There's the Reproducibility Project: Psychology the genesis of which included the discovery of a widespread "culture of 'verification bias'" (h/t ErrorStatistics) among researchers and their practices and methodologies that "inevitably tends to confirm the researcher's research hypotheses, and essentially render the hypotheses immune to the facts...". In the biomedical sciences only 6 of 53 papers deemed to be "landmark studies" in the fields of hematology and oncology could be reproduced, "a shocking result" to those engaged in finding the molecular drivers of cancer.

Calls to reform the "entrenched culture" are widespread and growing. Take for instance this recent piece in Nature by Regina Nuzzo in which one aspect of those reforms is discussed:

It would have to change how statistics is taught, how data analysis is done and how results are reported and interpreted. But at least researchers are admitting that they have a problem, says (Steven) Goodman [physician and statistician at Stanford]. "The wake-up call is that so many of our published findings are not true."

How did we get here? A tiny fraction of the bad science is the result of outright fraud. Of the rest some is due to the natural human tendency to unquestioningly accept, and overweigh the import of, any evidence that supports our beliefs while hypercritically questioning and minimizing any that undercuts it (here's an excellent paper on the phenomenon). Thanks to ever greater computing power it's becoming easier by the day to "squint just a little bit harder" until you discover the evidence you were looking for. For evidence that some researchers are using data analysis to "push" until they find something to support their beliefs and then immediately proclaim it read: "The life of p: 'Just significant' results are on the rise." For evidence that it's easy to find a mountain of statistical associations in almost any large data set (whereafter you grab just the ones that make you look smart) visit ButlerScientifics which promises to generate 10,000 statistical relationships per minute from your data. Their motto, inadvertently we assume, makes our case: "Sooner than later, your future discovery will pop up."

Of the remaining bad science, i.e. that not due to fraud or cognitive biases, apparently a lot of it arises because researchers often misunderstand the very methods they use to draw conclusions from data. For example, read "Robust misinterpretation of confidence intervals" and you'll get the point:

In this study, 120 researchers and 442 students - all in the field of psychology - were asked to assess the truth value of six particular statements involving different interpretations of a CI (confidence interval). Although all six statements were false, both researchers and students endorsed, on average more than three statements, indicating a gross misunderstanding of CIs. Self-declared experience with statistics was not related to researchers' performance, and, even more surprisingly, researchers hardly outperformed the students, even though the students had not received any education on statistical inference whatsoever.

We suppose such results would have surprised us before we got out of law school. Nowadays we just nod in agreement; our skepticism regarding the pronouncements of noted scientific authorities becoming complete after recently deposing an epidemiologist/causation expert who didn't even know what "central tendency" meant. He also had never heard of "The Ecological Fallacy" which explains why he committed the error throughout his report. He couldn't estimate how likely it was that the chemical in question was causative nor did he know the rate of the disease in plaintiff's age/gender bracket. No matter. His opinions came wrapped in the same non-existent scientific methods and the court has been duly impressed with his extensive credentials and service on panels at NCI, IARC, etc. So it goes. 

Hopefully courts will begin to take notice of the rot that sets in when scientists substitute personal judgment, distorted by cognitive biases to which they are blind and intuitions which can easily lead their causal inferences astray, for measurement and experiment in their quest to generate scientific knowledge. That and the fact that the method some experts parade about in are not in fact a way of doing science but rather just a way of shielding their unscientific opinions from scrutiny.

Too bad about the method though. If it worked we could hire the appropriate scientific authorities to come up with a cure for cancer. They would ponder the matter, render their opinions as to the cure and testify as to why their "qualitative analysis" which points to the cure is obviously the correct one. The jury would pick the best treatment among those on offer and the court would enter a judgment whereby cancer was ordered to yield to the cure. That's not how it works and it wasn't how it worked in the early 1600s when the sun refused to revolve about the earth, heedless of the pronouncements of scientific authorities and courts of the day. Maybe history will repeat itself in full and scientific knowledge, the product of observation, measurement, hypothesis and experiment will again mean just that and not the musings of "experts" bearing resumes and personal biases rather than facts. Maybe if we're lucky the rot will be cut out and the tide will finally turn in the long war on cancer. We'll see.

Bostic Oral Argument: Plaintiffs Play A Clever Tune

Notwithstanding the briefs of Georgia-Pacific and numerous amici, appellant Bostic, appellee Georgia-Pacific and (seemingly) most of the justices appeared by the end of oral argument on Monday to reach at least partial agreement on the big issue. Specifically, that somehow or another it ought not be the law when multiple defendants create conditions each independently capable of causing plaintiff's injury that none of them be held liable merely because it would be impossible for plaintiff to prove that any one of them was the "but for" cause of her injury. It wasn't exactly a Kumbaya moment but it was close. And the refrain was of Ford v. Boomer and of Merrell Dow v. Havner; and it made us very worried about the future of one of the most important defense victories ever - Borg-Warner v. Flores.

Until the last third of the proceedings a sensible guess as to which way things might go was hard to come by. Much of the briefing and a fair bit of the argument was hopelessly confused due to the tendency of the various parties to attribute decidedly different meanings to identical causal language. It's hardly the fault of the attorneys. Most causal distinctions made in legal opinions still consist, however solemnly invoked, of little more than "moonshine and vapor" (see "Proximate Cause in California" by William L. Prosser, 1950 - a really fun paper btw). Maybe the court in whatever opinion it authors will adopt a modern lexicon of causality with readily translatable and transportable ideas like "necessary cause" and "sufficient cause". We can only hope. But in any event Bostic's counsel cleverly suggested a compromise, the Davidson rule with a little Havner on top, and suddenly, alarmingly, everyone seemed in agreement.

The Davidson rule, like that of Ford v. Boomer, settles the question of where to draw the line for the outer limit of liability for asbestos-related disease by requiring that plaintiff's exposure from any potentially liable defendant's product (or premises) be in and of itself sufficient to have caused the disease. In Texas (see Havner) that would mean given the current state of uncertainty about the causal mechanisms underlying asbestos exposure and mesothelioma that plaintiff would have to show whatever exposure she attributes to a particular defendant doubled her risk of developing mesothelioma. Any defendant whose contribution could be shown to satisfy the risk doubling requirement would have to face a jury; and any defendant whose contribution did not double the risk could have its summary judgment and go home. Seems fair; what's not to like?

Plenty. Remember that causation is necessary but not sufficient for the determination of substantial factor causation. It is not enough for legal causation to show that grabbing a stumbling passenger's arm dislodged a plain brown package containing fireworks that fell to the ground, exploded and caused some distance away a scale to bonk Mrs. Palsgraf on the head.  The risk posed by the act of grabbing the stumbling passenger's arm must have been of such a degree as to generate a duty for the ordinarily prudent railroad employee to have done something different. Unless we missed it, not once during oral argument did anyone utter "legal cause" or "de minimis risk". Why? We suspect it's not because everyone forgot that the substantial factor test of legal causation requires causation plus a non-de minimis risk but rather because everyone assumes a 100% risk increase must be substantial - an all too common consequence of our cognitive blind spot for percentages.

Something that increases the risk of mesothelioma by 100% hardly sounds de minimis. But think about it this way, your odds, absent asbestos exposure, of developing mesothelioma are 1:1,000,000 (one in a million). Doubling the risk increases the odds to 1:500,000. Those are your odds of being struck by lightning this year according to National Weather Service estimates. And that risk is tiny compared to your risk of having say the wind drop a tree limb on your head.

So should a 1:500,000 risk be big enough for the imposition of a duty? That's for the courts to decide by way of public policy analysis but they ought to go into the exercise understanding what it would mean to say that someone who creates a 1:500,000 risk of death can be subject to liability and even punitive damages. Consider these examples of activities that increase the risk of death by 1:500,000: two days of snow skiing, going horseback riding 4 times or eating one peanut butter and jelly sandwich per year (aflatoxin). If that doesn't make the point consider this: 1:500,000 odds are less than those of flipping a fair coin 18 times and having it come up heads every time.

So here's to hoping the court keeps in mind that whether or not a duty should be imposed in a given case is gauged by whether the defendant has created a substantial risk and not whether a risk has been altered substantially. Otherwise we'd wind up with the absurd conclusion that doubling an infinitesimal risk creates a substantial one.

P.S. If you're interested in how the counterfactual or "but for" view of causation survives a multiple sufficient causes problem like that seen in Bostic see chapter 10 of Judea Pearl's book "Causality".

Lawyers Have Learned To Distort Pharmacovigilance Signals

The goal of pharmacovigilance is to detect the subtle signal of a causal effect otherwise buried amongst the noise of all the maladies which by coincidence alone happened to manifest after a drug was taken. The FDA Adverse Event Reporting System (FAERS) gathers reports of these adverse events and presents them in a database that can be analyzed for just such signals. Since previously unknown causal associations are what are being sought there is no requirement that the reported adverse effect be demonstrably causal. To work properly the system merely requires accurate and unbiased reporting of as much adverse event data as possible.

You'd think health care professionals would be responsible for most of the reported adverse events and most of the time you'd be right. But zealous advocates (aka lawyers) can submit adverse reports too and when they do the resulting signal amplification is amazing (or appalling, depending on your perspective). Take the case of metoclopramide and tardive dyskinesia (TD) examined in:  "The Metoclopramide Black Box Warning for Tardive Dyskinesia: Effect on Clinical Practice, Adverse Event Reporting, and Prescription Drug Lawsuits".

For years the rate of TD per metoclopramide (Reglan) prescription bumped along at the bottom of the graph never rising above one half of one tenth of one percent. It is, or was, commonly prescribed in those suffering from gastroparesis. Then came a black box warning advising of the very rare but very serious side effect TD. Suddenly the TD rate took off like the Blue Angels at an airshow. What was behind it? "In the FAERS, only 3.6% of all the reports are from lawyers, whereas 70% of TD reports related to metoclopramide came from lawyers, resulting in a significant magnification of TD reports disproportionate to all other adverse reports." Interestingly, the authors using published legal opinions regarding TD/metoclopramide as a proxy for filings found that a wave of claims took off just before the wave of reports of TD. 

Distorting the metoclopramide/TD risk signal caused doctors and patients to overestimate the risk posed by metoclopramide. Often they chose instead domperidone which has not been approved by the FDA; unfortunately that "[puts] patients receiving this drug at potential risk for serious or even fatal arrhythmias."

Perhaps even more unsettling is the fact that as fewer and fewer prescriptions for metoclopramide were written the increase in the rate of TD got steeper and steeper. One hypothesis that readily emerges is that lawsuits drove the increase in TD cases rather than the other way around. If so, it points to another chronic problem in mass tort litigation - expert witnesses whose primary contribution is to dramatically over-diagnose ailments like TD.

The authors note that theirs is not the first study to find that lawyers are able to modulate the signals relied on for pharmacovigilance. It'll be interesting to see what if anything the FDA does about it.

Painting By Numbers

It's hard to argue with the decision of the U.S. Court of Appeals for the Seventh Circuit in Joann Schultz v. Akzo Nobel Paints, LLC; a benzene/AML (acute myelogenous leukemia) wrongful death claim filed by the wife of a painter. The opinion frames the question before the court as follows: Is the fact that plaintiff's oncology expert holds to the linear no-threshold model for carcinogens a sufficient reason under Daubert to exclude his opinion that plaintiff's estimated high benzene exposure was causative given published studies demonstrating an eleven-fold risk of AML among those similarly exposed? The obviously correct answer is "no" and so the court held. (Behold the power of framing!)

We haven't read any of the briefing and so don't know if the question as framed was really what the fight was all about (though we certainly hope there was more to it than just that) but we did read the entire opinion and noted a couple of things you might find of interest. One involves the fact that plaintiffs are finally getting why dose matters (and helps) another is the opportunity that arises when dose is calculated. The last is a lament about the common problem of conflating observational epi studies with the scientific method, casual causal inference via "differential diagnosis" and a pointer to a new tool you might find helpful.

Unlike most toxic tort plaintiffs Schultz had her expert perform a sophisticated dose reconstruction. From it the expert generated a cumulative dose estimate which was then compared to risk data drawn from epi studies plaintiff thought she could defend as scientifically sound. The comparison yielded a large increase in her deceased husband's risk of AML attributable to his benzene exposure. Now that's the way to do it. Better yet, it was essential to getting the summary judgment rendered against her reversed. How did she do it?

According to the appellate court Plaintiff reconstructed the decedent's benzene exposure "using Monte Carlo Analysis, a risk assessment model that accounts for variability and uncertainty in risk factors such as the likely variation in [decedent's] exposure to benzene during different periods and at different plants." The court then proceeded to write "[t]he U.S. Environmental Protection Agency (EPA) has endorsed this methodology as a reliable way to evaluate risk arising from environmental exposure." Sound good?

For the unwary it sounds as though Monte Carlo Analysis(/simulation/etc) is (a) some sort of mathematical equation that (b) generates reliable (and therefore presumed to be admissible) risk estimates while (c) accounting (somehow) for missing data, and it comes with (d) Uncle Sam's seal of approval. Unfortunately, it isn't so.

Rather than going into detail about Monte Carlo simulations and their promise and limitations let's briefly discuss what makes them invaluable when it comes to cross examining the other side's expert. It turns out that it's not some sort of mathematically deduced equation that "accounts for variability and uncertainty" in these Monte Carlo exercises - it's the expert who picks which variables matter along with the formula that expresses the pattern wherein the variables are expected to be found. In other words, the expert using a Monte Carlo method has translated her opinions into a mathematical language. So whereas an expert's deposition fought only in English typically yields dissembling about methods and sharp advocacy about results, a translation of the mathematical language of her model reveals her tactics and much of the other side's strategy. Words like "high" and "low" become e.g. 2 ppm and 0.01 ppm, "increasing" and "decreasing" become calculable slopes, and "it varied throughout his shift" becomes e.g. a power law - each suddenly vulnerable to an informed cross examination.

Yet while we cheered the use of (potentially) explicit and transparent models (we don't know if plaintiff's estimator divulged his spreadsheets and formulae) for estimating dose we groaned at an embarrassingly shabby standard for causal inference.

First there's the method: the differential diagnosis. Since plaintiff's expert ruled-in most of, or at least the important, "risk factors" for AML and then ruled-out everything besides benzene his opinion that benzene caused decedent's AML was deemed admissible. Ugh. Saying something is a risk factor is not the same thing as saying that it's a cause. That so-called risk factor epidemiology isn't science and isn't even likely to turn up real risks has been known for some time. Then there's the category error FAIL of ruling-in and -out of the set of causes things that aren't even causes. Next there's the "best of a bad lot" problem. If you don't have all the real causes "ruled-in" your diagnosis is iffy at best. If you don't have the most likely cause ruled-in then all you're likely doing is picking the least wrong cause. Since the cause of the vast majority of AML cases is unknown and as there was nothing to distinguish Schultz' AML from the thousands that arise spontaneously every year plaintiff's expert's failure to rule-out "whatever it is that causes 90% of all AMLs" should have been fatal to his differential diagnosis. (Note: it wouldn't however be fatal to plaintiff's case assuming the admissibility of her claim of an eleven-fold relative risk given decedent's estimated dose).

Second, there's the claim that because plaintiff's and defendant's epi studies share "the identical methodology - observing AML rates in populations exposed to benzene over time", "Rule 702 did not require, or even permit, the district court to choose between those two studies at the gatekeeping stage." The court would do well to read "The Scandal of Poor Epidemiological Research: Reporting guidelines are needed for observational epidemiology" before pronouncing such a rule. As one of the FDA EMDAC committee members said during the recent Avandia meeting, when it comes to evidence "observational studies are at the bottom of the totem pole." Courts should keep in mind the fact that small effects detected in such studies even though, and perhaps especially when, statistically significant (i.e. report a low p-value) are likely to be false - and that goes for the ones cited by defendants as well as plaintiffs.

If you're still harboring doubts about whether or not there really is an unfolding scandal involving observational epidemiology read the editor's choice, "Improving Observational Epidemiology" in the current edition of International Journal of Epidemiology. If you don't have free access to the entire paper this should encourage you to pay the price for it:

"The ability of observational datasets to generate spurious associations of non-genetic exposures and outcomes is extremely high, reflecting the correlated nature of many variables, and the temptation to publish such findings must rise as the P-values for the associations get smaller. The forces involved - the imperative to publish for a successful research career, the journal publishers' and editors' desire to publish material that gets cited to increase their profiles and the isolation of many epidemiologists working on small,  often non-contributory, studies - are strong. Perhaps epidemiology needs to re-define its training and knowledge base and build in subsequent accreditation routes to promote better standards of epidemiological professional practice. Very few epidemiology departments impose the discipline of laboratory daily log books in which every experiment and analysis is recorded to provide some verification of what was a priori and what was post hoc. Academics involved in 'handle-turning circular research', highlighted nearly a century ago by Paul de Kruif, and commented upon recently in this journal, really do need to find alternative pursuits."

Finally, if you're interested in uncovering abusive practices in observational epidemiology add p-hacking to your vocabulary (you know your meme has gone big time when it's on Urban Dictionary) and "P-Curve: A Key to the File Drawer" to your arsenal. A number of statisticians, alarmed at the realization that the tools of their trade have been used to gin up spurious science on an industrial scale, have developed new tools to detect it. Plaintiffs are turning such tools on drug studies and company-financed employee mortality studies. Meanwhile, in one case of which we're aware, defendants are using them with effect on a whole series of studies resting on nothing more than the curious coincidence that the reported p-values all fell between 0.044 and 0.05. Go figure. Literally.

A Duty To Mine Big Data

We had another jury trial and thus were offline for a few weeks but it didn't take long to dig up something I hope you'll find of interest. I ran across it in a recent opinion by the district court in the In Re Fosamax Product Liability Litigation. What is it? It's a duty to actively mine the FDA's data for a signal, a hint, that your approved pharmaceutical product might be associated with an adverse event.

As an initial matter I almost didn't get to the interesting part of In Re Fosamax Product Liability Litigation thanks to this eye-roller: "In applying the nine Bradford Hill factors, he [Dr. Cornell] reviewed Plaintiff's medical records from 1996 to present, the office notes and depositions of her treating physicians, and 'past and current medical literature on the topics of osteopenia, osteoporosis and their prevention and treatment with bisphosphonate drugs including alendronate'". Which was followed by: "The methodology Dr. Cornell used is sufficiently reliable because the Bradford Hill criteria are 'broadly accepted' in the scientific community 'for evaluating causation, and 'are so well established in epidemiological research". This business of giving expert witnesses a pass for doing nothing more than invoking the great epidemiologist's name and saying that their method consisted of peering at the evidence through the supposed lens of Hill's "criteria" is utterly appalling but it would take several paragraphs to explain and we've done it before so I'll leave it at that.

The portion worth pondering is found further down in the discussion of defendant's motion to exclude a different expert witness, Dr. Madigan. Madigan is a statistician from Columbia with an impressive resume. He was tasked with assessing "whether a signal of problematic oversuppression of bone turnover and associated [atypical femur fractures (AFF)] . . . existed for Fosamax, using industry standard pharmacovigilance techniques and data sources, and the adverse event terms selected by Merck to internally evaluate the same" and whether "the strength of that signal, if any, in comparison to the signal, if any, for such events in other products indicated for the prevention and treatment of osteoporosis". To identify and evaluate such a signal Madigan took several medical terms considered by the defendant to be possible indicators of "oversuppression of bone turnover" and/or AFF and, using a program called Qscan, ran them through FDA's Adverse Event Reporting System ("AERS") database looking for associations with Fosamax use.

The data revealed "the presence of a clear signal for oversuppression of bone turnover and associated atypical femur fracture events utilizing the terms selected by Merck for such analysis. By standard metrics of 'signal' detection, the signal is strong, consistent, and not ambiguous. Of perhaps greater concern, the signal was striking in comparison to that for other drugs indicated for the prevention and treatment of osteoporosis. As early as 2001-2002, the spontaneous report data for Fosamax provide signals for a number of indicators of suppression of bone turnover. For the comparator drugs, such signals either never appear or appear years later." As Qscan (or similar software) data mining is widely used (and often mandated in the pharmaceutical industry) and as peer-reviewed papers arising out of data generated by the software had been published the court concluded that "data mining in pharmacovigilance" is a reliable method. Fair enough.

The excitement comes in the next paragraph in which the court concludes that Madigan's testimony "fits", and so is relevant to, an issue in the case because it informs the question of whether the defendant should have warned of the later-perceived risk of AFF. The court thereby implicitly held, I think, that the defendant had a duty to mine the FDA's data as early as 2001-2002. In other words, the existence of powerful data mining tools capable of uncovering an early signal of a possible harm associated with defendant's product created a duty to use such a tool. Ultimately, that's a duty to discover any statistical association between your product and some harm in the FDA's (admittedly accessible) that might be causal and to thereafter warn about it; and it's a duty to mine not only your data but any data that might shed light on your product.

It's hard to know what to make of a duty to mine big data. Obviously it's a potential problem for defendants. "Should have known" is no longer what was reasonably knowable (by humans). Instead it's what was knowable given a duty to use "powerful data mining and signal detection capabilities" including "a powerful query-by-example module that allows users to mine and visualize data through inquiries utilizing multiple case data elements." We're already in the middle of something similar; a case in which the plaintiff is demanding to see all of the death certificates collected by our client's benefits department claiming that we had, or had assumed, a duty to look for mortality patterns among our workers that might suggest a work-related etiology - the idea being that the plaintiff's decedent had succumbed to one such workplace illness and we either knew or should have known from looking at the death certificates that danger had been lurking.

And of course there's the problem of experts coming in after the fact and running term after term after modified term in varying combinations until an association emerges. Working backwards they'll then construct a narrative about why the set of terms eventually founded to produce the association would have been the obvious choice at the time the data mining ought to have been done; and the failure to look for such an obvious potential association will thereafter be cast as willful ignorance.

Then there's the bane of defendants in all latent disease cases - the hindsight bias. It's the "knew it all along" fallacy that emerges when a jury is shown the picture on the box before they see the puzzle pieces inside. They can't thereafter imagine that the few anecdotes and case reports that constitute a handful of the pieces that make up the picture on the box could ever have suggested mere randomness. That means the ability to mine huge amounts of data will make signals easier to find while making it harder to mount a successful state-of-the-art defense any time Qscan can tease a signal from the data.

Data mining has led, and will lead to startling discoveries in the sciences. In the law it may well lead to startling liabilities - especially if defendants are made to pay for harms foreseeable only by the most powerful software available. Ponder that.

Very Little Authority For Now, But Maybe Not For Long

Two yellow pads are full of notes, diagrams, thoughts and arguments and still the answer eludes me. So, rather than continue not to post anything about all the interesting stuff going on in mass torts while I try to figure it out I'll just throw out what I've got so far over a series of posts and move on to something less difficult (and likely more interesting). On then to the question that's been bugging me for a month.

Should alternative liability, in the form of burden of proof shifting, apply in the following case: (1) a neonate contracted a Cronobacter sakazakii infection and was seriously injured; (2)  C. sakazakii is a ubiquitous pathogen and readily forms biofilms on stainless steel, inside household water pipes and upon other surfaces (3) C. sakazakii infections in neonates have also been repeatedly traced to PIFs; (4) plaintiff's experts opined that it's more likely than not that the source of C. sakazakii was the powdered infant formula (PIF) fed to the neonate; (5) PIFs are not sterile since the process of sterilization would destroy the nutritional value of the PIF; (6)  there were two or more suppliers of PIF whose product was prepared for the neonate; (7) none of the remaining PIF fed to the newborn, nor any of the lots from which they were drawn, were found to contain C. sakazakii; and, (7) the wrong complained of was a failure to warn that full term neonates, like the plaintiff, were at risk of C. sakazakii infections.

Alternate liability analysis often begins with Summers v. TiceIn that case both hunters who had fired their weapons in plaintiff's direction had been sued and both could be shown to have breached their duty to safely handle those weapons. Because it was impossible for the plaintiff to show whose buckshot was responsible for his injury, and because it was deemed just that the consequence of that impossibility fall on the culpable defendants rather than the innocent and injured plaintiff, the court held that the defendants, rather than the plaintiff, should bear the burden of proving from which shotgun the pellets had originated. Fair enough.

Here, in Burks v. Abbott Laboratories, both of the manufacturers of PIF consumed by the plaintiff had also been sued. Furthermore, neither's product bore a warning about the hazard which plaintiff claimed they had a duty to disclose. However, not all the possible sources of C. sakazakii (Mother Nature being judgment-proof) were before the court. Nevertheless, the court held, though it "located very little authority on this specific question" that  the determination of whether it was more likely than not  that the source of plaintiff's C. sakazakii infection was the defendants' PIF should be applied to the defendants collectively.

Ponder the consequences. Let's say that 51% of all C. sakazakii infections in neonates are due to PIFs even when C. sakazakii can't be isolated from the product or the lot from which it was drawn, and that 49% of all C. sakazakii infections in neonates are due to C. sakazakii found in the household water used to reconstitute the PIF or on kitchen surfaces. Also, assume the warning could fairly be said to be lacking (which in this case is not at all a given and in fact raises as many questions as stacking defendants to get to the 51% threshold - but that'll be addressed in subsequent posts).

If there's only one supplier of PIF there's no need for alternative liability so assume there are at least two. But what happens when you start dividing up the 51% among the defendants? Unless one of them was responsible for ~99% of the product the result is that you've stacked two defendants who might, but probably didn't, have something to do with plaintiff's infection and handed them all of the liability for it. Is that fair? What if there were 100 suppliers? And what's the justification for stacking defendants? Is it because they're in the same business? If so, how similar must their businesses be to permit such stacking? If in order to get to a 51% likelihood as to the source of the infection you had to stack PIF manufacturers with stainless steel kitchen appliance manufacturers (because C. sakazakii happily lives on stainless steel and creates biofilms that makes it nearly impossible to remove with household cleaning products) could you justify handing them the burden of proof by saying they were all in the food business? 

Or what about reducing defendants' liability by Mother Nature's share? Would that solve the "overdeterrence" problem? What follows from the fact that the potential for these sorts of infections, due to the nature of pathogens, is essentially binary (you get it or you don't) and not of the dose-response variety seen in typical mass tort cases?  These are the sorts of questions that have led to a lot of head scratching but so far few answers.Over the next couple of days I'll type up more of these questions and the paths down which they lead (at least the ones I've thought of and followed).

How a fact pattern like the one in Burks gets resolved is I think a very big deal. That's because an awful lot of diseases laid over the last forty years at the feet of man-made substances and bad habits turn out to have been due to pathogens all along. It also appears we're entering an era in which old scourges reemerge thanks to having evolved antibiotic resistance and new ones arise thanks to globalization.  The resulting morbidity and mortality will makesevery other mass tort pale in comparison and so far juries aren't having much trouble blaming defendants for the depredations of Mother Nature's tiniest critters. We think there's a wave of litigation coming in which plaintiffs will assert liability for facilitating the transmission of pathogenic agents. The answers to questions like those posed by Burks will be critical in determining how it all plays out. 



The Annual Report to the Nation on the Status of Cancer (covering 1979 - 2009) is out. The good news is that overall death rates for some of the biggest killers continues to decline. The bad news is that deaths from cancers caused by infectious agents like HPV and hepatitis-C are up; doubling in some cases. Get your daughters, and sons, vaccinated.

It took several decades but the egg has now been cleared on the charges of murder by heart attack and stroke.

It also took decades to clear caffeinated coffee on all charges of murder by cancer. Now drinking 4+ cups per day has been shown to cut your risk of some cancers by half.

Many common food ingredients have been scientifically demonstrated to double or halve, and often double and halve, your risk of cancer. Click here to find out why.

The human breast milk microbiome is far more diverse than previously imagined and it's composition is impacted by factors such as obesity and Cesarean delivery. Could it be that her microbes, rather than a mother's genes, are to blame for her obese children? Could it be that it's the absence of certain breast microbes in mothers who underwent Cesarean delivery that's responsible for the increased risk of asthma in their children?

In the past, proponents of the Precautionary Principle have tended to deny that hormesis exists. As the evidence in favor of hormesis has gotten harder to ignore their narrative has changed to (1) it hasn't been shown to be the sort of general phenomenon that would permit an inference of hormesis for all toxins and (2) too little is known about the mechanism to permit its incorporation in to risk models.

Be Careful What You Wish For When You Wish For A Standardless Standard Like Lohrmann

As promised we're weighing in on Holcomb v. Georgia Pacific,  et  al - the most recent effort by a court, this time Nevada's supreme court, to paint a fig leaf over the judicial embarrassment that is modern asbestos litigation.

To recap, by 1989 (twenty years after Clarence Borel filed the complaint that launched the mother of all mass torts) the litigation appeared to be winding down. The personal injury (and school abatement) cases had bankrupted most of the companies that once had constituted the lion's share of the asbestos industry. A little over a decade later Pittsburgh-Corning, and soon thereafter Owens-Corning, sought bankruptcy protection. With that, market share-wise, the vast majority of the American "asbestos industry" had been put out of its misery. The remaining defendants (with the exception of Owens-Illinois which serendipitously exited the business back in 1958) were each responsible for a microscopic share of the asbestos used in the United States. Surely the end was near. Instead, because courts tended to create special causation rules in asbestos cases which conflated risk with causation and because those same courts assiduously avoided the question of whether some risks were so small that liability could not fairly be predicated on them, the litigation continued unabated.

Drowning defendants, desperate for anything that might help against the "every asbestos fiber poses risk, mesothelioma is the actualization of risk, therefore plaintiff's meso was caused by every fiber" sophistry that goes on down at the courthouse, often grab for Lohrmann v. Pittsburgh Corning . It's an 80's era asbestosis case holding, essentially, that two to three weeks of work cutting/applying Unibestos wasn't enough to impose liability on Pittsburgh Corning (though things went less well for the other defendants). There was no discussion of dose, nor of the relative potency of amosite nor of the risk posed by each of the defendants' products. Instead, Lohrmann accepted proof of frequent, regular and proximate exposure to a defendant's asbestos-containing product as a proxy for a quantitative assessment of exposure and thereby risk or whatever other consideration drove the court's approximation of the line between de minimis and non-de minimis exposures. But how frequent is frequent? How regular is regular? How proximate is proximate?

"It's better than nothing", one assumes the Holcomb defendants thought when they asked the Nevada Supreme Court to adopt the so-called Lohrmann standard. So how did it work out? Would plaintiff's testimony that exposures were "numerous" be sufficiently regular and frequent? Would working "around" a joint-compound user proximate enough?

According to the Nevada Supreme Court it's enough. And thus the problem with Lohrmann.

Today there's an extensive peer-reviewed literature demonstrating the typical distribution of exposures resulting from almost every conceivable use of asbestos, and a well refined risk model for asbestos-induced mesothelioma that lets anyone estimate the risk associated with the exposures described by a plaintiff and his co-workers. Coming up with a plausible range of exposure is neither too hard nor too expensive. Down here in Texas plaintiffs need someone to testify to a supportable dose range and a review of their experts' bills reveals a typical cost of about $2500 - a fraction of amount they spend on their experts who testify about the history of the use and recognition of the hazards of asbestos exposure. 

So would it be too much of a burden to make plaintiff state a supportable range of his likely exposure? The Nevada Supreme Court thought so - though it didn't say how much it thought such an estimation would cost, nor how much is too much. It also bought the straw man argument that states like Texas which actually ask "about how much" are instead asking the impossible to answer "state precisely how much". From there the court went on to conclude that an inference of causation may reasonably be drawn from expert testimony that infrequent and low level exposures can cause mesothelioma plus evidence that the plaintiff sustained "numerous" instances of working "around" the asbestos-containing product. And sure enough, that's the gist of Lohrmann.

As for why defendants continue to go from court to court demanding the adoption of the Lohrmann standard, that remains a mystery. As for why plaintiffs hate to say "about how much", we already know the answer - compared to the risks posed by some of the products now caught up in the litigation, taking a shower is a death defying feat.

2013 will be the International Year of Statistics. Maybe it'll be the year more judges and lawyers come to appreciate how much better our decision-making can be when we have the courage to demand the data and to accept what it implies.



Causation is Hard: Statins and Diabetes Edition

So what to make of a chart of associations like this? Some studies, and studies of studies, show that the risk of diabetes is decreased in those on statins. Most however show a small increase in risk and as a result overall risk is slightly elevated. It looks like causation. But is it?

Across the studies there are differences in statins, in dosing regimens and, of course, in patients. The opportunities for bias and confounding are legion.

And then there's the larger issue. Statins unquestionably save lives when prescribed to those with cardiovascular disease and elevated cholesterol.

So what to do when the question is one of picking your poison (your risk) when you don't know, and have no way to reliably estimate, whether you're at greater risk of heart attack or diabetes? That's the question debated here.


Causation is Hard: Multiverse Edition Part II

Gold in "Certainty Into Probability" proposes to do away with the requirement of "but for" causation in toxic tort litigation and to replace it with an apportionment of liability among all potentially causative factors, whether tortious or not, so long as each factor passes the Milward v. Acuity holistic-weight-of-the-evidence-via-subjective-judgment-performed-by-an-adequately-credentialed-person "general causation" test. The impetus for the proposed change is despair. Despairing that scientific discovery seems only to propagate more and more causal associations he concludes that they are each ultimately "population-based", and thus probabilistic. The reasoning goes as follows: not every predisposing gene generates a cancer, not every environmental encounter produces a biomarker record of it, and not every toxic insult produces a damaged chromosome to confirm it. Therefore causation is more like a probability density function and less like the ordinary cause and effect relationship of hammer-missed-the-nail and sore thumb.

To illustrate he gives an example: "The plaintiff worked for many years at a job that daily entailed the inhalation of vapors of some solvent. After the appropriate latency period, the plaintiff's doctors diagnosed a particular cancer. Undisputed, peer-reviewed scientific research shows that (1) cells of this cancer almost always have mutations in a particular set of genes; (2) DNA treated with the solvent in vitro is statistically significantly more likely than untreated DNA to contain mutations in at least some of those genes; (3) the frequency of this cancer among exposed individuals with a specific susceptible genotype is slightly, but statistically significantly, greater than among unexposed individuals of the same genotype; and (4) no other specific risk factors have yet been identified for this cancer, so the vast majority of cases are considered unexplained or idiopathic." (The foregoing, by the way, "should be considered sufficient to support a factual finding of "general causation", according to Gold.  What that means is despite the fact that (1) genome-wide association studies attempting to tie certain genes or groups of genes to certain cancers are notoriously prone to spurious findings, (2) biological associations resting on simple statistical significance are usually false, and (3) conclusions derived from epidemiological studies finding "slightly" increased risk are almost always false, if you add enough zeros together a jury can somehow eventually conclude that the likelihood the solvent is a human carcinogen is greater than 50%. Admittedly, that is indeed the central teaching of Milward v. Acuity ... but we digress.) The hypothetical plaintiff also has a "susceptible genotype" thereby further adding to risk.

So how to do justice? Under Gold's approach the fact-finder would be asked to determine whether the solvent was responsible for "a non-trivial increase in plaintiff's risk of developing [the (presumably)] cancer. Upon an affirmative answer, the fact-finder would estimate, as a percentage, the extent to which the solvent exposure contributed to the plaintiff's risk of cancer." That percentage would then be multiplied by the damages to determine the award. All other non-tortious factors go into the mix of "background" risk. So how might it work?

Let's start with an example. Think of cancer risk as a six-sided die. If you roll a 1 you get cancer and die of it. Now imagine that the die has been weighted and the odds of getting a 1 have gone from 1 in 6, or 16.67%, to 1 in 5, or 20% (which conveniently also works out to a 20% increase in risk). Under the "more likely than not" standard of "but for" causation the plaintiff must lose as, out of 1,000 people exposed to the solvent who also got cancer, 167/200 would have gotten it anyway. Per Gold however, the entity that weighted the die may be sued nonetheless, and the 20% increase in risk, obviously beyond de minimis, entitles the plaintiff to 20% of his damages. We can't figure out which 33 of the 200 victims developed cancer as a result of the solvent but collectively justice is done. Cosmic justice. What's not to like?

At least three things.  First, there's the problem of trying to say something about an individual based on population frequencies. Indeed such an approach is so grossly prone to error that it's got it's own name: the ecological fallacy. Beware the tyranny of the central tendency - failure to do so results in anticipating your being perfectly content with your feet in the freezer and your head in the oven. Remember also the case of the Pliofilm workers' relative risk. Whether working with benzene significantly increased their risk of acute myelogenous leukemia depends more on the year each observer measured their outcomes than the benzene to which they were exposed.

Second there's the frequentist issue; which is to say the interpretation of the frequencies calculated in the hypothetical solvent study two paragraph above means that somewhere, necessarily elsewhere and in an infinite space, the number of people developing cancer as a result of the solvent exposure is exactly 20% greater than would otherwise have been the case. Extrapolating from a typical epidemiological sample size of a few hundred to maybe a few thousand, to infinity, is quite a leap. It's like pronouncing what nature is like based upon your examination of an impatiens in a pot on your patio.

Third, assuming arguendo that something like "a 20% increase in risk" is both accurate and has some concrete meaning beyond games of chance where rules (seem to) encompass and control for all known variables, Gold's formulation violates his own edict of "risk as cause, not as harm". To demonstrate let's go back to our hypothetical above of 1,000 workers exposed to a solvent that increases their risk of cancer by 20%.

Normally we'd expect, through no fault of anyone's save Mother Nature's, 167 of the workers to develop cancer. Instead, taking as true and absolute the 20% increase in risk, 200 workers develop cancer. However, all 200 (per Gold) have a viable claim to 20% of the lost wages, medical bills, pain, suffering and mental anguish even though the cancers of 167 of them had nothing to do with exposure to the solvent. For what then are they being compensated? Not a harm that manifested from the risk. In them it manifestly did not. Rather, the vast majority of plaintiffs wind up being compensated solely for a risk that never produced a harm. Tell us that won't increase the number of claimants in toxic tort litigation.

In the end, Gold's formulation only does justice to an individual if you believe that (1) epidemiological studies generate risk measurements nearly as accurate as "what are the odds of drawing a face card from a standard deck of cards" and (2) the individual's circumstance is best represented not by what actually happened to him but rather by the sum of all his possible outcomes. Unfortunately, the evidence for both (1) the ability to accurately predict the fate of an individual based on population studies and (2) the multiverse, ranks no higher than that for unicorns and elves.




Gatekeepers Will Be In Demand For The Foreseeable Future

Why? Read Jurors And Scientific Causation: What Don’t They Know, And What Can Be Done About it?.

Try as they might, researchers aren't having much luck finding ways to teach lay jurors (or judges, or lawyers) how to draw sound causal judgments from scientific studies. Our causal heuristics have failed to keep up as we've moved beyond discerning why ripened apples invariably fall (rather than float away, etc.), to probabilistic judgments made under conditions of deep uncertainty -  judgments hinging upon the unsettling notion that only some people, in some circumstances, experiencing some exposure, to some thing, have a somewhat increased risk of something else.

Short courses designed to bring lay jurors up to speed on sound causal reasoning managed, in one iteration of the study reported, to make the jurors slightly more pro-plaintiff (when the scientific study in question reliably pointed to a pro-plaintiff outcome). But the would-be jurors in other scenarios remained blind e.g. to the need to rule out an obvious alternative causal explanation. Specifically, despite the fact that the jurors were told that a bromine compound to which plaintiff was also exposed was itself perfectly capable of causing plaintiff's illness, the jurors failed to demand that it be "ruled out" before settling on the putative cause (beryllium) as the actual cause. "[E]ven trained jurors overlooked an obvious confound in which participants in an experimental group were simultaneously exposed  to two different chemicals, with the resulting detrimental effects attributed to only one of the chemicals (defendant's)."

In the end, the mere ipse dixit of a credentialed expert willing to say that a hopelessly flawed study established causation was, over and over, enough to carry the day for plaintiff.

Ultimately, counseling mock jurors that cause ought to precede effect and that effects ought to be correlated with putative causes before causation is imputed improved their reasoning; but only a little. It was still the case that even when plaintiff had no (zip, zero, nada) credible evidence of causation a juror was inclined to rule in plaintiff's favor more than a third of the time. Any plausible scientific study tending to support the hypothesis of general causation was enough to move the needle past 40% before specific causation was (apparently) even addressed.

So again we see why judicial gatekeepers will remain indispensable to toxic tort litigation. We could subject jurors to a short course on statistical inference and nudge them, perhaps, a bit closer to sound causal judgments but we'd still end up giving one side an enormous advantage. Have a look at the tables starting on page 31 of the study if you have any doubt. 



The Best Causation Opinion of 2012

In fact, it may well be the best causation opinion of the last half century; and we're willing to bet it will be one of the most important causation opinions going forward. Dixon v. Ford Motor Company nails substantial factor causation and in the process proves that there are still plenty of judges willing to think deeply about causal inference, about uncertainty and about the limits of liability in a world of inevitable risk. Ultimately, the court held that risk is the measure of legal causation in those cases where causal inferences are made probabilistically, and therefore when a causation expert opines that a putative cause was a "substantial factor" without saying how much risk it imparted she fails to answer the question she was called to give; and so has nothing helpful to say about the matter.

Dixon is another tragic mesothelioma case in which a defendant, having contributed to the victim's cumulative asbestos exposure something between nothing and next to nothing, was hammered by the jury. It then appealed, after taking a few judicial deductions, a $3+ million judgment. As usual the defendant complained that plaintiff's causation expert (this time an epidemiologist) ought not to have been allowed to testify because she had "extrapolated downward" from the known segment of the asbestos/mesothelioma dose/response curve to an area in which hard data was lacking and thus could not reliably say that the defendant's small contribution to the victim's dose was a substantial causative factor. 1) That's not plaintiffs' game these days, as we said in Small Glasses; but more importantly, 2) as the court made plain in Dixon, "substantial factor" in such cases isn't about causation, it's about risk.

"'Substantiality' is a legal concept and not an objective property testable by the scientific method", wrote the Dixon court. The question thus required to get at the essence of substantial factor causation in a dose/response disease case is not "was it a big cause or a little cause?" It's not even "was it really and truly a cause?" The first question is nonsensical and the second is unanswerable. Instead, the question is: "assuming it was a cause, was the risk it imparted prospectively of such a degree as to justly warrant the imposition of liability?" Risk, said the court, is thereby the measure of (legal) causation and proving that the risk imparted was substantial is plaintiff's burden. Showing that defendant imparted a substantial degree of risk, according to the Dixon court, is thereby what is required to bridge the "analytical gap" between "asbestos causes mesothelioma" and "plaintiff's exposure to defendant's asbestos caused her mesothelioma".

Accordingly, the court held that when all plaintiff's causation expert could say about causation was that "every exposure to asbestos is a substantial contributing cause" the only thing she wound up saying about the risk given plaintiff by Ford was that it was "more than nothing." "For obvious reasons an infinitesimal change in risk cannot suffice to maintain a cause of action in tort". Thus, the opinion of plaintiff's expert "merely implied that there was some non-zero probability that [plaintiff] was exposed to asbestos from Ford's product, and that this resulted in some non-zero increase in her risk of contracting mesothelioma. As such, [the conclusion of plaintiff's expert] that the risk and probability of causation was 'substantial' provided the jury with nothing more than her subjective opinion of 'responsibility,' not scientific evidence of causation."

So how does a plaintiff establish a substantial risk? Not by proving the exact dose and thus exact risk incurred.The Dixon court disposed of the straw man argument that requiring plaintiff to show risk (and thereby dose) quantitatively demands an impossible degree of certainty and precision. Such a rule, wrote the court, would obviously be "folly". Rather, all plaintiff is being asked to do is to "estimate exposure and risk with reasonable scientific or medical certainty." Once such an estimate is made the jury can decide whether it is sound and if so whether the risk imparted was substantial - subject to the law's requirement that it be more than de minimis.

That's exactly what we've been arguing since a client was kind enough to let us write an amicus in Borg-Warner v. Flores. Make the plaintiff say what dose, and thereby what risk, was given. Why? The effect of plaintiff's estimate of dose in one of the first post-Borg-Warner cases should suffice for an answer. Using their expert's dose estimate the calculated risk of death posed by our client's product was demonstrated to have been less than 1 in six billion; that's equivalent to the risk of death (from cancer caused by radon) imparted by spending just fifteen minutes in a building constructed of brick or stone. Such calculations and comparative risk exercises serve to vividly demonstrate both the de minimis nature of the risks imparted and the absurdity of imposing liability for them.

PLoS Medicine is Publishing An Attack On "Big Food"

A new series in PLoS Medicine says we're going through another epidemiologic transition; this time it's a "nutrition transition", from a simple traditional diet to a highly processed food diet "resulting in a stark and sick irony: one billion people on the planet are hungry while two billion are obese or overweight". Can you guess who gets the blame? Can you guess what playbook they use? Here are some hints:

"In contrast to the actions of Big Tobacco, soda industry CSR initiatives are explicitly and aggressively profit-seeking."  CSR = corporate social responsibility

Neoliberal policies, including the opening of markets to trade and foreign investment, create environments that are conducive to the widespread distribution of unhealthy commodities by multinational firms.

Big Food attains profit by expanding markets to reach more people, increasing people's sense of hunger so that they buy more food, and increasing profit margins through encouraging consumption of products with higher price/cost surpluses

So are we in the midst of yet another epidemiologic transition? The last one was a bust. It turned out that we never really left the age of infectious diseases. Our bet is that the war on "Big Food" may generate fees but will do little to alleviate either hunger or the obesity epidemic.

Small Glasses

The Betz v. Pneumo Abex commentary has generally sounded the following themes:

(a) The "novelty" threshold requirement for a Frye hearing has a broader meaning than previously thought. Henceforth, "a Frye hearing is warranted when a trial judge has articulable grounds to believe that an expert witness has not applied accepted scientific methodology in a conventional fashion in reaching his or her conclusion."

(b) The trial judge, who "was unable to discern a coherent methodology supporting the notion that every single fiber from among, potentially, millions is substantially causative of disease", did not abuse his discretion by excluding the "every fiber" causal theory of Dr. Maddox.

(c) Maddox' opinion that "every fiber was a substantial factor in causing plaintiff's mesothelioma" is riven by an "irreconcilable conflict with itself" because "one cannot simultaneously maintain that a single fiber among millions is substantially causative, while also conceding that a disease is dose responsive."

(d) Maddox reached his conclusion about causation not by his claimed "series of 'small bridges'" but rather by improperly extrapolating from known portions of the asbestos/mesothelioma dose-response curve to find causation at much lower levels - levels never demonstrated by epidemiological studies to be associated with the disease.

We're glad, of course, that the court found that novelty doesn't wear off expert opinions (i.e. they don't become immune to scrutiny under Frye) just because they've been peddled to many juries for many years. And we're similarly pleased so see shot down the untestable/unverifiable/unfalsifiable claim that a single fiber not only might have caused, but was in fact a substantial cause, of a given case of mesothelioma. But we're afraid the court missed the subtle game Maddox was really playing.

He wasn't extrapolating down. He wasn't playing the one-hit, linear no-threshold, conflate causation with risk game (though he does in other jurisdictions). And his causal model can account for both a single fiber being a necessary cause of a given plaintiff's mesothelioma and a correlation between dose and disease without any tension. Best of all, it's perfect for exploiting jurisdictions with naive liability attribution schemes such as Pennsylvania's at the time Maddox's opinion was rendered (Pennsylvania finally overhauled its joint and several liability scheme in 2011).

To understand what's up think about the following opinions of Maddox:

1) "it is the total and cumulative exposure that should be considered for causation purposes."

2) "Cumulative exposure, on a probability basis, should thus be considered the main criterion for the attribution of a substantial contribution by asbestos to lung cancer risk."


3) "[T]he more common analogy that has been used is the example of a glass of water. One drops marbles into the glass of water until the water finally overflows from the glass. Is it the first marble or the last marble that causes the glass to overflow? Well, both, all of them. The marbles cause the glass to overflow. That's a cumulative effect."

So it's clearly not a one-hit model that he's proposing; and for good reason. As more and more courts have become savvy about risk it's been harder and harder for plaintiffs to survive the objection that a de minimis exposure presents a de minimis risk and thus cannot by necessity be a "substantial factor". That's what the Pennsylvania Supreme Court was getting at in Betz when it wondered how "if all Dr. Maddox could say is that a risk attaches to a single asbestos fiber - that he could also say that such risk is substantial when the test plaintiffs may have been (and likely were) exposed to millions of other fibers from other sources including background exposure."

The point is made explicitly a few pages later when the court refers back to its discussion in Gregg about the plaintiff's proof problem in such cases:

"... we do not believe that it is a viable solution to indulge in a fiction that each and every exposure to asbestos, no matter how minimal in relation to other exposures, implicates a fact issue concerning substantial-factor causation in every "direct-evidence" case. The result, in our view, is to subject defendants to full joint-and-several liability for injuries and fatalities in the absence of any reasonably developed scientific reasoning that would support the conclusion that the product sold by the defendant was a substantial factor in causing the harm."

So what sort of model makes each asbestos fiber a substantial factor in causing mesothelioma and yet is consistent with a dose-response relationship between asbestos and mesothelioma? It's something we're seeing more and more often. It's the idea that each person has, to apply Maddox' metaphor from above, her or his own unique water glass of a defense mechanism. Some people's defense capacities are bigger and some are smaller and some are microscopic. But whatever the size, once they're overwhelmed mesothelioma or leukemia or whatever ensue. Thus, when Maddox says that every fiber to which plaintiff was exposed contributed to his risk and "once an individual develops a mesothelioma, the risk becomes the cause" what he's really saying is that though some marbles dropped in the glass might be bigger than others (e.g. crocidolite > amosite > chrysotile) and some might have been added with thimbles while others with coal shovels the only thing that really matters is whether or not the body's defenses were breached. Once they are the glass overflows, the mesothelioma develops and every last fiber was literally a necessary "but for" cause of the disease.

So what does the dose-response curve for asbestos and mesothelioma actually represent in such a model? It describes the outcomes of varying abilities to withstand asbestos across varying levels of exposure to asbestos. A lower defense capacity (small glass) requires less asbestos to trigger mesothelioma; higher defenses require more, etc. Think of the data points on the curve then as small glasses that have overflowed. What such a model suggests is a human population that mostly has large glasses {which fits the observation that even the most heavily exposed workers have less than a 1 in 10 chance of developing mesothelioma); a small portion has small glasses; and a tiny portion have smaller glasses still - all the way down until you get to those rare but unlucky souls who have no defense whatsoever. For them the background exposure dose doesn't increase their risk since it's already 1.

It's an especially clever model for for litigation because:

a) every fiber is a necessary element of a sufficient causal set (NESS) so causation is a snap;

b) it escapes the no duty problem posed by de minimis exposures in states that view substantial factor causation from a risk/foreseeability perspective;

c) it turns modern victims into eggshell plaintiffs and so makes every case that much more foreseeable; and,

d) because it's a Landers v. East Texas Salt Water Disposal Co sort of cumulative causal claim it's especially dangerous in states with joint and several liability schemes.

The problem is that there's no evidence for the model. It rests solely on the following two generalizations (that do little more than highlight our ignorance of the mechanisms whereby asbestos causes mesothelioma) and the conclusion drawn from them:

Mesothelioma is caused by exposure to asbestos fibers

A victim's asbestos exposure consists of every fiber inhaled

Therefore, a victim's mesothelioma was caused by every asbestos fiber inhaled

As for the equally evidence-free small glasses theory it goes like this:

Not everyone exposed to asbestos develops mesothelioma

But every victim's mesothelioma was caused by her or his asbestos exposure

And every victim has had a different asbestos exposure

Therefore something about the victim (small glasses) determines the outcome of exposure

If you haven't seen it yet it's surely on its way to a courtroom near you. Our advice? Attack the premises - they're made of clouds.






I thought of fulvene, also known as 5-methylene-1,3-cyclopentadiene, when I read the following in a new law review article (funded, strangely enough, by a National Science Foundation grant):

Tort actions may impel industry to take voluntary steps to redesign chemical molecules ... to be less toxic.

Fulvene you see is made up of six carbon and six hydrogen atoms. So is benzene and so are a few other molecules. The point of course is that while you might be able to rearrange a car's component parts to make it somehow safer while leaving it a car you can't rearrange benzene's atoms (or those of any other complex molecule for that matter) without turning benzene into something else. Something with a different boiling point, solubility, reactivity and the like. Something that cannot, as benzene can, be used to make the breast cancer drug tamoxifen.

The law review article is "Litigating Toxic Risks Ahead of Regulation: Biomonitoring Science in the Courtroom" and it dovetails with "How Chemicals Affect Us" which you've likely seen in the NYTimes. Each claims that very low levels of exposure to substances previously thought safe may be causing subtle changes and each ends with a call for regulation; the former by way of lowering evidentiary standards in tort proceedings so as to bring about more claims and bigger awards and the latter by way of the regulatory state. Irrespective of wielder the same tool is urged: one that resolves all uncertainties in favor of stasis, of inaction, i.e. the Precautionary Principle.

"Litigating Toxic Risks", funded under a $366,785 research grant for "Toxic Ignorance and the New Right-to-Know: The Implications of Biomonitoring for Regulatory Science", proceeds from the hypothesis that "toxic tort litigation has emerged as a means of controlling risks." It recounts 1) the number of chemicals that have never been tested for toxicity (tens of thousands); 2) the non-stop synthesis of new ones; 3) the purported shortcomings of TSCA; 4) the fact that asbestos and lead paint are made of chemicals and turned out to adversely affect some of those exposed; 5) the apparently obvious conclusion "it follows that many of today's routine chemical exposures are cause for great health concern"; and, finally, 6) the ability of biomonitoring to demonstrate those chemicals to which we've been exposed. The authors then deduce that the effort to regulate chemicals via toxic tort litigation "depends greatly on whether courts are able to apply tort theories to the scientific data used in appraising the health risks of chemicals".

They lament, however, that there's no cause of action for simply being exposed to the activities of other people; that plaintiffs must show harm - an adverse health effect - before they can prevail. Regarding those chemicals to which everyone is exposed in low doses they complain that it's not practical for plaintiffs to do epidemiological studies since there is (unsurprisingly) no unexposed reference population. Furthermore, the cost and time involved in doing epi and tox studies are significant. So, if standards of proof could just be lowered the class action mechanism would expose potential defendants to existential liability risks for harms they probably didn't cause (see pg. 6) so that vast sums could be extracted from them and the production of synthetic chemicals would be thereby curtailed or eliminated.

Additional helpful measures would include dropping the requirement that class members demonstrate that they have actually been exposed to the substance in question. As support for this assertion the authors write "[t]he courts' current stance contradicts standard scientific procedure, where it is well recognized that sampling can lead to reliable assumptions about population characteristics". (Really? A calculated sample mean is superior to knowledge of the actual population mean for making conclusions about the population? And superior to even knowing the actual exposure of each member of the population?)

To make sure that as many people as possible can assert medical monitoring claims the article's authors urge "implementation of the precautionary principle in the legal standards required to show significant exposure and increased risk of disease". The precautionary principle apparently will turn every "is it likely" hurdle to plaintiffs' recovery into an "is it possible" speed bump.

As for damages "courts can accept, as legally actionable injuries, subtle health and developmental impacts as well as emotional concern and stress related to chemical exposure."

So far some 50 million different chemical substances have been cataloged and 12,000 new ones are added every day. Most were synthesized by nature rather than by man. Over the eons our ancestors managed to survive in this sea of chemicals, surrounded and inhabited by countless biochemical factories constantly synthesizing new molecules in order to survive in and/or exploit their ever-changing environment - and our ancestors largely did it by synthesizing their own new molecules. We've only had trouble when we've been out-engineered by our biochemical competitors or when we've violated the rule: "all things in moderation". So what's with the chemohysteria over trace exposures and the discovery that our bodies notice and adapt to them on the fly?

I think a large part of it stems from the fact that we've come to realize our genetic code is more toolbox than blueprint; that we're far more impermanent than we ever imagined; and, that so much of what we believed about how it all works, especially decades old myths about the principal causes of human diseases, is being swept away by remorseless empiricism. The attempt to incorporate the Precautionary Principle into the law can thus be seen as part of a deeply conservative movement, standing athwart science, yelling Stop!




Why Don't Multiple Statistically Significant Studies Demonstrating A Strong Association, Plus Biologic Plausibility, Add Up To Causation?

Imagine that you've got a case involving a drug or chemical and there exist multiple well done studies including randomized controlled trials that show consistently strong and statistically significant associations between the drug or chemical and the plaintiff's disease. There's also a very plausible biologic mechanism whereby the substance causes the disease which has been proposed in the scientific literature. Furthermore, the medical records demonstrate via biomarkers that the plaintiff was indeed extensively exposed to the drug or chemical. Causation's a snap, right?

Probably, but it shouldn't be. Consider the case of periodontal disease (PD) and atherosclerotic vascular disease (ASVD). As we've noted previously there are some very intriguing studies published in the literature suggesting a link between the two; a link that has been theorized for many decades. Now, using an evidence-based approach to deriving recommendations from available research (Level of evidence A: recommendation based on evidence from multiple randomized trials or meta-analyses; Level of evidence B: recommendation based on evidence from a single randomized trial or nonrandomized studies; Level of evidence C: recommendation based on expert opinion, case studies, or standards of care) the American Heart Association has put the theory to the test and found it wanting. 

You can download (free) a copy of the paper, "Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independant Association? A Scientific Statement From the American Heart Association" and see how sound causal inferences are made.

Even though "[a]n association between PD and ASVD is supported by evidence that meets standards for Level of Evidence A" and "[a] benefit of periodontal intervention in decreasing local periodontal inflammation is also supported by level A evidence. Causation of ASVD by PD is not supported by either level A or level B evidence." How could this be?

"[P]eriodontal and cardiovascular diseases share multiple risk factors that are prevalent and powerful promoters of disease, including tobacco use, diabetes mellitus, and age." Accordingly, "statements that imply a causative association between PD and specific ASVD events or claim that therapeutic interventions may be useful on the basis of that assumption are unwarranted."

So again, correlation, even strong and consistent, and even coupled to biologic plausibility, ain't causation.




Pretty Good, Except for Footnotes 82 and 105

See: "Admissibility Versus Sufficiency: Controlling the Quality of Expert Witness Testimony in the United States".

Though a co-author hails from a law school named after one of the lawyers who is said to have made hundreds of millions of dollars off of the breast implant hoax and the lead was one of the first experts called by plaintiffs to testify in Texas' asbestos MDL, they get it right, more or less, when writing that the decision to exclude an expert under Daubert is really a query into the sufficiency of plaintiff's evidence rather than the raw admissibility of the proffered testimony. Can the expert sustain plaintiff's burden of production? That's the question. If not, why bother wasting everyone's time and money to go through the motions of holding a horse race the outcome of which has already been decided?

Their second point, that Daubert's inquiries about falsifiability and the likelihood that the expert's method has produced a false positive, is less compelling. While it's true that you can find a heap of non-analytical philosophical papers positing that truth is personal, that the quest for objective knowledge is meaningless and that nothing can really be falsified, the people who design and especially the people who board airplanes prefer to have them tested first. So don't expect to see falsifiability or rate of error vanish anytime soon.

The third point, that the abuse of discretion standard on appeal needs a "hard look" seems a bit undeveloped and rates a "meh" in our opinion.

The fourth, and best point, is that courts ought not simply let the jury figure it out and then fix the verdict if they get it wrong. I first ran into the issue in a trace benzene case. Admitting that the plaintiff's exposure to benzene at my client's facility was considerably less than his EPA and OSHA estimated background dose the plaintiff's expert opined that "naturally occurring benzene has a different electron resonance orbit than synthetic benzene" and that only man-made benzene had the toxic electron resonance orbit. Having a chemistry degree undergrad came in handy (though a BS-O-Meter would work as well), but not handy enough. The judge refused to exclude the expert saying he'd "take care of it" if the jury didn't. Needless to say a cost-of-defense settlement was reached. So hooray for the conclusion that "in an adversarial system employing lay fact finders there are multiple reasons for imposing a reliability filter on expert evidence."

Our main gripes are with footnotes 82 and 105. In footnote 82 the authors write: "The idea that a regulatory agency would make a carcinogenicity determination if it were not the best explanations of the evidence, i.e., more likely than not, is silly." First, the idea that critical thinking and regulatory agencies subject to political whims make strange bedfellows ought not be surprising. Second, the idea that "specific causation is not scientific" fails both to acknowledge the usefulness of biomarkers and that the very same probabilistic approach to causal inference that works for general causation works for specific causation. Finally, sneaking in reasoning to the explanation as a proxy for "more likely than not" ignores the method's provenance. It is rather a "guess" awaiting a test.

Footnote 105 quibbles with the role of statistics in all this (quoting Haack approvingly) "as the phrase 'tested or verified' suggests, what this really says is that the plaintiff's experts have produced no statistically significant evidence supporting the claim that Parlodel increases the risk of postpartum stroke." No, what the cited case says is that what the plaintiff's experts produced was highly likely to have been wrong. The point of the statistical test is to ask how likely it is that your hypothesis rejecting the null hypothesis is wrong. If you remember that all we know, as we make our way through Galileo's dark labyrinth towards the truth, is what isn't so you'll appreciate the difference.

All in all it's a good read and its conclusion, that courts indeed ought to filter out those claims that can never be proven, makes it well worth the time invested.


Bending the Dose Response Curve

The linear no-threshold model of dose-response meant that plaintiffs could continue to prevail on toxic tort claims even though their exposures had occurred in the modern era and thus were tiny fractions of those that led to epidemics in years past. Either courts permitted plaintiffs to rely on a one molecule / one particle theory of causation (consistent with the view that some risk is associated with a single molecule or particle) or they allowed plaintiffs to conflate causation with risk.

Eventually some courts began to grasp the absurdity that follows from basing proximate cause on a "one-hit" model in a world of trillions of hits while others began to take notice of the fact that despite probing larger and larger populations with low exposures epidemiology was unable to verify the linear no-threshold model for numerous diseases; thereby suggesting that there is indeed a threshold for diseases including leukemia (a new case making the latter point is Schultz v. Glidden Company.) Meanwhile we have argued that the old cases got it right - that causation in an individual toxic tort case is unfathomable and that the most sensible approach is to estimate the risk imparted (e.g. by a single molecule); to ask why it makes sense to impose liability for creating a 1:1,000,000,000,000,000,000 chance of harm; and, further asking why it wouldn't make sense to impose liability for a 1:100,000 or greater risk.

But all of that assumes risk goes to zero or at least continues to decrease as exposure is reduced below previously measured levels. If that assumption is false, if risk starts heading back up as exposure goes down, especially if unpredictably so, then all bets are off. We will have entered another period of great uncertainty, And it's in such times that toxic tort claims flourish. The horsemen of this new age of uncertainty have published a review paper on the topic and if you want to understand what's coming, why it's pitch perfect for the health and wellness movement and why what happened to BPA will be repeated again and again for other chemicals until some new way is established to either verify or refute their claim that dose doesn't make the poison you need to read it:  "Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses"



When it comes to lung cancer, keep your chickens close but keep your flock closer.

"They've internalized their own confusion": watch this video if you want to understand the difference between humble falsificationist evidence-based science and the authoritarian "because I say so" approach adopted by the 1st Circuit in Milward.

Antibiotic use in children less than six months old is strongly associated with the subsequent development of asthma, especially in those without a family history of asthma, and the greater the intake of antibiotics the greater the odds of developing asthma.

Attacks on randomized controlled trials (RCTs) miss the point.

A new paradigm for cancer prevention, indeed.


April's "Gut" Has Some Very Interesting Articles.

Have a look at the cover and you'll see why double-dipping chip dippers are frowned upon. Elsewhere you'll find evidence that that if you want to stay lean or if you want to avoid type II diabetes you need to hold down the ratio of Firmicutes to Bacteroidetes that live in your gut. If you're looking for evidence that keeping H. pylori at bay keeps gastric MALT lymphoma away you'll find that too. There's also evidence that pancreatic cancer is associated with just a couple of bacteria found inthe saliva of those at risk of the deadly disease. Here's the link: Gut



There's Something About Nevada

After getting hammered in quick succession for $500 million, $162 million and $90 million worth of punitive damages in three cases involving a total of just five plaintiffs, Teva settled its Nevada hepatitis C (HCV) / Propofol claims.  The price tag was just past a quarter billion dollars. 

So what happened?  Teva's generic Propofol wasn't defective.  It didn't leave the factory contaminated with HCV.  Instead the claims arose out of the following findings of the CDC:

Inappropriate reuse of syringes on individual persons and use of medication vials intended for single-person use on multiple persons was identified through direct observation of infection-control practices at clinic A (Desert Shadow Endoscopy Center). Specifically, a clean needle and syringe were used to draw medication from a single-use vial of propofol, a short-acting intravenous anesthetic agent. The medication was injected directly through an intravenous catheter into the patient's arm. If a patient required more sedation, the needle was removed from the syringe and replaced with a new needle; the new needle with the old syringe was used to draw more medication. Backflow from the patient's intravenous catheter or from needle removal might have contaminated the syringe with HCV and subsequently contaminated the vial. Medication remaining in the vial was used to sedate the next patient.

and the final report of the Southern Nevada Health District which includes the following graphic demonstrating how the clinic contaminated the Propofol:

The vials were clearly labeled for single use and the warning was further emphasized when reports surfaced that some were being used for multiple doses.  Discovery apparently revealed that the larger vial size helped reduce manufacturing costs. 

Okay, so Teva was found liable for not guarding against the (allegedly) foreseeable blatant disregard of its warning labels and of standard vaccination administration safety procedures by the endoscopy clinic.  Nevada seemingly has an expansive view of duty and its jurors a limitless view of foreseeability.  But what explains the repeated mega punitive verdicts?  Every mass tort has its outliers but we've not seen anything like this.  If we hear any scuttlebutt we'll let you know.

Along the way it certainly looked like the cases were going well for Teva.  For example, it made some good law at the Nevada Supreme Court which we've mentioned previously.  Specifically the court recognized that a rule preventing a defendant from discussing other possible causes (unless its experts are willing to testify that such alternate cause(s) were, in reasonable medical probability, the cause in fact of plaintiff's illness) would work a great injustice.  As we've said before the effect of such a rule would be to admit the most speculative claims of causation while excluding the most reasoned and sober assessments of causal attribution.

Why did Teva settle?  Again, we're not privy to any inside information but hazard the following guess.  The recent tendency of the Nevada Supreme Court to affirm eye-popping jackpot verdicts weighed heavily in Teva's analysis.  Usually when you get a huge judgment before a supreme court, as Teva had here, you're pretty confident that at the very least the outlier award will be substantially reduced.  Yet in Nevada these days such payouts are quite likely to be affirmed. In any event we're betting that the Nevada civil courts will be busy and that tort claims arising out of the spread of pathogenic bacteria, viruses and prions will increasingly be the focus of the plaintiffs' bar.


Texas Appellate Court Upholds Big Enterovirus Verdict - We Don't Know Why

Before we get to why we think the dissent got it right in Scott's Marina v. Brown assume the following:

1) plaintiff contracted an enterovirus infection resulting first in pharyngitis, then in meningitis and finally in Lemierre's syndrome - an extrordinarily rare and potentially fatal complication following a throat infection (Lemierre's is invariably blamed on Fusobacterium necrophorum or its cousins but go with it and assume the virus triggered the bacterial infection);

2) the plaintiff established that he was negligently exposed to raw sewage at work;

3) the majority of enterovirus infections are transmitted via the "fecal-oral" route

4) according to the CDC, which runs the National Enterovirus Surveillance System (NESS), only about 1300 to 1500 enterovirus are detected annually by NESS; 

5) the onset of plaintiff's symptoms were within the accepted incubation period; and

6) a "leading expert in the field of anaerobic infectious disease" is of the opinion that the sewage exposure was the likely cause of plaintiff's illnesses.

Sounds like a pretty good case, doesn't it?

Now consider a couple of additional facts:

1) according to the same CDC report there are 10 - 15 million cases of symptomatic enterovirus infections in the U.S. annually; and

2) as anyone who's experienced gastroenteritis (thanks, norovirus) can attest, even when the predominate route of exposure is fecal-oral that hardly means you have to be exposed to sewage to get it - having children in school is more than sufficient.

So, back to the case. Was the strain of enterovirus that caused plaintiff's infection ever detected in the sewage to which he was exposed? No testing was done. So what are the odds that a given sample of sewage would contain an amount of enterovirus sufficient to cause an infection? The expert couldn't say. But if the overwhelming majority of enterovirus infections result from someone with insufficiently washed hands contaminating kitchen surfaces, plates and eating utensils or by shaking hands or sneezing, and when the virus can survive in all manner of environments including the lake in which plaintiff had been wakeboarding (and the polio virus is one of the enteroviruses - polio, lake water, ring any bells?), how did the expert rule rule out all the other routes of exposure? He wouldn't say.

The dissent gets at the heart of the matter writing: "Nothing in this record explains why [the expert's] opinion Brown contracted an enterovirus from his "exposure to sewage water" is superior based on science. Rather, his opinions rested on his ipse dixit." Think about it. Somewhere between 1:20 and 1:30 Americans get an enterovirus infection each year. How many came through his store? How many are likely among his friends and family? How many swam in Grapevine Lake?




"... It is Unacceptably Easy to Publish "Statistically Significant" Evidence Consistent with Any Hypothesis"

Want to look and feel younger?  Well, there's a properly done study, statistically significant at p < .05, showing that people who listen to The Beatles "When I'm Sixty-Four" actually became a year and a half younger!  Far fetched?  Sure, but no more so than umpteen conclusions published in the scientific literature every day purporting to establish some causal connection based on nothing more than a statistical analysis of a series of observations.  That's the point demonstrated conclusively in False-Positive Psychology: Undisclosed Flexibility in Data Collection and Analysis Allows Presenting Anything as Significant.

Though a paper may validly claim that the likelihood of the reported causal connection being due to chance alone is 5% or less (i.e. p < .05), "False-Positive Psychology" demonstrates that researchers free to modify as few as four variables (such as the number of observations to be made, sorting those observed by gender or stratifying outcomes) more likely than not have "discovered" a causal association that doesn't exist.  The harm done by publishing such false-positives are obvious.  As the authors put it:

 "First, once they appear in the literature, false positives are particularly persistent. Because null results have many possible causes, failures to replicate previous findings are never conclusive. Furthermore, because it is uncommon for prestigious journals to publish null findings or exact replications, researchers have little incentive to even attempt them. Second, false positives waste resources: They inspire investment in fruitless research programs and can lead to ineffective policy changes. Finally, a field known for publishing false positives risks losing its credibility."

To vaccinate against infecting the scientific literature with false-positives the authors conclude with suggestions similar to those we've seen elsewhere in efforts to promote evidence-based science.  At the heart of the suggested approach is transparency from the moment the experiment is conceived all the way through publication.  There are six for authors and four for reviewers; be sure to read them all.


What Do Reputable Scientific Organizations Consider To Be Evidence?

The new IOM report, "Breast Cancer and the Environment: A Life Course Approach", again emphasizes the difference between how scientific panels go about making a causal inference and the approach too often approved of by credulous judges often insecure about their own ability to think critically and mesmerized by the jargon-laden pronouncements of credentialed experts. Beginning on page 82 under "Hierarchy of Studies" and followed by "Categories of Evidence" the report does a great job of detailing what counts as evidence and the methods and criteria used by organizations like the International Agency for Research on Cancer, the National Toxicology Program, the World Cancer Research Fund / American Institute for Cancer Research in going about collecting, assessing and weighing evidence when making causal judgments. They even put together a helpful summary of the classification systems (see Appendix C, "Classifications Systems Used in Evidence Reviews" at page 312).

Here are a couple of takeaways: (1) "The criteria aim to be explicit about the weight, or relative importance, given to studies in humans and in animals or other experimental systems"; and (2) "Strong and consistent positive epidemiologic evidence in rigorously conducted studies is prima facie evidence that the substance is a risk factor." You will quickly note upon reviewing the summary of systems of causal inference that none support anything like the notion embraced by the court in Milward v. Acuity that an expert weighing a subset of the data (each piece of which is either weak, irrelevant or inconsistent) upon the scales of his personal scientific judgment can by "reasoning to the best explanation" reliably reach a causal inference  - especially in the complete absence of any epidemiological evidence to support it. Indeed the "atomization" of evidence decried by the Milward court and those in the "public health movement" who promote mass tort litigation is exactly what IARC, IOM, NTP, EPA and WCRF/AICR do - they assess each piece of evidence, they do it transparently, they do it according to rules laid down before they even go looking for the evidence and then they weigh what's left; again, according to weighting systems that are explicit, consistent and established before the first piece of evidence is examined.

The idea that knowledge comes from scientists taking a "holistic approach to the data" and applying their personal judgment to it is, to be blunt, hooey. That may be a way to arrive at a testable conjecture but without the conjecture passing a test of its predictive power (e.g. a rigorous epidemiological study) it remains nothing but a bald, personal opinion with no foundation beyond the ipse dixit of the expert who induced it.


What To Do When a Miracle Drug Is Found to be The Cause of a Host of Unexpected Maladies?

There's an epidemic of immune disorders in America.  Allergies (especially food allergies), asthma, atopy, hypersensitivity disorders including Stevens Johnson Syndrome, Crohn's disease, type1 diabetes, obesity and more are being laid at the feet of perinatal use of antibiotics.  Evidence is mounting rapidly that the use of antibiotics in newborns or their mothers disrupts the intestinal microbiota essential to a well-functioning immune system. The consequences are seen in the host of immune-related disorders which have become perhaps the most significant cause of morbidity and mortality in the United States today.  For a new primer try: Perinatal Programming of Asthma: The Role of Gut Microbiota.

So what should we make of a drug that when first administered saved a young woman, allowing her to have a family and to live to 90* and yet which (because the role that gut bacteria play in generating a healthy immune system was decades away from being known) would eventually precipitate a wave of autoimmune disease in the United States?  If antibiotics are indeed responsible for as many cases of debilitating illness as is now widely suspected, should we ban them and vilify their makers?  Should their makers be driven to ruin by our tort system to ensure that nothing like penicillin is ever unleashed on the public again?  Or should we instead finally recognize that we must take the good with the bad;  that with every advance comes risk; and, that unintended consequences, the nature and extent of which may not be known for years to come, is the price of progress?

* The First American Civilian Saved by Penicillin

The first U.S. civilian whose life was saved by penicillin died in June 1999 at the age of 90 years. In March 1942, a 33-year-old woman was hospitalized for a month with a life-threatening streptococcal infection at a New Haven, Connecticut, hospital. She was delirious, and her temperature reached almost 107 F (41.6 C). Treatments with sulfa drugs, blood transfusions, and surgery had no effect.

As a last resort, her doctors injected her with a tiny amount of an obscure experimental drug called penicillin. Her hospital chart, now at the Smithsonian Institution, indicates a sharp overnight drop in temperature; by the next day she was no longer delirious. She survived to marry, raise a family, and meet Sir Alexander Fleming, the scientist who discovered penicillin. In 1945, Fleming was awarded the Nobel Prize in Physiology and Medicine, along with Ernst Chain and Howard Florey, who helped develop penicillin into a widely available medical product.


For Want of an Exit

For want of an exit the restroom was lost

For want of a restroom decorum was lost

For want of decorum a tree was sought

For want of a tree the field was crossed

But the field's hidden hole bore a great cost

Yet because of a storm sight of it had been lost

Sadly the use of his leg was thus lost

And all for the want of an exit ramp

Apparently in Kentucky everything is foreseeable and "substantial factor" causation is nothing more than simple "but for" causation.  See, Waldsachs v. Inland Marine Service, Inc.



2011 DRI Annual Meeting

To the followers of Mass Torts:  State of the Art, apologies for our absence. Summer was unusually hectic and this fall has been a nightmare. 

We were out the end of last week to attend and to speak at the DRI annual meeting in Washington. Here's our PowerPoint from the presentation on the Restatement (Third) re: duty, risk and causation (and how, and why, it got all mixed up).  If you find some or all of it helpful feel free to use it. Attribution is always appreciated.





"... the only group of organisms that have been convincingly shown to cause extinction."

What are they? They're responsible for massive worldwide die-offs of frogs and other amphibians. They're killing huge numbers of bats across the United States and threatening some local populations with outright extinction. They've also been convincingly associated with bee-colony collapse disorder which has wiped out 20 - 40 percent of U.S. honeybee colonies.

But they're not all bad. They invented penicillin and make other good things like beer and bread.

So, what are they? Read all about them in the Institute of Medicine's new report: "Fungal Diseases: An Emerging Threat to Human, Animal and Plant Health: Workshop Summary". The partial quote in our blog title comes from one of the participants, Arturo Casadevall, who said "Fungi are the only group of organisms that have been convincingly shown to cause extinction." And if you want more proof that infectious disease have most certainly not been conquered (and in fact have been invisible to investigators until now) be sure to read the story of the Cryptococcus gatti epidemic that emerged on Vancouver Island and has spread to the Northwestern U.S. killing 40 and sickening over 300 so far.



Evidence and Causality

If you're interested in the issue of causation a great place to start is page 4 (through 9) of the Institute of Medicine's new report "Adverse Effects of Vaccines: Evidence and Causality". There's lots to consider. For example,support for the Texas Supreme Court's recent determination that plaintiff's will need two well done epi studies to support a claim of general causation:

      "The committee does not consider a single epidemiologic study - regardless of how well it is designed, the size of the estimated effect, or the narrowness of the confidence interval - sufficient to merit a weight of 'high' or, in the absence of strong or intermediate mechanistic evidence, sufficient evidence to support a causality conclusion other than 'inadequate to accept or reject a causal relationship.' This requirement might seem overly rigorous to some readers. However, the Agency for Healthcare Research and Quality advises the Evidence-based Practice Centers that it has funded to produce evidence reports on important issues in health care to view an evidence base of a single study with caution (Owens et al., 2010). It does so due to the inability to judge consistency of results, an important contributor to a strength of evidence, because one cannot 'be certain that a single trial, no matter how large or well designed, presents the definitive picture of any particular clinical benefit or harm for a given treatment' (Owens et al., 2010)." (pg. 6)

You'll also get an introduction to the similar yet different GRADE v. EPC approaches to assessing and weighing scientific evidence when making causal judgments. Hopefully, as we've said in the past, courts will one day demand of experts the same sort of transparency in evidence accumulation, assessment and weight assignment that sound science demands.

Along the way you'll note the conspicuous absence of the pronouncements of experts among the things to be determinative in reaching causal judgments. By now that ought not be surprising. As Dr. Steven N. Goodman reported in his journal article "Judgment For Judges: What Traditional Statistics Don't Tell You About Causal Claims" the US Preventive Services Task Force, which is committed to evidence-based medicine, has ranked by reliability the different sorts  of evidence that go into making supportable causal judgments. At the top of the list, the strongest sort of evidence, is the well done randomized controlled trial. Then comes the non-randomized controlled trial. Then cohort or case-control studies. Then multiple time series. Dead last, and weakest of all, comes "opinions of respected authorities ..." If science hasn't much use for the mere ipse dixit of credentialed experts it's hard to imagine why the law should hold otherwise.

Anyway, to find out what vaccines cause, and don't cause, and how sound causal judgments are made, this new IOM report is well worth your time.



"The Cost to the Health of Our Microbial Ecosystems"

Gina Kolata has another good read at the NYTimes in "The New Generation of Microbe Hunters". The word, as you can see, is quickly getting out; the old ways of thinking about the determinants of human health are crumbling as the discovery that we are "super-organisms", more bacterial than human - at least from a genetic perspective, sweeps away old notions about what makes us sick, what keeps us healthy and even what (and maybe who) we are.

For other dispatches from the revolution you might want to read about just how big a deal this is, how much we know, how much remains to be understood and the promise of biotherapeutics; or maybe, since there's a little Gilgamesh in each of us, how  changing the bacteria in the gut of mice makes the rodents live significantly longer;  then there's a dysregulated microbiome and rheumatoid arthritis; new insights into how H. pylori causes gastric cancer; and gut microbes can cause cancer of the liver and breast (in mice anyway); and changing the gut microbiota to treat type 2 diabetes and, and, and ... There's a torrent of literature but that'll give you an idea what's out there and what's coming.

None of that is to say "Eureka!" they've found the answer. Likely (as it's wise to hedge bets) the causation onion has many layers still uncovered. No, the point is twofold. First, the 40 year old idea championed by public health advocates pushing what they call social, or environmental, justice - that much if not most human suffering is due to bad industrial chemicals or the bad habits inculcated in consumers by nefarious corporations bent on selling them things they don't want or need - was never sound but now it's just silly. Second, if you've been paying attention, you'll understand that an awful lot of illness and suffering has been caused by stuff nobody, we presume, ever fretted about. But who knows? Maybe somebody somewhere has the disrupted microbiome version of the Sumner Simpson Papers. Wouldn't that be something?

Bostic: Baron & Budd Swings For The Fences

As we've discussed previously, the Dallas Court of Appeals in Bostic made it logically impossible for a plaintiff injured as the result of multiple potentially causative exposures to recover from any of those responsible for the exposures. They did so by holding that a plaintiff must not only show that the aggregate dose was the "but for" cause of his injury, but also that each defendant's component dose was the "but for" cause of his injury. Thus, if plaintiff were exposed to two doses, each sufficient to have caused his injury, both defendants could argue with equal force under a "but for" standard "had my product never existed plaintiff would still have been injured because of the other guy's product and so my product cannot possibly have been the 'but for' cause of plaintiff's injury".

The source of the problem seems to originate in confusion over what the Texas Supreme Court means by "substantial factor", We've been arguing since our amicus in Borg-Warner that the essence of every court's discussion of foreseeability or proximate cause is risk. Since, as the National Academies put it in Science and Decisions, "[v]irtually every aspect of life involves risk", what courts have been doing is drawing boundaries between those risks for which the imposition of liability would be just and those for which the imposition of liability would be unjust. Substantial factor then means substantial risk and in toxic tort cases risk is measured by exposure, or dose. A plaintiff need only show that "but for" his exposure to asbestos (in the aggregate) he would not have developed mesothelioma but if he's to carry his burden of showing substantial factor causation he must estimate dose for each defendant's contribution to the overall dose. And that's what we thought Borg-Warner said.

Bostic argues in her brief however that any requirement that a plaintiff show what the dose received from an individual defendants product or premises was likely to have been would make it "scientifically impossible" for any plaintiff to prevail. She says that her expert Dr. Longo testified "that it would be scientifically impossible for him to calculate the precise dose of asbestos" that Bostic experienced as a result of his use of Georgia-Pacific's products. Of course Borg-Warner specifically says that a plaintiff is not required to state with mathematical precision the dose-contribution of each defendant. A supportable approximation is good enough. Bostic further implies that coming up with even an approximation of dose is impossible. Is it?

In 1995 Harvey Checkoway wrote: "Quantitative estimation of exposure has become a central focus in occupational epidemiology over the past decade as a result of the increasing emphasis put on exposure-response characterisation for occupational hazards." He concluded by writing: "Methods of assessment of exposure have been given much more attention in recent years. As a result, increasingly sophisticated approaches to retrospective assessment have been developed ... Nevertheless, no amount of foresight and prospective monitoring will replace the need for sound approaches to retrospective estimation of exposure, and the variety of methods now available provide a basis for that work." Not only have such methods been available to expert witnesses for years their use in benzene and other toxic tort litigation is nowadays utterly unexceptional.  

Of course a supportable retrospective dose estimation is possible and it's done all the time. The attempt to substitute Dr. Longo's estimation of the highest dose from a one time use of Georgia-Pacific's product for Bostic's estimated total dose from its product is akin to substituting the amount of tar and other particulate generated by one cigarette for a plaintiff's pack-years of smoking - it evades the real question of "what was the risk?" and answers instead another question "was there any risk?" It's an effort to conflate risk and causation and so, without saying so, to get the Texas Supreme Court to adopt the Restatement (Third) of Torts and its attempt to substitute any risk for a substantial risk as the outer boundary of liability. Should they prevail they'll have knocked the cover off the ball.


For Want Of A Nail? It's Worse Than That (If You're A Railroad Company)

The Supreme Court decided CSX v. McBride and here's our take. The majority held that whatever proximate cause might be it isn't a hurdle an FELA plaintiff must clear. Instead, without saying so, the court concluded that such a plaintiff has only the causation obstacle set out by the dissent in Palsgraf to deal with. Specifically, "but for", or counterfactual, causation plus the act of a not ordinarily prudent railroad company (requiring foreseeability of some, though not necessarily the, harm). A railroad company thus owes a duty not to the whole world but to its employees' whole future. Put another way, should a railroad do something "wrong" that produces not the harm the apprehension of which would have counseled a different course but which instead puts the employee in a place he otherwise wouldn't be so that he subsequently suffers a completely unforeseeable injury, the railroad is on the hook for the damages.

We are sad of course that the Court didn't take the opportunity to consider legal causation to be properly understood as "but for" causation plus risk. However, given the fact that the Court was interpreting a statute half a century old (one that Congress, by its steadfast refusal to change the Act's language regarding the causation standard, apparently doesn't consider to be the source of absurd or unjust results) the outcome isn't surprising. And it didn't help that the jury instruction on causation requested by CSX, "any cause which, in natural or probable sequence, produced the injury complained of", would shed no light on the distinction between pure "but for" causation and legal causation anyway. Most if not all proximate cause instructions indeed appear to be little more than, as one of our mock jurors muttered of the instruction, "typical lawyer BS".

Had Ms Palsgraf been an employee of the Long Island RR (and had the FELA's "played any part" causation standard been around) she would have prevailed. Bad news for the railroads but good news for anyone else not stuck with the FELA causation standard since whatever the court thinks proximate cause might be at least it's more than "played any part".

This Week Cell Phones Don't Cause Brain Cancer

The ICNIRP (International Commission on Non-Ionizing Radiation Protection) Standing Committee on Epidemiology recently analyzed published research related to cell phones and brain cancer. This review concludes that evidence from a growing number of studies does not support the theory that cell phones raise the risk of brain cancer.

It's interesting to note that early on D. Savitz, a member of the ICNIRP Standing Committee on Epidemiology, was in the EMF causes childhood leukemia camp. In 1993 with the accumulation of additional data Savitz was able to concluded that “the evidence falls short of demonstrating a causal association between electric and magnetic fields and cancer.”

In 2004 the same members of the ICNIRP Standing Committee on Epidemiology published a detailed review of epidemiological studies of health effects from exposure to radio waves. The reviewers concluded that "results of these studies to date give no consistent or convincing evidence of a causal relation between RF exposure and any adverse health effect."

In 2009 the ICNIRP Standing Committee on Epidemiology published an update of their 2004 review. They noted that the number of papers on this topic had grown since 2004, but concluded that the available data does not suggest a causal association between mobile phone use and fast growing tumours in the brain such as malignant glioma. The similar absence of an association for slow growing tumours such as meningioma and acoustic neuroma is far less conclusive because the period of observation is simply too short.

With ICNIRP’s caveat “the possibility of a small or a longer term effect cannot be ruled out", I’m sure this isn't the end of the story. We’ll keep you posted.

"Hypotheses Are Verified By Testing, Not By Submitting Them To Lay Juries For A Vote"

That quote comes from the conclusion of Judge Cecilia Altonaga's Order granting defendant's motion to exclude plaintiffs' experts in In Re Denture Cream Products Liability Litigation. If you're interested in the problem of causation in toxic tort cases this little gem would make a great primer.

Of particular interest are the following: (a) the court's dissection of the experts' arrangement of bits of unrelated data into what to the casual observer might appear to be a sound deductive argument; (b) the court's discussion of causal inference via induction and its implicit requirement that experts assess ( weigh) and then disclose the strength of their belief in each premise of the argument; and, (c) the court's recognition of the problem of selection bias when paid experts are allowed to opine as to causation using a so-called differential diagnosis or differential etiology approach - they tend, presumably subconsciously, to populate the line-up of suspect causes with the defendant's product and three or four easily ruled-out alternatives.

We especially liked the following about the opinion of plaintiffs' experts: "This theory is not ridiculous, but neither is it necessarily true; it is ripe for testing." That's what we said about Milward. All the plaintiff had was a plausible yet untested (because, said her expert, it was untestable) theory. Traditionally, that hadn't been nearly enough.

There's a clear split between the circuits with most requiring evidence that a theory's prediction has been confirmed at least once before it can go to a jury while a couple of others require only plausibility and an expert willing to say that it's so based on his or her scientific judgment. So it's the empiricists vs. the epistemological anarchists; Popper v. Feyerabend. If the Supremes decide to have a look it'll be a very big deal.


A risk-based tax on rubber duckies?

Tumors are superorganisms.

Kentucky adopts the economic loss rule. (An especially well written opinion btw).

To be injured, you have to be injured. (Wis Ct of Appeals: another well-reasoned opinion worth reading)

Roggli shows that brake repair workers got their meso from commercial amphiboles.

The Texas Supreme Court Issues an Unsettling Opinion on Causation

BIC Pen Corp. v. Carter has been decided, again, and seemingly for the last time. The court previously disposed of the design defect claims and this time the tragic case of a little girl severely burned as a consequence of her five-year-old brother playing with a lighter was before the court on the issues of manufacturing defect and causation.

Given that BIC's own tests of the lighter involved in the accident showed that a flame was produced more readily (because less force was required) than designed the court steamrolled over BIC's manufacturing defect arguments. It gave especially short shrift to the manufacturing variance argument (which actually has a lot of merit). Thus, by the time the opinion gets to causation, a defect for which liability may be imposed having just been found, to the reader things look pretty grim for BIC.

The court focused immediately on the issue that decides causation. Since lighters are designed to be child-resistant and not child-proof (as otherwise lots of adults could not operate them) how do we know that Carter's brother wouldn't have been able to light it anyway? Which is to ask how do we know that but for the defect Carter's brother would not have started the fire? Clearly Carter has to produce some evidence that her brother was enabled by the defect since even if a lighter meets the CPSC standard for lighters it may still be usable by 15% of children his age.

First the court looks at evidence that the brother was developing more slowly than a typical boy his age. The idea is that if the boy was cognitively more like a four-year-old than like a five-year-old then it's more likely that he was indeed enabled by the defect. The court quite rightly decided that it was an apples to oranges assertion because the defect was in a feature meant to physically deter children whereas there was no defect found in the mechanism meant to confound them. Next the court turned to Carter's contention that she could prove her brother was enabled by the defect using the reasoning of Havner.

Carter points to data indicating that low-force-to-operate levels in lighters such as the one in question quadruple the likelihood of a child being able to produce a flame. If Havner requires a doubling of the risk isn't a quadrupling more than enough? Before we get to how the court decided this issue let's run the numbers. As best we can tell there is at least one good test showing that the number of children able to active the lighter goes from 4% to 16% when the physical deterrent to ignition (force) is reduced. Now, assuming that the lighter in question produced a reduction in force necessary to produce a flame similar to the one used in the test then we can calculate how likely it was that Carter's brother was enabled by the defect. Using Bayes' Rule, the likelihoods of ignition for as-designed lighters and reduced force lighters and our knowledge that the lighter in question was in fact defective we can calculated that the likelihood that Carter's brother would not have been able to start the fire (i.e. was enabled by the defect) but for the defect is 75% - a result easily clearing the "more likely than not" hurdle.

Now, the court could have decided that the quadrupling of risk of ignition involved a different level of force (which, in fact, it did) and that plaintiff had zip, zero, nada evidence that the reduction in force at issue (a very tiny one) has ever been shown to double, much less quadruple, risk (which, apparently, it has not). That would have preserved and extended to manufacturing defect cases the rational decision-making approach to uncertain cases established by the court in Havner. Instead, the court decided that probabilistic reasoning can't be used in manufacturing defect cases and gave an extraordinarily weak rationale for doing so.

The court held that "[t]he nature of the injury-causing activities and testing that would have to be done to show causation in this case are not similar to, nor do they pose the practical difficulties posed by, those we considered in Havner. In this case, testing of J-26 lighters posed no unreasonable risk of injury to the test subjects as would have been the case if testing of the drug on humans had been performed under the facts of Havner ... In such instances, tests are done with surrogate lighters that do not pose a risk of harm to the participating children. And testing was also performed on the Subject Lighter itself that posed no risk of injury. Thus we decline to adopt a Havner-type analysis as to causation in this case where manufacturing defects are the basis for the liability claim."

So, because the test subjects tested lighters that didn't contain butane and because the lighter in question posed no risk of burning children when it was tested in a lab post accident, modern techniques for inferring causation aren't appropriate? With all due deference that makes no sense whatsoever.

Maybe the court was worried about permitting Havner-esque analysis in manufacturing defect cases because eventually it would be deployed in a case where the allegedly defective product had been lost or destroyed. If so, a defendant's product could indeed be found to have been more likely than not the cause of the accident even though the product was lost or destroyed. But for that to happen one of two things would have to hold true. Either the defect was responsible for a huge percentage of all such accidents or a huge percentage of the product had been manufactured defectively. In this case, for example, had the lighter been destroyed in the fire plaintiff could not show "more likely than not" (even assuming a quadrupling of the risk) unless she could also show that at least two-thirds of all lighters had the reduced-force defect. Either way, imposing liability when a defect is almost always the cause of an accident or when almost all of the product involved has been defectively manufactured hardly seems an injustice.

Case by case for more than a decade the Texas Supreme Court has worked to produce a coherent and just approach to causation by demanding sound science and utilizing modern decision theory approaches when reasoning out the cases before it. Hopefully, given our fondness for Havner, the true meaning of BIC Pen Corp. v. Carter is exceptio probat regulam in casibus non exceptis.




The Every Fiber Theory: Reductio Ad Absurdum

There's been considerable buzz about Betz v. Pneumo Abex; an asbestos case pending before the Pennsylvania Supreme Court.  Recently several noted scientists underscored the importance of the case when they filed an amicus brief asking that the court reverse the Superior Court's ruling - a decision which would result in the plaintiff's expert being permitted to testify that each and every fiber of asbestos to which the plaintiff had been exposed was in fact a cause of his illness.  The brief itself is somewhat odd and doesn't read much like the other works of the scientists involved; some scientific concepts having seemingly been lost in translation.  They do however make one important point.  Unfortunately, they don't address the fundamental issue that bedevil this litigation.

The point they make clearly is that the assertion that every fiber of asbestos is the cause of a subsequent disease is not a scientific one.  Scientific claims require confirmation, which is to say that they're not merely hypotheses but are ideas that are testable, that have been tested and have survived those tests.  In the case of the "every fiber" claim the scientists note that there's no evidence for it and that multiple studies involving exposure to low levels of asbestos have repeatedly refuted the claim.  They make an especially strong plea for courts to remember the role that empiricism plays in the scientific method.

What remains unaddressed is what to do with a case in which the illness was allegedly caused by the aggregation of multiple small doses.  In other words, as the plaintiffs frame the question, what is to be done when a camel is found with a broken back and a pile of straw the cause?  Under what theory could any straw be absolved of blame?

Let's answer that question with some graphics.  First up a typical modern case in which a plaintiff with mesothelioma had a combination of exposures from very high to very low.  For the purposes of this discussion assume that 100 f yr/mL is a cumulative exposure that is recognized by plaintiffs and defendants as one that would have been sufficient to have caused plaintiff's illness.  Here's what one such scenario might look like:


Let's further define each exposure according to what we think the law is and ought to be with regard to what is called substantial factor analysis.  Those exposures which in and of themselves are sufficient to have caused the illness are necessarily substantial factors.  Those that pose a significantly increased risk, a question for the court and one that may vary  from jurisdiction to jurisdiction, are also substantial factors.  Those that produce only a remote or de minimis risk are not substantial factors.  The graphic looks like this:

Our slide titled "How It Might Play Out" shows a case in which the court has defined the limits of liability and the jury has thereafter determined which of the substantial factors were foreseeable, which is to say risky in their estimation.

The harder case is the one in which plaintiffs argue that exposures that were substantial as well as those that were de minimis can just as arbitrarily be grouped into a subset of exposures the aggregate dose from which could clearly have been causative.  It looks something like this:

As formerly peripheral defendants who were bit players in the asbestos industry have gone bankrupt we've increasingly seen cases with nothing but defendants whose conduct individually never produced more than a nearly infinitesimal risk of illness.  And given that trend this is what plaintiffs' cases will look like in the future:

Assuming arguendo that multiple small doses of asbestos which have never been shown to have caused any illness whatsoever are in the aggregate capable of producing mesothelioma, how do defendants argue that they ought not be liable?  The answer begins with the fact that an unwritten rule for asbestos litigation has evolved over the years. That rule is "causation equals liability".  That was never the rule.

Now however, as with the circumstance of Ms. Palsgraf in which she could not recover because the risk to her created by a guard trying to help a stumbling passenger was too remote, courts wrestling with asbestos litigation are beginning to come to grips with the fact that many of the defendants left in the litigation are being sued for producing risks that were orders of magnitude smaller than those posed by everyday facets of life such as taking a shower, shaking a stranger's hand or eating an extra slice of pizza. And some courts are starting to apply the same rules that they apply to other cases in which the conduct was ordinary and the outcome remote - that it cannot be the law that any action a person takes, however benign or ordinary, subjects her to being hauled into court should she be that one in a million person whose ordinary conduct produces an extraordinary outcome.

And thus to the camel's claim. Ultimately the question is whether some conduct is so common and so unexceptional as to not, as a matter of law, subject the actor to liability; even though by way of one of life's tragic chances her simple action one day manifests in harm to another. The Restatement (Third) of Torts answers "no, never".  On the other hand, in every context outside of asbestos litigation, American courts have overwhelmingly answered "yes".  "Yes", because they recognize that we all make our way, with rare exceptions, as best we can through a world of inevitable and mostly unknown risks. They hold that the extra straw added to the camel's load then, in every case, asbestos or otherwise, ought not subject she who added it to massive and equally unpredictable liability.

The Power of Prayer and Belief Influenced by Legal Outcomes

When considering how legal outcomes may affect beliefs (think experts opining on general causation in the face of a lack of science), it is interesting to consider not just science but pure belief.

A beer joint in a small Texas town built an addition. A congregation prayed that it not be built. Lightning struck. The church rejoiced, firm in the belief of the power of prayer. The bar owner sued the church for causing, directly or indirectly, the lightning strike which smote his expansion. The church then denied the power of prayer. No really. True story.

Let’s again consider general causation and the power of process of elimination causation determinations.

Sound Causal Inference: Transparency, Transparency, Transparency, Transparency

The recent Milward opinion out of the U.S. First Circuit Court of Appeals notwithstanding, the subjective assessment of an expert, weighing whatever evidence he selects for consideration in the scales of his own "scientific judgment", is not how causal inferences should be reached. At least not according to the National Academy of Sciences (NAS).

Last Friday NAS released its report on EPA's Integrated Risk Information System (IRIS) assessment of formaldehyde. It wasn't impressed with the overlong and detailed discussions of each study the EPA had considered. Rather, it expressed its concern that all EPA had at the end of the day was a pile of studies and its scientific judgment. Specifically the NAS reiterated, as it has in the past, that data + a statement that proper methods of causal inference had been followed ≠ sound science.

Of the criticisms leveled against the EPA's report the most frequent was for a lack of transparency. The EPA hadn't made it at all clear how it was going to go about assembling data, how it was going to assess the data, by what criteria it would include or exclude a given piece of data or how, and by what standards, it was going to weigh the data it found worthy of consideration. How can another scientist assess the soundness of an expert's conclusion if she has nothing other than "I considered the following studies and reached the following conclusion using my best judgment" to go on? She can't.

So on page 115 the NAS reviews best practices for conducting and assessing comprehensive reviews. If you're dealing with an expert who says "I used the A.B. Hill criteria and my scientific judgment to reach my opinions" you'll find the discussion that follows full of great cross examination material. Where, for example, is the evidence table prepared by the expert? What weight does he assign to each datum? How did he come by it? If a particular study has a potential for bias by how much did he lessen the weight assigned, how did he come up with the number and in what other matter has he used the same modifier to account for possible bias?

Finally, the NAS took a particularly dim view of the EPA's conclusion that formaldehyde likely causes all lymphohematopoietic (LHP) cancers. (See pages 80 - 87). There's "[t]he grouping of 'all LHP cancers' includes at least 14 biologically distinct diagnoses in humans and should not be used in determinations of causality". And "there is no clearly articulated framework for establishing causation on the basis of the weight and strength of evidence". Finally "the conclusion of causation appears to be based on a subjective view of the overall data ... [t]he absence of a causation framework is especially problematic for the individual LHP cancers, given the highly variable epidemiologic literature and the high uncertainty of mode of action."

Bottom line: if you're going to use a "weight of the evidence" approach you have to say how you decided what to weigh and by what standards you weighed it. Pretty basic stuff really.



Getting at the Truth: Improving Systematic Reviews

Systematic reviews and meta-analyses are considered to be perhaps the best evidence about treatments/exposures and outcomes from which causal inferences can be drawn. The problem is that they're susceptible to a variety of biases. See e.g. "Bias Due to Changes in Specified Outcomes During the Systematic Review Process".

In the litigation context we increasingly see a systematic review launched by an expert-to-be before the first suit is even filed.  They will thus have already gone through the studies; used their "judgment" to select which ones ought to be considered (and which ought not); determined how much weight to give each; and established a protocol for conducting the review which, surprise surprise, demonstrates a causal link supporting the lawsuits. The strong suspicion is that selection bias (a form of the Texas Sharpshooter effect) is at work (and that, of course, is being charitable). And the biggest problem is that uncovering selection bias is notoriously difficult.

Now there's a move afoot to bring transparency to systematic reviews by requiring that plans, methods and protocols be registered before the systematic review is begun. See "Best Practice in Systematic Reviews: The Importance of Protocols and Registration"; "New Initiative to Make Systematic Review Protocols More Transparent"  and "Open Medicine Endorses PROSPERO". Here's the press release from the Cochrane Collaboration and here's a link to PROSPERO.

Until we get courts to make experts disclose their methods and justifications for selecting, weighing and interpreting data before they develop their opinions articles like the following may come in handy: "How Can We Improve the Interpretation of Systematic Reviews?"

Population Mixing, Childhood Leukemia, Viruses and Vaccines

There's good epidemiological evidence that population mixing is responsible for several clusters of childhood leukemia (acute lymphocytic leukemia, or ALL). Some have hypothesized that viruses are to blame but there hasn't been much evidence to support that hypothesis; at least not until now.

In the current Journal of Pediatrics you'll find "Associations Between Vaccination and Childhood Cancers in Texas Regions" which compares the risk of ALL to vaccination rates in different public health regions. With all the caveats that must go along with hypotheses generated by statistical analysis it is nevertheless quite intriguing to see that children vaccinated against a wide range of viruses had a large and consistent reduction in their risk of ALL; so much so that it leading the researchers to conclude that "[s]ome common childhood vaccines appear to be protective against ALL at the population level."

Be sure to also note that 4 doses of diptheria-tetanus-pertussis, 3 doses of polio, 1 dose of measles-mumps-rubella, 3 doses of H. influenza, type B, 3 doses of hepatitis B and one dose of Varicella, the 4-3-1-3-3 vaccine regimen claimed by some anti-vaccine activists to be capable of "overloading young immune systems" and thereby (some-unstated-how) causing autism, produced a 38% decrease in the risk of a child developing leukemia.

Hopefully the anti-vaccine crowd is paying attention. The list of harms to children for which they may be made to answer is apparently growing.

Nulliparous Plaintiffs, Fault and Causation

It has been known for a couple of decades now that women who never have children (i.e. women who are nulliparous) and women who do have children but not until they are 30 or older suffer a striking increase in their risk of developing breast cancer. The evidence for the association between never giving birth or delaying having a child continues to accumulate and now it appears that the increased risk is focused on hornmone receptor-positive breast cancers. See "Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies" in the current issue of the Journal of the National Cancer Institute. So let's say you've got a nulliparous plaintiff alleging that your drug or device or chemical caused or accelerated her hormone receptor-positive breast cancer; how do you handle her status?

The first problem a defendant faces in such a case is the risk of inadvertently wandering into the minefield called "blaming the victim". The plaintiff has either freely made a choice or has tragically been unable to have a child. Either way the jury will react strongly and negatively to any discussion about parity status and causation that makes even the slightest trespass into the issue of fault. Keep the discussion limited to risk factors and their relative potency. But that leads to another problem.

In some of the jurisdictions in which I practice plaintiff's counsel will successfully argue to the trial court that only evidence about about the actual cause of plaintiff's injury is admissible. In other words, unless my expert is prepared to say e.g. that "to a reasonable degree of medical probability plaintiff's breast cancer was caused by her not having children when she was young" testimony about "mere risks" is irrelevant and so inadmissible. The practical effect of such a ruling is that only junk science is admissible on the issue of the actual cause of plaintiff's cancer since my experts tend to be modest about the claims science can make regarding the cause of any individual's cancer. We're stuck then trying to prove a negative, showing we acted reasonably and preserving error.

In this age in which much that was certain (e.g. that we've conquered infectious diseases) is proving not to be so it's time I think for courts to recognize not only that the reasonableness of actions can fairly and effectively be judged according to the risks they conferred but also that causation is in many cases most precisely weighed when competing risks are allowed to be compared against one another.

Finally, and hopefully still on topic, for more evidence of the complexity of causation see "Does Pregnancy Provide Vaccine-Like Protection Against Rheumatoid Arthritis?" Why would pregnancy protect against auto-immune disorders and what's the connection with breast cancer? There are a variety of hypotheses offered but so far no one knows.


New Review Article on SJS and TEN

It's very thorough and it's free, full text, in this month's Orphanet Journal of Rare Diseases.See "Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome".

SJS/TEN cases typically involve very high damages as the injury is akin to a severe burn.  The article contains a list of known causative agents as well as standards for diagnosis and treatment.


The Linear No-Threshold Theory: A Crumbling Foundation

The idea that a known cause of cancer, e.g. ionizing radiation, poses a risk of cancer at any dose, no matter how small, is a central thesis informing modern environmental and occupational regulations and modern, which is to say low dose, toxic tort cancer litigation. In the toxic tort context plaintiffs regularly employ the logical fallacy of the appeal to ignorance (argumentum ad ignorantiam) to prove that even the slightest exposure was risky. They say that because defendants cannot establish a safe level of exposure it follows that every exposure is necessarily unsafe. The formal name for the idea that risk doesn't drop to zero until exposure drops to zero is the linear no-threshold dose theory or LNT. The LNT theory, always longer on theory and politics than evidence is increasingly under attack. Now even NIOSH has had to concede that at least in some circumstances there is indeed a safe dose for a carcinogen.

In "Checking the Foundation: Recent Radiobiology and the Linear No-Threshold Theory" the author states "a large and rapidly growing body of radiobiological evidence indicates that cell and tissue level responses to [radiation damage], particularly at low doses and/or dose-rates, are nonlinear and may exhibit thresholds ... this evidence directly contradicts the assumptions upon which the microdosimetric [LNT] argument is based". The idea that a substance that is harmful at high levels can be harmless or better yet beneficial or protective (the idea of hormesis) at low levels is discussed at length in this month's issue of Human & Experimental Toxicology.

The claim that "if it takes an ounce to kill ten men then a drop will thousands" was itself just a theory based on the idea that carcinogenesis was a stochastic process. Getting cancer was sort of like hitting the anti-lottery and the more tickets you bought (exposures you sustained) the more likely you were to lose yet if you were unlucky enough just one ticket could do it. Like black box epidemiology LNT was simply a way to ignore the formerly incomprehensible molecular biological mechanisms responsible for cancer. Now that those mechanisms are being uncovered and understood they can no longer be ignored as they shatter one paradigm after another.

Maybe That's Why You Fell For Her. She Cooks Just The Way Your Mom's Gut Microbes Like It.

Biological causation gets more complex by the day and the simple, reductionist model of toxin in - disease out common to toxic tort cases gets more absurd by the day. Imagine what you'd have thought two years ago about this claim: the diet of a fruit fly changes the composition of the bacteria in its gut and those bacteria then change the pheromones she releases so that she will attract a male fruit fly with the same sort of bacteria in his gut resulting in a mating preference change that lasts up to 37 generations even if her offspring's diet changes along the way.

Thus, it's not just a matter of "They Are What You Eat"; it may well also be a matter of "You Are What Your Great Great Great Great Grandmother's Intestinal Bacteria Ate". See "Bacteria Can Drive the Evolution of New Species" in Nature News for the write-up and "Commensal Bacteria Play a Role in Mating Preference of Drosophila melanogaster" for the paper that heralds the discovery.

For more on the idea of a "hologenome" - i.e. the idea of thinking of "your" genetic code as consisting of the genes in your chromosomes plus those in the bacteria that live in and on you - see the following:

"Role of Microorganisms in the Evolution of Animals and Plants: the Hologenome Theory of Evolution"

"The Hologenome Theory of Evolution Contains Lamarckian Aspects Within a Darwinian Framework"

"Whole-Body Systems Approaches for Gut Microbiota-Targeted Preventive Healthcare"

A Man Is Not A Mouse, At Least When It Comes To Butadiene

Why are mice so much more susceptible to butadiene? Apparently it's because they metabolize it into potent mutagens at 200 times the rate of humans. As a result, while mice exposed to butadiene at current occupational levels promptly yield evidence of genotoxicity there's no evidence of genotoxicity in humans at current workplace exposure levels. See: "1,3-Butadiene: Biomarkers and Application to Risk Assessment".

Is Benzene a Teratogen?

Back when I was an associate we had a refinery client with a benzene unit and the unit generated litigation along with the benzene. Interestingly, the union knew that benzene could cause fatal blood diseases back when the unit was built in the late 1950s. The union even sent down a benzene safety poster which was framed and hung in the control room. The operators were issued cartridge respirators for aromatics and had blood samples taken for testing on a regular basis. Far from being a worry, even after the Emergency Temporary Standard for benzene came out the unit was a favorite of those union members with the seniority to bid on to it. So much so that women with the requisite seniority would have hysterectomies so they could get around the so-called fertile female policy that prevented them from working on it.

Some early, and I might add poorly done, studies had suggested that benzene might cause birth defects. Accordingly many companies adopted policies that kept women who were otherwise qualified from working with materials or in operations feared to be teratogenic. Eventually the U.S. Supreme Court struck down such policies. See: International Union, United Automobile, Aerospace & Agricultural Implement Workers of America, UAW, et al v. Johnson Controls, Inc.

Nothing ever came of the claim that benzene was a teratogen and even in southeast Texas where injury and illness would otherwise not exist but for deep pocketed corporations we never had any benzene birth defect claims.

Now however there's a new study in Environmental Health Perspectives that compares EPA estimates of benzene exposures in Texas and the rates of spina bifida among people living in those areas during a recent five year period. It found for the area with the highest exposure a 2.3-fold increase in spina bifida; an association which was statistically significant.
Read all about it (free) in "Maternal Exposure to Ambient Levels of Benzene and Neural Tube Defects Among Offspring, Texas, 1999 - 2004"

Hat tip: The Houston Chronicle

High Priestess of Climate Change Questions IPCC Inerrancy; Declared Apostate

Industry and military scientists get rewarded when they come up with things that work. Academic scientists tend to get rewarded when they come up with narratives that generate more grant money. Ok, nothing new there. But what happens when an academic scientist suggests that a prevailing academic paradigm be subjected to the same criterion of falsifiability as any other claim to knowledge? Hilarity ensues, though only for those on the outside looking in at the absurdity of simultaneously dismissive and panicky academic internecine warfare.

Though she does not question the idea that man influences climate and may well do so harmfully, Judith Curry, from one of those few remaining institutions (e.g. the Ramblin' Wreck of Georgia Tech) that yet dare to question societal dogma has gathered the courage to question the prevailing groupthink of the Intergovernmental Panel on Climate Change (IPCC) and for her trouble has garnered the enmity of the Global Warming clergy and its laity.

Read all about it (free) at Scientific American in "Climate Heretic: Judith Curry Turns on Her Colleagues. Why Can't We Have a Civil Conversation About Climate?"

A Placebo a Day Keeps the Doctor Away

Do you comply with your doctor's orders? If you're on a daily medication do you always take it, every day, at the same time, with say the recommended glass of water? If you do, even if there's no medicine in the pill, your odds of living a long and healthy life are good and getting better and it's because you've made yourself the beneficiary of the compliance effect.

I was reminded of a recent study of the so-called compliance effect while reading "Secrets of the Centenarians" in today's NYTimes. In the Times piece the author examines the long life and sharp mind of Mrs Esther Tuttle and her particularly keen insight into the source of good health. She says:"If you respect what the doctors tell you to do, you can live a long life, but you have to do it. You can't ignore the advice."

Though currently inexplicable it turns out that people who follow their doctor's orders, even if it's just to take a sugar pill a day (they don't know it's a sugar pill, of course), do better than those who take a less disciplined approach to their health. The article of which I was reminded is: "The Relationship Between Bisphosphonate Adherence and Fracture: Is it the Behavior or the Medication? Results From the Placebo Arm of the Fracture Intervention Trial". In it the authors report the results of a study of the outcomes of those women on placebo in a drug trial for a drug designed to prevent bone loss (osteoporosis). Even though they didn't get any real medicine and even though they were on the same sugar pill as the women who didn't strictly adhere to their doctor's orders regarding the drug, those women who took their sugar pill religiously had significantly lower bone loss and fewer hip fractures.

This and other recent research on the compliance effect confirm what Mrs Tuttle somehow figured out: resolve (along with resourcefulness, resilience and a refusal to succumb to cynicism) somehow, some way, keeps you alive and keeps you healthy.

Trichloroethylene + Gene Variant = Renal Cancer?

Workers exposed to trichloroethylene (TCE) who carry at least one copy of the GSTT1 allele are reported to have an 88% increase in risk of renal cancer in the new paper "Occupational Trichloroethylene Exposure and Renal Carcinoma Risk: Evidence of Genetic Susceptibility by Reductive Metabolism Gene Variants." Those workers without the polymorphism had a slight decrease in risk. Given that the allele occurs on a gene coding for cysteine β-lyase, which plays an important role in the metabolism of TCE among other molecules, the finding demonstrates biologic plausibility as well as increased risk.

So back to yesterday's post about risk : which risk, if any, would be relevant in a TCE toxic tort case? The risk given to all workers collectively; the risk at a particular range of exposure; the risk given to those carrying the polymorphism; or, the risk to those with the polymorphism exposed at high levels? And could it be the case that one risk is relevant to the question of whether a defendant's conduct was reasonable while another was relevant to the question of causation? How would that work?

However it works, as the causes of individual susceptibility are identified expect these sorts of challenges to multiply. 

Avandia's Revenge

The Avandia witch hunt saga just gets more and more absurd. Guess what just popped up from the FDA's Division of Drug Information? Notice of an ongoing safety review of pioglitazone (the "safer alternative" generic pushed by those urging Avandia be pulled from the market.). Apparently "an increased risk of bladder cancer was observed among patients with the longest exposure to Actos (pioglitazone) as well as in those exposed to the highest cumulative dose of Actos."

So does this mean that pioglitazone ought to be banned? Does this mean that the ongoing study of pioglitazone users needs to be discontinued because it's unethical? That's what the anti-Avandia activists argued re: Avandia and the TIDE trial; they wanted everyone off Avandia, on pioglitazone and the experiment halted - pronto.

No; it ought not mean any of those things. What it does mean is that it's foolish to let our decisions be bound by the results of a single data dredge.

For more on the Avandia issue see: "Avandia: Burn Her Anyway?" For more on the perils of data mining see "Lies, Damned Lies and P-Values". Here's the full text of today's FDA missive on pioglitazone:


FDA/CDER/Division of Drug Information (DDI)

The Division of Drug Information (DDI) is CDER's focal point for public inquiries. We serve the public by providing information on human drug products and drug product regulation by FDA.

The U.S. Food and Drug Administration (FDA) is reviewing data from an ongoing, ten-year epidemiological study designed to evaluate whether Actos (pioglitazone), is associated with an increased risk of bladder cancer. Findings from studies in animals and humans suggest this is a potential safety risk that needs further study.

Actos is used along with diet and exercise to control blood sugar or improve control of blood sugar in adults with type 2 diabetes mellitus.

Bladder cancer is estimated to occur in 20 per 100,000 persons per year in the United States and is thought to be higher in diabetics.

The drug manufacturer, Takeda, has conducted a planned analysis of the study data at the five-year mark, and submitted their results to FDA. Overall, there was no statistically significant association between Actos exposure and bladder cancer risk. However, further analyses were also performed looking at how long patients were on Actos and the total amount of the drug they received during that time. An increased risk of bladder cancer was observed among patients with the longest exposure to Actos, as well as in those exposed to the highest cumulative dose of Actos.

At this time, FDA has not concluded that Actos increases the risk of bladder cancer. Its review is ongoing, and the Agency will update the public when it has additional information.

For more information, please visit: Actos


Most Prostate Screening Unnecessary, Useless

A new study, reviewing and pooling results from prior studies in prostate cancer screening, shows that screening men for prostate cancer does not increase life expectancy.

While the PSA test is effective at predicting which men may eventually get prostate cancer, it is ineffective in increasing life expectancy. This is because most men with a high PSA will not get prostate cancer in their lifetimes and will eventually die from something else. Many men, some of whom I have debated the value of a PSA test with, get a high PSA test result and live in fear of cancer for decades, even though prostate cancer never develops. Further, prostate cancer treatments, including surgery or radiation, can lead to incontinence and erectile dysfunction in about a third of patients. Unfortunately, some men get the treatments after a high PSA from fear of cancer which may never reach them in their lifetime. Other men get the treatments when they contract prostate cancer, even though this slow-growing tumor will not hurt them in their lifetimes. It is a case where the cure is sometimes worse than the cause.

The study is part of an effort to streamline which medical tests are effective, not just in detecting disease or the potential for disease, but for actually increasing life expectancy and increasing quality of life. A similar effort was undertaken to critically and empirically view breast cancer screening. The breast cancer screening recommendations were met with a flurry of criticism. Hopefully, this recommendation will not meet the same result.


Parkinson's: Not Much Evidence for Manganese; Strong Evidence for Vitamin D Deficiency

In Tamraz v. Lincoln Electric Company, et al the 6th Circuit held that an expert could not stack speculation about mechanisms upon unseen and undetected lesions in the plaintiff to get from manganese exposure to his Parkinson's disease. Furthermore, the court ruled that you can't reasonably arrive at a causation opinion using what's erroneously called a differential diagnosis (it's more properly called simply a process of elimination) when you've no sound basis for ruling anything either in or out.

On the other hand, there's growing evidence that vitamin D deficiency is strongly associated with Parkinson's. Best of all, it makes sense. It looks like the enteric nervous system is first to be degraded in Parkinson's and that system is exquisitely sensitive to the gut mediated immune system which in turn is adversely affected by vitamin D deficiency. See: "Parkinson Disease: Could Sunlight Offer Protection from Parkinson Disease?"

Koch's Postulates Revised

Whenever epidemiological data is used to support a claim of causation in a toxic tort case a fight over causal inference invariably erupts and for the last twenty years or so that has meant an argument about whether Sir A. B. Hill's so-called causal criteria have been met. Long before Hill tried to prove that smoking causes lung cancer Robert Koch tried to find a defensible argument for the claim that microbes were the cause of anthrax. What he came up with are known as Koch's postulates and they've been around for well over one hundred years. Now, in an attempt to update them for a world in which often only bits of pathogens long gone remain an attempt to update the postulates has been published.

In "Microbe Hunting"  the author summarizes the problem of causal attribution when the responsible bacteria can't be cultured or even found and when their role in disease is the result of an incredibly complex interplay between host, uncounted trillions of microbes and the external environment. He discusses the methods for teasing out pathogens from dense webs of causation and proposes a refined set of causal criteria. It's well worth reading because if you do mass torts you'll be dealing with this issue for years to come.

How Quickly Do Bacteria Evolve? Lots Faster Than You Thought.

It has generally been assumed that bacteria evolve to overcome host defenses at a rate much slower than that of viruses. That assumption appears to be wrong. Helicobacter pylori, a cause of multiple cancers in humans, mutates at a rate similar to many viruses. See: "Microevolution of Helicobacter pylori During Prolonged Infection of Single Hosts and Within Families".

Just how fast can bacteria evolve? Would you be surprised to learn that within the lifetime of mice, bred to be free of gastrointestinal bacteria, bacteria from drinking water cannot only set up shop and colonize their hosts' guts but evolve into whole new species? If you are surprised, read: "Bacteria From Drinking Water Supply and Their Fate in Gastrointestinal Tracts of Germ-Free Mice: A Phylogenetic Comparison Study".

The long war continues, of course; and while we've been basking in our assumed victory over them for the last forty years our ancient enemies, descended from a long line of brilliant sappers, have been hard at work.

Causation and the Restatement (Third) of Torts: Part II

What does it mean, in the law of torts, for one to have caused another's injury? The standard legal account of causality has been that of the counterfactual put forward by David Hume as follows: "where, if the first object had not been, the second never had existed." (1748, Section VII). In the law it's the "but for" test and for our purposes then the courts tend to attach legal liability (assuming the existence of a duty and its breach) only upon the following: had Defendant done otherwise, Plaintiff would today be uninjured. 

Generally speaking the "but for" test is easy to use and produces a nice clean binary answer of the sort favored by courts trying to resolve disputes. (e.g.  "But for" Defendant having run the red light Plaintiff would have passed through the intersection without incident and would not have suffered the broken leg of which she complains.) Of course there are innumerable "but for" causes of the accident, including the Defendant's mother having given birth to him and the rudeness of the fellow with a cart full of groceries in the "10 items or less" line who slowed Plaintiff down so that she wound up in the intersection at the same moment as Defendant. Nevertheless, and almost invariably without much analysis, the parties settle on just one among the countless posibilities as the sine qua non act (or omission) to be subjected to the "but for" test.

However, when deployed in a case in which plaintiff's injury was caused by only one of several identical and indistinguishable acts (see e.g.  Summers v. Tice) or by the cumulative effect of some subset of several identical and indistinguishable acts (see e.g. Landers v. East Texas Salt Water Disposal Co.) the "but for" test would, without some other rule, produce the jarring judgment that none of the defendants, considered individually, were more likely than not the sine qua non cause of the plaintiff's injury. In those cases, finding that the acts (divorced from the inquiry of whether they were actually causative) were tortious, the courts held that the defendants should bear the burden of proof that theirs was not the act that caused the plaintiff's injury. The instances in which such a rule would apply were surely few and even a century ago the idea of treating the defendants collectively and shifting the burden on to them was not unheard of. See 2 J. Wigmore, Select Cases on the Law of Torts Section 153, p. 865 (1912) ("When two or more persons by their acts are possibly the sole cause of a harm, or when two or more acts of the same person are possibly the sole cause, and the plaintiff has introduced evidence that one of the two persons, or one of the same person's two acts, is culpable, then the defendant has the burden of proving that the other person, or his other act, was the sole cause of the harm.")

An effort to distill all judicial reasoning about causation down to its essence and to make a rule of it has been underway for some time. Probably the most cited rule, a form of which is incorporated into the Restatement (Third) of Torts, is the NESS test. NESS stands for "necessary element of a sufficient set". The NESS test is itself a restatement of an older test in which a singular putative cause is said to indeed be causative if it, though insufficient, is nevertheless a necessary element of a precipitating event which event, though perhaps itself unnecessary, would nevertheless have been sufficient to have produced the outcome under investigation (see "Causes and Conditions" by J.L. Mackie). What in the world does any of that mean? In Mackie's example investigators of a fire are satisfied that a short-circuit was the cause of a house fire when conditions were such that the short circuit existed, flammable rags were nearby and those rags once ignited were sufficient to cause a conflagration that would burn down the house. The short-circuit alone was insufficient to burn down the house but it was necessary (other causes having been ruled out) to catch nearby flammable rags on fire. Lots of things can ignite and so burn down a house (so burning rags are not necessary to have a burning house) but burning rags are sufficient to torch the place. Whew.

"But for", causal analysis seems then to be about ruling things out and settling on what's left (the short-circuit). On the other hand, the investigation of the product of the remaining thing(s) (sufficient set) seems aimed towards the propensity of one condition (burning rags) to lead to another (burning house). It is out of this second analysis, of the propensity for one thing to lead to another, that queries about reasonableness and foreseeability and risk arise. More on that later though when I get to risk.

Anyway, the reductionist effort itself precipitated a debate about whether the NESS test accounts for all judicial causal reasoning that continues to this day. Take for instance the hypothetical case of the desert traveler. The desert traveler set off to hike across the desert with just enough water to make it to the other side. Unbeknownst to the desert traveler, defendant "A" had poisoned his water such once that he'd consumed all of it he would surely die. Along his way across the desert however, defendant "B" stole the desert traveler's water bottle. The desert traveler was found dead in the desert. If defendant "A's" conduct was not the cause of his death, why not?

Such conundrums would normally make for nothing more than an obscure niche in the law in which a few academics could regularly generate tedious and unread papers. Then forty one years ago Clarence Borel, dying of mesothelioma, filed a products liability claim in Beaumont, TX culminating in an opinion that would usher in the age of mass torts. Concluding that as it was impossible "to determine with absolute certainty which particular exposure to asbestos dust resulted in injury" and because "each exposure may result in an additional and separate injury" the 5th Circuit held in Borel v. Fibreboard that a jury could reasonably conclude "that each defendant was the cause in fact" of Borel's injury.

Twenty seven years after Johns Manville sank under the wave of litigation unleashed by Borel the practical effect of the ruling continues to drive companies into bankruptcy. The Restatement (Third) of Torts was awkwardly silent on the issue of "the mother of all mass torts" but recent musings by its Reporters and others suggest that they thought rather a lot about it and that its impact on the restatement effort was in fact profound. The shame of it is that they almost got it exactly right. All that was needed was to distinguish between risk and causation and to embrace Palsgraf's true meaning: that the risk imparted is the measure of the reasonableness of the man.

Next time: Risk.

Sanded Joint Compound With Chrysotile Doesn't Migrate to the Pleura Nor Does it Produce Inflammation

Six hours a day, for five days, rats were exposed either to amosite or to joint compound with chrysotile. Over the course of a year subsets were sacrificed and their lungs examined. The rats exposed to amosite sustained an inflammatory response and by the end of four weeks had developed evidence of interstitial fibrosis and inflammation in the parietal pleura. Those rats exposed to chrysotile-containing joint compound never showed evidence of fibrosis and their bodies cleared the chrysotile fibers quickly. By the end of the year there was still no evidence of inflammation or migration.

See: "The Pathological Response and Fate in the Lung and Pleura of Chrysotile in Combination with Fine Particles Compared to Amosite Asbestos Following Short-Term Inhalation Exposure: Interim Results"


Restatement (Third) of Torts: Causality and Risk Turned Upside Down

Would you believe that an act that was neither sufficient nor even necessary to produce an injury could still be considered a legal cause of it simply because it had exposed an injured plaintiff to risk? You need to read Restatement (Third) of Torts: Liability for Physical Harm. Wherever adopted it will expand liability in asbestos cases against those that almost certainly had nothing to do with plaintiffs' injuries; it will extend asbestos litigation's special rules to any claim for a cumulative or indivisible injury due to toxic exposure; and, it will do it by standing modern thinking about causality and risk on its head.

To understand why Restatement 3rd will change everything you need to read "The Insubstantially of the 'Substantial Factor' Test for Causation". Among the authors are the Reporters for the Restatement (Third) of Torts and they specifically examine the problem of causation in asbestos cases. They survey the landscape of modern attempts to deal with the issue and settle on Lohrmann, Rutherford, Gregg and Flores as representative.

Concluding that Rutherford stands for the rule that "[p]laintiff need only prove that defendant contributed to the risk of disease by exposing the plaintiff to asbestos" the authors conclude: "[g]iven the reality of causal uncertainty, we believe the Rutherford solution to the problem is the best yet devised. The Rutherford approach of imposing liability for risk contribution is self correcting in the case of small doses, at least in jurisdictions with several liability. The defendant who contributes .05% of the dose to which the plaintiff was exposed will be liable for that same percentage of the plaintiff's damages."

What’s wrong with that? Well they've conflated risk and causation. They're defining cause as risk and risk as cause and imposing liability without regard to cause or even the degree of risk imparted. How so? By saying that dose, which is only an aspect of risk, is the measure of cause; and by saying that cause is simply the set of all proven doses (which is to say risks)- thus: 0.05% dose (risk) = 0.05% of the causation.

The authors make it clear that there is no lower limit above zero that could not be the basis for liability. Either each fiber was a necessary cause under the “straw that broke the camel’s back” view or each fiber was a member of some sufficient group or set of fibers thus satisfying the Restatements’ version of the NESS (Necessary Element of a Sufficient Set) test for causation. How do we know this? There is a “trivial-contribution exemption” that applies in situations where there are multiple sufficient causal sets but the authors state that this exemption does not apply in the asbestos context. How could that be so? They must have determined that asbestos doses are fungible and the disease the result of the dose such that the sufficient set of causes of say mesothelioma necessarily includes all asbestos exposures; and thus by extension, each fiber “a factual cause subject to liability”. Otherwise, calculating the answer to the "how many sufficient sets can we make out of the total dose" question would lead to the logical conclusion that it is impossible to say that any given defendant's contribution to dose was causative. To be sure that can't happen there's Section 27.  

If you doubt that each fiber can be a legal cause or still doubt that that there's no lower limit of liability read section 27, especially comment f. 

"Section 27. Multiple Sufficient Causes

If multiple acts occur, each of which alone would have been a factual cause under section 26 (what the Reporters say is the essence of causation, the "but for" test) of the physical harm at the same time in the absence of the other act(s), each act is regarded as a factual cause of the harm.

... comment f. The fact that an actor's conduct requires other conduct to be sufficient to cause another's harm does not obviate the applicability of this Section. Moreover, the fact that the other person's conduct is sufficient to cause the harm does not prevent the actor's conduct from being a factual cause of harm pursuant to this Section, if the actor's conduct is necessary to at least one causal set."

Basically, this is just the old game of "How do you know asbestos caused his mesothelioma? Because he was exposed to a sufficient dose. But how do you know he had a sufficient dose? Because he got mesothelioma. How do you know that every exposure contributed? Because otherwise he wouldn’t have had a sufficient dose. But how much was needed for a sufficient dose? Enough to cause his mesothelioma.”

If courts adopt such a rule it'll be a happy day indeed for plaintiffs' lawyers. Their refrain, and that of their experts, that "every dose is causative because the risk doesn't become zero until dose is zero" - the logical fallacy behind conflating risk and causation and behind the "one fiber" theory - will have become law; and the law will be deeply biased against defendants.

Next up, we'll discuss causation and risk and why the reasoning in Borg-Warner v. Flores best captures the essence of American tort jurisprudence. Hint: "the risk reasonably perceived defines the duty to be obeyed" is best understood as being about risk and the reasonable man, and not about foreseeability.

What's Behind the Rise in Food Allergies?

The incidence of food allergies in children is rising. Wheat, milk, egg, fish, peanut, walnut, shellfish and soy allergies have led to recalls of pork, turkey, cream of wheat mushroom soup, roast beef, ice cream and corn pasta in recent months. What's behind the increase in allergies?

There are at least two good hypotheses for which there's sound evidence. First, despite what our pediatrician told us, it's probably a good idea to introduce babies to e.g. cow milk sooner rather than later (see "Early Exposure to Cow's Milk Protein is Protective Against IgE-Mediated Cow's Milk Protein Allergy") and make sure they get a large enough dose to produce tolerance as it's apparently the low doses of say peanuts that lead to sensitization and allergy (see e.g. "Peanut Sensitization and Allergy: Influence of Early Life Exposure to Peanuts").

The second emerging hypothesis, another of the increasingly common "Grandma was right" sort of ideas, is that lack of sunshine is also responsible for the rise in food allergies in children. It turns out that vitamin D is crucial to a properly functioning immune system and without it you wind up with a gut full of the wrong sorts of bacteria behaving badly. (See "Potential Mechanisms for the Hypothesized Link Between Sunshine, Vitamin D, and Food Allergy in Children" and "The Role of the Gut Mucosal Immunity in the Development of Tolerance Versus Development of Allergy to Food").

And while we're on the topic of the consequences of this needless epidemic of vitamin D deficiency in the U.S. due to four decades of anti-sun/anti-reason activism you should also read: "North-South Differences in U.S. Emergency Department Visits for Acute Allergic Reactions", "Are Active Sun Exposure Habits Related to Lowering Risk of Type 2 Diabetes Mellitus in Women, a Prospective Cohort Study?" and "Vitamin D and Risk of Cognitive Decline in Elderly Persons" along with "Vitamin D: A Place in the Sun?" and "Vitamin D in Asthma: Panacea or True Promise?"

The takeaway here is that by overreacting to rare and likely uncontrollable risks we've been stampeded right into far more common and otherwise avoidable risks. So who should be liable to all of the eggshell plaintiffs manufactured out of junk science? Should it be the companies whose products would not have caused harm but for the activists or should the activists be called to account for what they have done?

Twenty Suspected Carcinogens

The American Cancer Society is calling for new research to settle the issue of whether or not twenty different agents do indeed cause the types of cancer in which they've been implicated. The twenty are:

(1) Lead and lead compounds; (2) indium phosphide (used in many flat screen TVs); (3) cobalt with tungsten carbide; titanium dioxide; (4) welding fumes; (5) refractory ceramic fibers; (6) diesel exhaust; (7) carbon black; (8) styrene oxide and styrene; (9) propylene oxide; (10) formaldehyde (does it cause leukemia?); (11) acetaldehyde; (12) formaldehyde; (13) methylene chloride; (14) trichloroethylene; (15) tetrachloroethylene; (16) chloroform; (17) PCBs; (18) DEHP (a phthalate); (19) atrazine (a herbicide and the subject of a coordinated attack by various activists groups resulting in a new EPA review); and, (20) shift work (the presumed exposure being "light at night" leading to a disruption of circadian rhythms and the most commonly associated malignancy being breast cancer).

You can find the press release here: Report Outlines Knowledge Gaps for 20 Suspected Carcinogens; and you can find the IARC report summarizing past rationale for assigning these suspected carcinogens to groups 2A - 3, the new evidence forming the basis for the recommendation that the status be updated and the sorts of epidemiological and mechanistic studies necessary to answer the question of whether they ought to be added to the list of 107 Group 1 agents known to be carcinogenic to humans, here: Identification of Research Needs to Resolve the Carcinogenicity of High-Priority IARC Carcinogens.

Which Came First, the Mutation or the Cancer?

The current paradigm, some 40 or 50 years old now, would say it was the mutation. As the first plaintiff's expert witness I ever cross examined at the courthouse said of the chemical in question "it messes with your DNA and if your DNA is messed up anything, especially cancer, can happen". By the way, for the younger set, before Daubert and Robinson/Havner that's what all too often passed for "science" in the courtroom.

Yet in the new Million Women Study of breast cancer, mutations associated with higher risk and environmental insults associated with higher risk seem to have no relation with one another such that hormone replacement therapy doesn't increase the risk of breast cancer even in women with genes predisposing them to estrogen-receptor positive disease. How can that be?

Well, here's some food for thought. Where do we come from? Bacteria, way back when. How do bacteria talk to each other? Quorum sensing (by the way, don't you wish all your teachers had been like Bonnie Bassler?) So if our stem cells want to monitor how many undifferentiated cells they need to be making and if those cells want to monitor their path to differentiation might they not do it via the same signaling pathways that their ancestors employed? If that's the case then could it be that a disruption in signaling causes runaway production of immature cells (cancer) and that the mutations only occur later? There's more than a scintilla of evidence for it.

What recruits bone marrow cells to the gut where their signaling is disrupted? Is it significant that many of the benzene workers thought to have developed leukemia as a result of exposure lived not only in the same building but were roommates? Is the parallel between the fall in cancer mortality and the rise of antibiotic use suggestive? It's something to think about anyway.

EPA Reanalyzing Dioxin Toxicity

On June 14, USEPA gave notice of a July 9, 2010 "listening session" related to its external review draft document entitled "EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments." The draft document includes new analyses on potential human effects from exposure to 2, 3, 7, 8 tetrachlorodibenzo-p-dioxin (TCDD). The draft document was also provided to EPA's Science Advisory Board for peer review.

How, and Why, Do Some Bacteria Facilitate Cancer Metastasis?

When you ask a physician or researcher how bacteria cause and/or promote cancer usually the only answer you get is "inflammation" and some hand waiving. It sort of makes sense. Lots of new and different stuff is going on, lots of new and different cells are running all around and lots of old cells are busily dividing and multiplying - surely a recipe for an accident.

But what if the bacteria are actively promoting the metastasis? That's the finding in "Bacteria Peptidoglycan Promoted Breast Cancer Cell Invasiveness and Adhesiveness by Targeting Toll-Like Receptor 2 in the Cancer Cells". Why, in the "what's in it for them" sense, would bacteria promote something that kills their host? Something to ponder over the weekend.

An Unusual Benzene/MDS Opinion

In Quillen v. Safety-Kleen Systems, Inc., 2010 WL 2044508 (E.D.Ky.) the court determined that plaintiff's expert, Dr. George Rogers, could properly attribute a case of myelodysplastic syndrome (MDS) to benzene by doing a differential diagnosis. That some courts have taken to using differential diagnosis to identify the root cause of say splenomegaly rather than to distinguish histoplasmosis induced splenomegaly from Hodgkin's disease induced splenomegaly would likely set many physicians' eyes rolling.  Yet, that's apparently what the 6th Circuit said in Hardyman v. Norfolk & Western Railway Co., 243 F.3d255 (6th Cir. 2001) and thus the thinking by the Quillen court.

The point of doing a differential diagnosis, of course, is to rule out possible causes until just one is left - it's a process of elimination. But just because every other cause of splenomegaly has been ruled out in the case of a male patient that doesn't mean that it makes sense to conclude that the cause must be the remaining possibility - a metastatic ovarian cancer. To be considered for elimination in the first place the putative cause has to be one that makes sense. In Quillen though there was no effort to demonstrate that plaintiff's experience with benzene was the sort that would make benzene a reasonably plausible cause of his MDS.

Finally, please ponder the following. In response to the defendant's objection that plaintiff's expert had not ruled out ionizing radiation  the court wrote: "Defendant points to nothing in the record demonstrating that Quillen was ever exposed to a statistically significant amount of such radiation." Somewhere an epidemiologist just fell out of her chair.

Autism/Vaccine Proponent Andrew Wakefield, Banned from Medicine in Britain

As a follow-up to our post on the death of the vaccine/autism litigation last week, we report the following news: Dr. Andrew Wakefield, the chief proponent of the now discredited junk science behind the MMR vaccine/autism link, has been banned from practicing medicine in his native UK.

Wakefield has moved to Texas and set up an autism clinic.

A brief synopsis of the whole sorry history of the MMR vaccine/autism scare is encapsulated in this prior post and comic strip which is eloquent in its brevity and accuracy.


Final Nail In the Vaccine/Autism Coffin?

The Court of Appeals for the Federal Circuit recently drove what we hope is the last nail in the coffin of the vaccine/autism litigation. Rarely has a toxic tort had the potential to cause so much harm based on such shoddy science. The history of this tort and its shortcomings have been reported in great detail.

In short, the scientific evidence that vaccines cause autism came from a discredited article by Andrew J. Wakefield and two follow-up articles. Dr. Wakefield’s article created a public health crisis with parents, including celebrity parents Jenny McCarthy and Jim Carey, urging parents not to get their children vaccinated. As a result, formerly endemic childhood diseases which had become effectively eradicated in the developed world began to make a reemergence. Wakefield’s article was finally withdrawn from the Lancet earlier this year after 10 of the 12 co-authors disavowed it. Wakefield, himself, refuses to withdraw the article even though it was found that he committed scientific misconduct and lied in the article. The UK’s General Medical counsel’s Fitness to Practice Panel issued a judgment against him for his vaccine/autism paper. Wakefield continues to testify. Others testify based on his work.

Thankfully, the vaccine litigation was consolidated in the federal Vaccine Court pursuant to The Vaccine Act (passed in response to the health scare where the DTP vaccine was accused of causing neurological damage and in response to lawsuits, stopped being manufactured). Plaintiffs in three bellwether cases all failed on causation. The Special Masters wrote massive opinions eviscerating Wakefield and the causation theories of Plaintiffs.

Hopefully parents can now rest assured that vaccines are not a risk for autism. And, they can recognize the far greater risks to their children and society from not vaccinating.

Can't Prove a Negative: Mobile Phones and Brain Cancer

A World Heath Organization (WHO) study on cell phones and brain cancer has been published. It tracked 13,000 cell phone users over a number of years. The study showed no association between brain cancer and cell phone use. Statistically, people who used cell phones had a decreased rate of brain cancer.

Despite this, and despite every prior study showing no statistical evidence of an increased rate of brain cancer in cell phone users, the authors state that “[t]he results really don’t allow us to conclude that there is any risk associated with mobile phone use but it is also premature to say that there is no risk associated with it.”

This is true. It is just about impossible to prove a negative. This has not stopped the authors of the recently released President’s Cancer Panel report from arguing for a “precautionary principle” approach to regulation. Their precautionary principle would have cell phones outlawed until they could be proven safe. Specifically, the panel argues that cell phones should be banned until there is no risk of cancer associated with them. The obvious question, however, is how to prove that there is no risk. Study after study finds no association but cannot prove the negative, an absolutely risk free product. All the freedoms and advances in wireless technology would be banned until a 30-year long term study showed there would be no risk. By 2040, what other life-changing technologies would we have missed?


An Epidemic of Head and Neck Cancer

Cancer of the oropharynx in men is on the rise. Such cancers have traditionally been blamed on smoking and/or drinking so what accounts for its increase in a time of reduced rates of smoking and alcohol abuse? A virus; human papillomavirus (HPV). See "HPV-Associated Head and Neck Cancer: A Virus-Related Cancer Epidemic".

Remember, (1) the focus of this year's World Cancer Day was a call for greater awareness of the contribution of infectious disease to cancer; and, (2) the "age of receding panemics" never really passed - we just stopped looking for them.


Anti-H.pylori Therapy Cures MALT Lymphoma in H.pylori-Negative Patients. Hmmmm

We've defended a few gastric lymphoma cases in which the alleged cause was benzene exposure. The discovery that Helicobacter pylori was was the cause of most instances of the disease made the litigation go away. Nevertheless there have continued to be cases of MALT lymphoma in patients without evidence of H. pylori infection. Could their cancers have been caused by something besides a bacteria?

In "Treatment Outcome of Localized Helicobacter pylori - Negative Low-Grade Gastric MALT Lymphoma" the authors report on what happened when they treated some MALT lymphoma patients who had no evidence of H. pylori infection with anti-H.pylori antibiotics. Complete remission was achieved in each case.

The authors offer the following hypotheses about why giving people a drug to kill a particular strain of bacteria that they don't have that bacteria might nevertheless cure them of lymphoma: (1) a first cousin, H. heilmannii, might actually be the causative organism; (2) unknown bacterial agents susceptible to the antibiotics caused the lymphoma; (3) H. pylori at populations too small to be detected are still enough to cause lymphoma; and, (4) antibiotics eradicate MALT lymphoma not by simply killing H. pylori but rather by altering the resident immune system - resetting the system as it were.

Unless the answer is (3) MALT lymphoma will serve as yet another example of the fact that, save for very rare instances like pleural mesothelioma and erionite, "but for" causal attribution in cancer cases is exceedingly difficult.


But Sometimes Causation is Really, Really, Really Easy

As we wrote yesterday, causal attribution in most toxic tort cases is hard and the discovery that life and many of its diseases are emergent rather than predetermined phenomena has made the exercise even more complex. That said, sometimes causal attribution is easy - as in the cases of falling, being shot or developing mesothelioma after exposure to erionite.

50.5% of all deaths were due to mesothelioma in one village in Turkey and of women who moved from areas without erionite to this same village 69% of all deaths were due to mesothelioma. Read about it in: "Endemic Malignant Mesothelioma: Exposure to Erionite is More Important Than Genetic Factors".

Is there any carcinogen as potent as erionite? What do these numbers suggest about the mode of action of erionite? It sure looks as though the biological insult from erionite is more akin to that of some physical trauma than from some molecular biological disruption as in the case of a genetic mutation.

Causation is Really, Really, Really Hard

Life would be so much simpler if causation were binary - e.g. stay out of the sun and never get melanoma or worship the sun and die young of skin cancer. That way we'd have real choice, the virtuous would be spared and the heedless would be plagued. It doesn't work that way, of course.

Shockingly (or not) most people who sunbathe, drink or smoke don't die of skin cancer, throat cancer or lung cancer. What gives? Maybe the numbers are wrong or maybe the statistics are just some trick of government / industry / academia / nefarious "other". Those are a few of the explanations offered up by the readers of the San Francisco Chronicle in response to its new article: "Vitamin D Levels Dip" in which the claim that sunbathing might be good for you is explored.

That biological cause and effect, even at the level of a single protein, can't be put into simple one-to-one correspondence doesn't just vex bloggers; it is profoundly troubling to researchers and it's prompting many to reexamine views about causality in biological systems that were being investigated decades ago but which fell out of favor in the modern reductionist era.

In "Order Without Design" Alexei Kurakin nicely sums up the evidence for life, and thus diseases of life, being emergent processes unexplainable by reducing the system to its parts and its inputs. Life (and its afflictions) instead seems to be a dynamic process driven essentially by economic competition for energy and materiel at the molecular level. What is the evidence for this claim? One very big piece of it is found in the amazing plasticity of proteins.

We've all been taught that proteins, especially cytokines, work like locks and keys. It's an easy to grasp metaphor and promised easy-ish cures for what ails us. Disease was the product of missing keys or broken locks. Supply the missing key, or one that worked the broken lock, and the door to good health was open again, right? Too often though it turned out that replacement keys didn't work as expected and that broken locks weren't actually broken - they were just performing other functions.

Closer examination revealed that proteins were often found far from where they were thought to do their work and were twisted and folded into completely unexpected shapes. Further investigations revealed that many if not most proteins exist not in some concrete form with concrete functionality but rather in a "disordered" state waiting to be shaped and directed not by some genetic program or external event but rather by the tides of energy and matter within the cell itself. And it is out of the ebb and flow of those tides that the organized activity of the cell emerges.

There's much more in the paper and those which it cites, of course, but for our purposes suffice it to say that the question of causation in biological systems cannot sensibly be asked, as we do in our courts, "Was chemical "X" a producing cause of Plaintiff's cancer?" Perhaps the question should be something more akin to "Given Plaintiff's condition before exposure to chemical "X"  by how much was her risk of cancer increased by that exposure?" But then that doesn't really get it either. Take mesothelioma and amphibole exposure as an example. 

It's commonly said that amphibole exposure is a risk factor for mesothelioma in humans. But if that's the case why didn't the other 95% of the workforce at say the unibestos plant in Tyler, Texas get mesothelioma? Is it that amphibole-induced mesothelioma is a purely stochastic process such that those who developed the disease were just unlucky? Or rather is it the case that causation, in the case of chronic diseases anyway, isn't generalizable? That's the takeaway - there may not be such a thing as what lawyers call "general causation".

Does Shift Work Cause Cancer?

IARC thinks so. Others have recently published papers claiming that breast cancers and melanomas are probably caused by exposure to electric lighting at night. However, a new study published in the American Journal of Epidemiology looked at 73,049 Chinese women and found no association between breast cancer and night-shift work, irrespective of frequency, duration or cumulative shift work. The authors conclude that "it may be premature to consider shift work a cause of cancer."

What if Everything You Knew About the Cause of Cancer Was Wrong?

Back in the day, a doctor from deep East Texas opined as follows about an alleged carcinogen: "It messes with your DNA and everybody knows that if your DNA gets messed up it can lead to cancer." Multimillion dollar verdicts were founded on little more than that sort of speculation.

Yet, what if that which everybody knows about cancer is wrong? The prevailing paradigm, that cancer comes from a single cell that develops a mutation and then grows out of control, is beginning to show a lot of cracks. Why do cancer outbreaks mimic those of pathogenic epidemics? Why would population mixing lead to cancer? Read about it at Carcinogenesis in "Hypothesis: Towards the Origin of Cancer Epidemics and Pathogenesis".


Diagnosing Asbestosis

What is the current state of the art for making an accurate diagnosis of asbestosis? See: "Pathology of Asbestosis - An Update of the Diagnostic Criteria: Report of the Asbestosis Committee of the College of American Pathologists and Pulmonary Pathology Society"



BPA: Hypotheses Begin to be Tested

In "Perinatal Exposure to Bisphenol-A and the Development of Metabolic Syndrome in CD-1 Mice", just published in the journal Endocrinology, researchers tested the claim that exposure to a typical dose of BPA (1ppb via diet) increases the risk of high-fat diet-induced obesity and glucose intolerance. The experimental data did not support the claim. Interestingly, the BPA-fed mice grew a bit quicker early in life but by adulthood were the same size and body composition as the mice not fed BPA.


EPA Goes After BPA

The New York Times reported today that EPA is adding Bisphenol-A (“BPA”) to its list of chemicals of concern. BPA is widely used in certain plastics, notably food packaging and baby bottles. New studies of concentrations of BPA in surface water, ground water and drinking water will be required. In addition, manufacturers using BPA in their products will be required to provide test data to help evaluate effects on growth, reproduction and development in aquatic organisms and wildlife.


"We Make Our Food Very Similar to Cocaine Now" - Gene-Jack Wang M.D.

Sometimes mass tort litigation feels a lot like being in the movie "Groundhog Day". The names and the products may change from day to day but the plaintiffs', the true believers' and the media's overarching narrative is always some aspect of the one refined in the tobacco litigation. One such narrative goes towards abrogating personal responsibility and does so by purporting to show that a product is both irresistibly addictive and insidiously malignant.

Today's vignette is thanks to a (free) paper just published in Nature Neuroscience titled "Dopamine D2 Receptors in Addiction-Like Reward Dysfunction and Compulsive Eating in Obese Rats". In the study being reported eleven rats got their fill of "bacon, sausage, cheesecake, pound cake, frosting and chocolate", eleven others got to pig out on "bacon, sausage ..." but for only one hour per day while nine other rats got nothing but "rat chow". Shockingly, the rats stuck in a cage all day with nothing to do but eat pound cake with frosting put on weight.

Various permutations of the experiment were run including some involving IHC staining with fluorescent proteins so that the now obligatory brilliantly colored photomicrographs could be produced. Some other rats considering pigging out were "punished" with electric foot shocks while yet others had "stimulating" electrodes implanted in their brains and held in place by four stainless steel skull screws.

The pound cake with frosting didn't affect life expectancy since all the rats were sacrificed two weeks after their 40 day food odyssey. However, the researchers found evidence of classic addiction response whereby reward mechanisms (pound cake with frosting makes you happy) were gradually suppressed by the body as it tried to adjust to the good times and maintain homeostasis so that more and more pound cake with frosting was needed to reproduce the initial reward level. The rat chow rats and the one hour per day bingers on the other hand lived out their 54 days in much slimmer bodies and with the normal compliment of dopamine receptors implying that living in a cage and eating rat chow is not excessively rewarding.

The quote above from Gene-Jack Wang, M.D. was found at The Situationist in its write-up of the Nature Neuroscience article. He's also quoted as saying that purified modern food makes people eat "unconsciously" and animals "eat like a drug abuser [uses drugs]". Wang is said to be the chair of the medical department at the U.S. Department of Energy's Brookhaven National Laboratory.


Lies, Damned Lies, and P-Values

In "Odds Are, It's Wrong", Tom Siegfried lays out the argument for the proposition that much of what you read in the scientific literature is wrong because many of the claims being made rely on statistical significance. You see, an impressive sounding statement like "the association between exposure and disease was highly significant (P<0.05)" does NOT mean (a) that there's a 95% chance that the association is causal; (b) that the absence of an association can almost certainly be ruled out; nor does it necessarily mean that (c) the finding is momentous, compelling or even important. It doesn't even say that if the test were to be repeated that its results would likely hold. A P-value, the arbitrary judge of "statistical significance", won't, and can't, have anything to say about the likelihood that a given hypothesis is or is not true.

The fact of the matter is that if you have a bunch of data and can't find at least one statistically significant association it in only proves one thing - that you're not trying hard enough. The magical P-value level of 0.05 is nothing but a trade-off; a balancing act between finding associations that don't exist (false positives) and missing true associations that do (false negatives). As a result, false associations are not only possible, they're guaranteed when you have enough data and slice it enough ways.

Now, lawyers are getting into the act. And while it's bad enough that "[a] lot of scientists don't understand statistics" (Steven Goodman quote from the "Odds Are, It's Wrong" article) it gets awful when lawyers try to deploy statistics to support or rebut claims. Law review articles are littered with claims resting on nothing more than small P-values. Some purport to show that certain appellate courts are biased against accident victims; others that tort reform is good for your health. And hardly a week goes by that I don't see a brief or a pleading asserting that Texas "jurisprudence" requires an epidemiological study with a risk ratio greater than 2 and a P<0.05 before a plaintiff can recover on a toxic tort claim. 

Apparently many lawyers, especially on the defense side, either forgot or never learned that it's easy to gin up false associations that meet the greater than 2 and less than 0.05 test. In fact, that's how most categories of toxic tort claims got started. Enshrining such a test in the law would turn out to be The Full Employment Act for toxic tort lawyers.

Causal inference from epidemiological statistical analysis is a crude method that nevertheless worked well for finding big effects like that of smoking on lung cancer risk and amphibole exposure on mesothelioma risk. On more subtle effects though, at the population level or molecular level, reliance on 20th century methods has produced so much bad science of late (bad only because statistics are routinely misused and abused and not because statistics aren't powerfully effective tools when properly used) that new methods of causal analysis are beginning to replace them. And these tools can answer the question of "how likely is it that drug A caused injury B?"

To see what the future of causal proof in toxic torts will look like read: "An Introduction to Causal Inference" by Judea Pearl.

Occupational Exposure to Endotoxins: A Good Thing?

In the newest edition of the journal Cancer Causes and Control you'll find a paper titled "Endotoxin Exposure and Lung Cancer Risk: A Systematic Review and Meta-Analysis of the Published Literature on Agriculture and Cotton Textile Workers". The authors examined 28 studies of workers occupationally exposed to high levels of endotoxins and their risk of developing lung cancer. Previous studies had suggested acute and chronic lung conditions could be caused by endotoxins.

Interestingly, endotoxin exposure was consistently associated with a large and statistically significant decrease in lung cancer. Furthermore, the protective effect was strengthened as dose was increased.

Also this month, in Cancer Epidemiology, Biomarkers & Prevention, you'll find "Lower Risk of Lung Cancer After Multiple Pneumonia Diagnoses". It turns out that getting pneumonia three or more times is even better than high exposure to endotoxins if you want to avoid lung cancer.

What is it about these biological challenges to the lung that leads to significant anti-lung cancer protective effect? It's anyone's guess but perhaps keeping your immune system tuned up is part of the answer.

No Association Between Industrial-Grade Talc and Mesothelioma

A new review of available toxicological, mineralogical and epidemiological data pertaining to talc mined in northern New York by R T Vanderbilt shows no support for the claim that exposure to it causes mesothelioma. See: "Industrial-Grade Talc Exposure and the Risk of Mesothelioma" just published in Critical Reviews in Toxicology.

No Association Between Paint Fumes in the Home and Fetal Growth

See "Non-Occupational Exposure to Paint Fumes During Pregnancy and Fetal Growth in a General Population"

Though about half of the mothers surveyed said they'd been exposed to paint fumes in the home while they were pregnant the data suggested that the more fumes to which they'd remembered being exposed the lower the risk that their baby would be underweight. What? This study probably has more to say about the use of interview data as a proxy for exposure than it does about the relationship being examined.

Children Spread Disease. Who Knew?

In this recent article in JAMA(2010;303(10):943-950), the authors evaluate the impact of vaccinating children and adolescents on the incidence of influenza among non-vaccinated populations. They conclude that, if you vaccinate your children and teenagers, there is less disease among the rest of the population. Tell us something else that every parent already knew. Now, go wash your hands and come in to dinner.


Coronary Heart Disease: Neither Degenerative Nor Man-Made?

In "On to a Fifth Age? How About We Finish the Second?" we discussed a JAMA editorial wherein Dr. Michael Gaziano asserted we may be entering a fifth age of the so-called epidemiologic transition. These transitions are claimed to be changes in the primary causes of morbidity and mortality and Dr. Gaziano opined that we are moving into an era in which obesity and inactivity will drive preventable illness. We discussed the origin of the idea of epidemiologic transitions and questioned  whether we'd ever finished the second age which would have required the conquest of infectious diseases.

The so-called third age was supposed to be the "age of degenerative and man-made diseases" but it keeps turning out that many illnesses thought to be due to wear and tear, lifestyle or pollutants actually have an infectious disease process at their core. Now there's growing evidence that coronary heart diseases (CHD) may in many cases have more to do with a number of infections, including influenza, than with lifestyle or the environment.

Here's a link to a letter published in the Reflections section of The Lancet: Infectious Diseases that nicely summarizes the pre-1970 thinking that pointed to infections as the cause of CHD, the subsequent predominating narrative of chronic diseases not being caused by infections, and the new evidence that chronic diseases are in fact often caused by previously undetected infectious processes: "Inflammation as the Cause of Coronary Heart Disease". And here's a link to a written debate about "this nascent field associating chronic diseases with infections" from 2002 with the author of the recent Lancet paper cited above: "Debate on the Paper by Maria Ines Reinert Azambuja & Bruce B. Duncan".

Given the enormous renewed interest in infections as a possible cause of chronic illness and the ease with which scientists can now find traces of bacterial, fungal and viral DNA (or RNA) at the scene of the suspected microbial crime it's fair to assume that we'll be seeing many more such stories in the future.

These Genes Determine Your Health: And They're Not Yours

The genes belong to bacteria living in your gut. They, along with their fellow microbes in and on "your" body outnumber human cells 10 to 1. But their genes collectively outnumber yours 150 to 1. These findings are just part of what you'll find in "A Human Gut Microbial Gene Catalogue Established by Metagenomic Sequencing"  published in Nature and free online.

The authors conclude that  this catalogue of bacterial genes found in the human gut "will lead to a much more complete understanding of human biology than the one we presently have." I think it's fair to say that the realization that the microbes we host have so much control over our lives will lead to a revolution in how we think of ourselves and how we prevent, diagnose and treat conditions like obesity, diabetes and cancer.

Alzheimer's: The Result of an Unnoticed, Chronic Low-Grade Infection?

Beta amyloid, aka abeta, builds up dramatically in the brains of patients with Alzheimer's. So, beta amyloid causes Alzheimer's, right? Or has something to do with causing it, right? At least it needs to be eliminated because people who don't have it don't have Alzheimer's so it must be bad somehow, right?

Maybe not. In a new report that demonstrates perfectly two (re-)emerging views about chronic diseases researchers at Massachusetts General Hospital have shown that beta amyloid is a potent antibiotic effective against fungi like Candida albicans and bacteria like Staphylococcus. They go on to hypothesize that far from being bad, beta amyloid may in fact be very good. It may well save you from brain infections that would otherwise kill you at a much younger age. An excellent write up can be found at Bloomberg and the article itself, "The Alzheimer's Disease-Associated Amyloid beta-Protein is an Antimicrobial Peptide", is at Plos One.

Oh, and those two (re-)emerging views about chronic diseases? The first is that too often scientists and physicians fall into the trap of assuming that the arrow of causation runs from biomarker to disease when in fact the body, with millions of years of fine tuning under the hood, has almost certainly some mechanism to deal with the build up of the by-products of its defenses such that fooling with that immune system, given our level of ignorance about how it works, is perilous at best. The second is that microbes, thought to have been essentially conquered 40 years ago, are in fact at the root of many if not most maladies commonly thought to be caused by man. Microbes it turns out have not been asleep over the eons nor even over the last 40 years. Almost weekly as new ways to culture and identify them are developed, new and heretofore unsuspected infections are identified. We're only beginning to understand the nature of the microbes that help us and prey upon us and so for now perhaps it's enough to consider the fact that in our own bodies they outnumber our human cells nine to one.

One last thing, isn't it interesting that many of the drugs currently being tested to determine their anti-aging potential are also potent anti-fungals? Correlation isn't, of course, causation, but it might be worth pondering.


Review Of 2008 Articles On Toxicity Of Metal And Carbon Based Nanomaterials

Since 2007, the results of certain animal studies have fueled speculation that certain nanomaterials may behave in ways suspiciously similar to asbestos. In this article published in the journal Nanotoxicology this month, the authors report on their review of 746 articles published or pre-published in 2008 on the possible health effects of carbon- and metal-based nanomaterials. These particular types of nanomaterials are produced and used worldwide. The authors conclude: “Unfortunately, due to the large variability in materials used and methods used conflicting data are generated hampering the risk assessment.”


World Cancer Day - Focus on the Link Between Infections and Cancer

Tomorrow, February 4, is World Cancer Day and the International Union Against Cancer (UICC) is calling for greater awareness of the contribution of infectious disease to cancer cases around the world. "Cancer can be prevented too" is the theme of the effort. According to the press release the campaign is backed by a new scientific report: Protection Against Cancer Causing Infections which focuses on the nine known infections that can lead to cancer.

There's already a highly effective vaccine against human papillomavirus that prevents cervical cancer, a dreadful disease that took the life of one of my law school classmates within a year of her graduation, though it's still not widely given for a variety of reasons associated with culture and values. There's also a vaccine to protect against hepatitis B virus which causes a staggering number of cases of liver cancer worldwide yet it too is grossly underutilized. For more on World Cancer Day 2010 try these links: UICC World Cancer Campaign, World Health Organization,  European Hospital and this book: Infections Causing Human Cancer 

On to a Fifth Age? How About We Finish the Second?

In a 1971 paper that profoundly influenced how scientists and policy makers approached public health issues Abdel Omran set out his theory of "The Epidemiologic Transition". He hypothesized that societies went through three different ages, or phases, that defined their experience with regard to mortality and life expectancy. In the first, the "age of pestilence and famine", life expectancy is low and episodes of widespread death are common. In the second, the "age of receding pandemics", infectious diseases are overcome and life expectancy increases dramatically. Finally, in the third, the "age of degenerative and man-made diseases", diseases of aging and self-inflicted suffering becomes the predominant determinant of mortality. Eventually others, noting the dramatic increase in life expectancy due to the rapid decline in deaths due to heart attack and stroke, posited a fourth age; essentially the same as the original third age but with cardiovascular disease removed from the "degenerative disease" category.

Now in an editorial in this month's JAMA  Dr. Michael Gaziano asserts that we may be entering a fifth phase, or age, of the epidemiologic transition. We are now, he writes, entering the "age of obesity and inactivity" in which ailments due to gluttony and sloth predominate on death certificates. The editorial references two new articles in the same issue purporting to show Americans are fat and getting fatter; especially the children.

But wait a minute. The age of man-made diseases barely materialized. Certainly there have been many many cases of people suffering terribly as a result of some man-made health hazard. Look no further than the cases of mesothelioma among the men who served aboard amosite laden Navy ships. And smoking continues to exact its terrible toll. Yet if you throw all the deaths due to occupational diseases and every last lung cancer/COPD death into the same category you can't get to 10% using worst case estimates. More sober estimates put the percentage of deaths due to man-made diseases at considerably less than one. Nevertheless, this powerful meme - that most of our woes are self-inflicted and due to some failure to live in a natural way - still propels not only mass tort litigation but also much scientific and political thinking.

However, there's more than just AIDS to demonstrate that we never really saw the "disappearance" of infectious diseases. Go to www.pubmed.gov/ and do some searches on helicobacter pylori and humanpapilloma virus and you'll see just how many cancers are now being attributed to just these two organisms. Investigate mollicutes and you'll find that all sorts of microbes are suddenly being found associated with disease and they're only now being found because the technology to identify them is only now being refined.

Finally, remember to read the fascinating journey of Barry Marshall and Robin Warren from authors of an abstract rejected as one of the year's worst to winners of the Nobel Prize in Medicine for the very same work. In the end, the view, supported by the work of one of the world's preeminent public health researchers, that peptic ulcers were caused by that most modern of man-made insults, stress, only gave way to the understanding that the cause was in fact a bacteria when the evidence was irrefutable.

Does Education Cause Autism?

If a strong and consistent association between autism and a single chemical or vaccine were found in ten separate clusters around California you'd expect to read about it; and you'd expect the researchers to infer that the chemical or vaccine was, in fact, the cause of autism. But what if the only strong and consistent association wasn't between autism and exposure to some substance but was instead between autism and something complex, like "high parental education"? Well, you'd probably expect a lot of frustration; and you'd be pretty sure autism wouldn't be laid at the feet of higher education.

So what should we make of "Geographic Distribution of Autism in California: a Retrospective Birth Cohort Analysis" ? Why would the children of parents with college degrees be at a 400% increased risk of autism? Why aren't chemicals to blame?

The authors concede in interviews with Scientific American that the results tend to undermine claims that industrial pollution causes autism. Yet rather than explore the possible reasons why college-educated parents might be significantly more likely to have autistic children the authors speculate that their results may be biased. Perhaps, they suggest, the less educated aren't educated enough to take their autistic children in to be diagnosed. Or maybe, they wondered, the educated are much more likely to use some unknown household chemical which does, in fact, cause autism. Scientific American hastens to add that there's an unpublished study that shows a doubling of the risk of autism in mothers who use pet flea shampoos.

But why point to a much smaller effect allegedly to be found in an unpublished paper when a much larger effect published in a peer reviewed journal is in front of you?

First, people tend to prefer simple answers with readily implemented solutions, the blame for which, and the costs of which, get imposed on someone else. 

Second, epidemiology, at least as practised in the West, tends to be reductionist. The triumph of linking tobacco to smoking led many epidemiologists to believe, or at least to want to believe, that indeed there are simple solutions to big problems and that silver bullets are out there just waiting to be found.

Finally, it's becoming increasingly clear that all sorts of ailments, from cancer to obesity, are highly complex and result in large part, from lifestyle, cultural and economic choices. Take breast cancer for example. One of the very best ways to reduce the risk of breast cancer is for a woman to bear children and to begin doing so in her late teens or early 20s. Yet no one wants to say that putting off children to get a degree and start a career is a cause of breast cancer.

And so, for now, the search is still on for the usual suspects.



It's National Radon Action Month

The EPA says that radon, a colorless, odorless gas, is responsible for 20,000 American lung cancer deaths annually. Because January is the best time to test for the gas it has been designated "National Radon Action Month". You can read the EPA's press release here and find its radon information and testing site here.


Bernie Goldstein States the Case for Benzene-Induced Lymphocytic Malignancies

Arguing that the target of benzene is a multipotent stem cell capable, when carrying the sort of mutations thought to be caused by benzene, of producing both myeloid and lymphoid malignancies, and that new classification systems are blurring the lines between previously thought distinct diseases, Goldstein's article concludes that  there is now sufficient evidence to attribute lymphomas to benzene exposure.

That's the same argument made years ago in benzene litigation, though with different references. So what should we make of the intervening science? What about alkylating chemotherapeutics that produced similar genotoxicity and t-AMLs but not lymphomas? What about the epi studies that show increased risk for AML but not lymphomas?

In many respects last year's benzene conference in Munich served mainly to demonstrate how little is known about leukemogenesis and how staggeringly complex is the causal web that leads to lymphoproliferative malignancies.


Don't Pitch the Water Softener

Have you been worrying that your water softener is significantly increasing your risk of dying from a heart attack? I didn't think so. But just because you haven't been feeling vulnerable around your water softener doesn't mean the WHO hasn't been fretting for you.

Thanks to epidemiological studies going back a decade or more (e.g. "Magnesium and Calcium in Drinking Water and Death from Acute Myocardial Infarction in Women") a worry arose that we were killing ourselves by eliminating the minerals naturally found in most drinking water. Yet subsequent studies have failed to confirm the finding including the just published "Effect of water hardness on cardiovascular mortality: an ecological time series approach". So what gives?

Well, what gives is that most of what gets published in peer reviewed journals is probably false; and when it comes to causal inferences drawn from epidemiological studies "the apparently indiscriminate indentification of particular aspects of daily life as dangerous to health" is, as witty programmers say, a feature, not a bug.


Sorting out Cause and Effect

We live in strange times. Though whole genomes, of an individual as well as a malignant progenitor stem cell responsible for AML, have been sequenced and though modern medical diagnositic machinery and implantable devices increasingly look like things that Gene Roddenberry would have rejected as too futuristic, the fact is that scientists know very little about how our bodies work. Take C-reactive protein for example.

Let's say you decide to study heart attacks by measuring the levels of certain proteins in the blood and then later checking to see if there's been an association between the levels measured and an adverse event like a subsequent heart attack. Bingo! People with high levels of C-reactive protein have a high risk of heart attack. Wow!

Ok, let's assume the association is strong and consistent so that the finding probably reveals something about how the body works. But what?

Too often these sorts of findings have precipitated a Whac-A-Mole reaction from the medical community whereby drugs are promptly designed and thereafter prescribed to begin whacking the protein back down to "normal" levels. Causes precede effects, right? So this must be a cause, right?

Well, what if C-reactive protein is actually part of the body's response to accumulating plaque and inflammation? What if its level correlates with risk because it's part of the body's attempt to fix whatever is broken? What if it's not a cause of heart disease but is really an effect of heart disease? Reuters is reporting on a new analysis published in Lancet indicating that at least in the case of C-reactive protein earlier assumptions had indeed confused cause and effect. The authors conclude that it is unlikely that C-reactive protein is a cause of heart disease.


The Global Burden of Cancer

The American Cancer Society has published "The Global Burden of Cancer: Priorities for Prevention" this month in the journal Carcinogenesis. While tobacco use is discussed first and diet, obesity and lack of physical activity second, it's cancers related to chronic infections that gets the most coverage. "Persistent infection with various microbial organisms accounts for about 18 percent of cancers worldwide." Preventive approaches including the development of vaccines and lifestyle modifications are discussed in detail.


Interstitial Fibrosis Among Farmworkers Due to Agricultural Dust

A series of lungs from California farm workers who died in accidents or from illness were examined for evidence of pneumoconiosis.   Despite being young these Hispanic farm workers had significantly more evidence of interstitial fibrosis than did non-farm workers.  A variety of analytical techniques demonstrated that those with pneumoconiosis had significant exposure to crystalline silica and aluminum silicate.

The article is "Pneumoconiosis from agricultural dust exposure among young California farmworkers".  As for the source of mineral dust exposure the authors note "most agricultural soils are composed largely of silicate materials (e.g., feldspars, mica, clay minerals) and crystalline silica (CSi) (quartz)".

New NHL Solvent Study

An important new study was recently released indicating that there is no causal association between ambient exposure to either solvents or benzene and the development of non-Hodgkin’s lymphoma (NHL). The report adds to a growing body of literature demonstrating no discernable risk for typical community benzene exposures.

Outbreak of Neurological Disorder Among Slaughterhouse Workers

Researchers from Mayo Clinic have published "An outbreak of neurological autoimmunity with polyradiculoneuropathy in workers exposed to aerosolised porcine neural tissue: a descriptive study" in The Lancet Neurology. Workers exposed to aerosolised pig brains (ugh) developed polyradiculoneuropathy - a painful and disabling autoimmune illness. Of the 24 workers affected 17 required immunomodulatory therapies, six improved after exposure ceased and one was lost to follow up.


Could Mammograms be the Cause of Some Breast Cancers?

In the on-going debate over when to start getting mammograms and how often to have them the assumption by many of those supporting an "early and often" policy has been that false positives lead to little more than worry and maybe a needle biopsy. Now The New York Times is reporting on a study that appears to demonstrate that young women already at heightened risk of breast cancer double that risk if they start getting mammograms early.

Five prior studies of women carrying a mutation that is thought to put them at increased risk of breast cancer were examined to determine whether low dose radiation exposures from mammograms further increased that risk. The results, which were statistically significant at a 95% confidence interval, showed that women carrying the breast cancer gene who started mammography early in life or who had five or more mammograms were more than twice as likely to develop breast cancer as women with the breast cancer gene who started getting mammogramps later and had fewer of them.

The working hypothesis is that mammography actually causes many cases of breast cancer in susceptible women. An alternate explanation, I suppose, is that about half of all breast cancers detected by mammography either aren't cancerous or were never going to develop into a malignancy.

Hopefully doctors are finally beginning to discuss the large and unsettling uncertainties associated with the diagnosis, treatment and causal attribution of poorly understood diseases like cancer.

A Biomarker of Past Benzene Exposure?

In their paper "Benzene-induced mutational pattern in the tumour suppressor gene TP53 analysed by use of a functional assay, the functional analysis of separated alleles in yeast, in human lung cells" Billet et al hypothesize that benzene-induced leukemia is the result of one or more mutations in the tumor suppressor gene known as TP53. They then report on their efforts to identify mutations in TP53 caused by benzene or its metabolites. It turns out that of the mutations linked to benzene exposure it is those in which guanine is substituted for adenine (A>G) that produce a pattern similar to that seen in benzene-induced acute myelogenous leukemia.

The authors conclude by suggesting that such an A>G transition could be "a fingerprint of benzene" that might help identify cases of AML produced by very low levels of past benzene exposure.

Parkinson's: A Microbial Etiology?

Articles published in the last several months raise the question whether microbes found in the gut are responsible for Parkinson's disease.  In September researchers published an article titled "The Second Brain and Parkinson's disease" in which they reviewed and elaborated on emerging evidence that the enteric nervous system and the microbes that in part constitute it may, be responsible for precipitating Parkinson's disease.   Another group published "Autoimmune Disease and risk for Parkinson disease" in which they failed to find support for the hypothesis that Parkinson's is an autoimmune disorder.  Most recently in Medical Hypotheses Mark Lyte's "The Microbial Organ in the Gut as a Driver of Homeostatsis and Disease" speculates that the microbes living in our guts along with the enteric nervous system form a sort of organism within an organism that when disrupted can lead to diseases such as Parkinson's.  For more on this unfolding understanding of the role of these microorganisms in our lives see "They Are What You Eat".


Is Non-Small Cell Lung Cancer Caused by the Measles Virus?

Why is the rate of lung cancer among nonsmokers increasing? In this paper published in Experimental Lung Research the authors not only found measles virus antigens in 83% of non-small cell lung cancer cases, they found that infection with the virus resulted in an excess of a protein typically seen in excess among lung cancer patients.

Pericardial Mesothelioma Following Radiation Treatment

Here's a case report of pericardial mesothelioma arising twenty-four years after the patient was treated with radiation therapy to the mediastinum for nodular sclerosing Hodgkin's disease.

Two Weeks to Copenhagen

In two weeks, representatives from 192 countries will assemble in Copenhagen for the purpose of setting global limits on carbon emissions. COP15, the official name of the climate change summit, referencing the 15th Conference of the Parties under the United Nations Framework Convention on Climate Change (UNFCCC), consists of environmental ministers who meet annually. The goal of the Copenhagen summit is “to secure binding emissions targets and overcome the division between the developed and developing world.”  Apparently, despite high hopes among proponents, it appears unlikely that a deal will be reached this year.

World leaders have confirmed that time has run out to secure a legally binding agreement at the COP15.  However, the United States and Britain hope to at least hammer out an outline of  the commitments to be put in place rather than postpone the formulation of a plan for an entire year.

So what's behind the delay?  Certainly the global economic turmoil makes it difficult for politicians to agree to changes that would at least in the short term cause even further job dislocations.  More significant perhaps is an apparent waning of public interest in the issue of global warming/climate change.

Recent polling has shown a marked decrease in both the belief that climate change is occurring and that such change is due to human agency.   What's behind this significant change in public opinion?  Over at Yale Environment 360 you'll find an excellent article addressing the concern that years of increasingly dire climate predictions have resulted not in more widespread and more confidently held belief in human-caused climate change but rather "apocalypse fatigue".


They Are What You Eat

We've written before about the dawning realization that the microbes that live in and on us can have a surprising degree of control over our lives. Today we learn that what we eat may control which microbes we host and whether we get fat or stay lean.

In a news release from Washington University titled "Junk food binge alters community of microbes in the gut in less than a day" researchers report that high fat / high sugar diets shift the distribution of bacteria in the intestines towards those bacteria which are exceedingly efficient at extracting calories from food. These super efficient microbes, once transplanted, could then cause weight gain and obesity even in mice fed a low-fat, plant-based diet. The shift towards the super efficient microbes occurred just 18 to 20 hours after the consumption of fatty/sugary foods. 

Finally, gut microbes were demonstrated to be capable of being passed from mother to offspring.

Continue Reading...

Asbestos Fiber Dimensions and Lung Cancer Mortality

A study published last week in Occupational and Environmental Medicine estimated exposures to asbestos fibers of specific sizes of workers exposed to chrysotile using data from transmission electron microscopy (TEM) and investigated the extent to which the risk of lung cancer varies with fiber length and diameter. The study used a cohort of 3803 workers that were employed from January of 1950 and December of 1973 in manufacturing asbestos textile products. Workers’ exposures to asbestos fibers were estimated from work histories and over 3500 industrial hygiene measurements.

Fiber length and diameter were significantly associated with an increasing risk of lung cancer. Exposures to longer and thinner fibers tended to be most strongly associated with lung cancer. The results supported the investigators hypothesis that the risk of lung cancer among workers exposed to chrysotile asbestos increases with exposure to longer fibers.

A New Study on Bisphenol A and Funding for Several More

In a study just published in the Oxford Journal of Toxicological Sciences the authors report that  bisphenol A (BPA) produced no sexual developmental disorders in the laboratory animals  tested.  Pregnant rats were exposed to very low to low doses of BPA and their offspring were studied for any signs of sex morphology disruptions.  The study was funded and conducted by Reproductive Toxicology Branch of the EPA.

Interestingly, ethinyl estradiol on the other hand even at very low doses produced numerous reproductive morphological disruptions.  Ethinyl estradiol is a form of estrogen used in almost all modern formulations of the Pill.

The National Institute of Environmental Health Sciences has announced a $30 million, two-year research effort to study the health effects of exposure to bisphenol A (BPA).  The funds for this effort were appropriated to the NIEHS as part of the American Recovery and Reinvestment Act.
BPA is an organic compound that is used in the production of polycarbonate plastics and epoxy resins. According to NIEHS’ press release in “2008, NTP [National Toxicology Program] and NIEHS concluded that there is evidence from animal studies that BPA may be causing adverse effects.” The press release continues that the “innovative two-year grants provided through the Recovery Act will support human and animal studies that address many of the research gaps identified by expert scientific panels, and provide a better understanding of how this chemical may impact human health.”

Dihydrogen Monoxide - Another Dose Response Toxin

The maxim “the dose makes the poison” is regularly offered by defendants in toxic tort cases as a premise for the assertion that a particular dose was too small to have been toxic. To demonstrate the concept examples of toxicity due even to essential substances like water are deployed. I’ve done it myself and the retort from plaintiff’s counsel has been invariably mocking. Here are sixteen million reasons why they should reconsider.


Bayesian Trials 77030

John Cook at The Endeavor posted this comment by Mithat Gönen of Memorial Sloan-Kettering Cancer Center about a recent paper concerning Bayesian clinical drug trials of chemotherapeutics.

"While there are certainly some at other centers, the bulk of applied Bayesian clinical trial design in this country is largely confined to a single zip code."

That zip code is 77030 and it’s the zip code for M.D. Anderson Cancer Center. Here’s a great article about M.D. Anderson just published in the New York Times by Gina Kolata.

Bayesian decision-making approaches are proving their worth every day in a wide variety of fields and more than a few courts are starting to grasp and apply probabilistic decision rules. Expect to see more and more Bayes decision theory as courts take an increasingly modern approach to the question of causal inference in mass tort cases.

Coal Ash is Dirty Stuff, But is it Hazardous?

This question has been posed by coal ash’s recent notoriety, and the answer is without consensus. European scientists recently published a paper aimed at determining the levels of mercury in coal ash (one of coal's more dangerous components) and its potential to leach into the surrounding environment. The researchers concluded that concentrations of mercury or leaching values were not so high as to justify considering coal ash a hazardous waste by European standards. (The EPA has made a similar determination but it is being reviewed.)

Such findings, while restricted to mercury, seem to take the fire out of recent lawsuits filed by individuals affected by coal ash spills and/or disposal claiming coal ash mercury and other components are leaching into water sources at dangerous levels. While mercury, arsenic, lead and other compounds are undeniably harmful at certain exposure levels their concentration and propensity to leach are not so clear. Thus, the question of coal ash harmfulness is subject to debate and will be studied in greater detail by courts and administrative agencies grappling with this issue.

What Role Does Immunosuppresion Play in the Pathogenesis of Mesothelioma?

Although the precise mechansim for mesothioma is currently unknown, one study has postulated that immunosupression plays a role in the pathogenesis of this cancer. Mesothelioma in an HIV/AIDS patient without history of asbestos exposure: possible role for immunosuppression in mesothelioma: a case report, involved the study was of 41-year-old man who had asthma, HIV with progression to AIDS in the past 3 years, and a 20-pack year smoking history, was diagnosed with malignant mesothelioma.  This individual had no occupational history of asbestos exposure but did have a brief history of assisting in the demolition of a house over an 8-hour period a year before his diagnosis but it was unknown if he was exposed to asbestos during that work.

The authors of the study noted that the polyoma virus SV-40 has been implicated as a participant in some cases of mesothelioma. Studies have postulated that since the virus inactivates anti-tumor genes such as retinoblastoma, it promotes immunosuppression that may lead to enhanced susceptibility to mesothelioma. Similar to SV-40 virus, HIV is also an oncovirus and therefore capable of inducing cancer. Because HIV suppresses the immune system the authors think that HIV increases the susceptible to mesothelioma.

The authors also noted that transplant patients are immunosuppressed due to administration of drugs to prevent transplant organ rejection and elderly patients undergo physiologic immunosenescence which is characterized by reduced immune responses. Mesothelioma has been reported in transplant patients, without notable asbestos exposure, and mesotheliomas are classically reported in elderly patients.

The study notes that mesothelioma may be more prevalent in SV-40 virus-infected patients, HIV/AIDS patients, organ transplant patients, and elderly patients, than in the general population. The study concludes the development of mesothelioma in patients with HIV/AIDS, SV-40 infection, organ transplant, or advanced age suggests that chronic immunosuppression enhances susceptibility to mesothelioma.

COPD is an Independent Risk Factor for Cancer

After adjusting for smoking chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema were associated with a doubling of the risk for lung cancer in this just published paper.  It's part of the ongoing Environment and Genetics in Lung Cancer Etiology (EAGLE) study.

Noting that a family history of chronic bronchitis and emphysema alone have been associated with lung cancer, that COPD has been associated with lung cancer in never-smokers and that COPD is thought to be responsible for 10% of all lung cancers, the authors concluded that these findings support the hypothesis that COPD alone causes lung cancer and they further conjectured that chronic inflammation is the essential mechanism in COPD/emphysema-induced lung cancer.

Why are Mesothelioma Rates Still Rising in Alberta?

The incidence rate for mesothelioma continues to rise in Alberta, Canada. This paper just published in Chronic Diseases in Canada reports a continuing and significant increase in reported cases of mesotheliomas among male Albertans and projects that the incidence of the disease may not peak for another 10 years.

An interesting issue touched upon but not worked out is the impact on current projections of past misdiagnoses. Think about what it would mean for these projections if past less refined diagnostic procedures understated the number of cases of mesothelioma; then think about what it would mean if reported cases of mesothelioma in the 1960s and 1970s were overstated.

Causation is Hard

What does it mean when an increase in cancer coincides with an increase in the ability to detect it? Nothing really, because correlation isn’t necessarily causation? Or something, because the new diagnostic technique has biased the data? Specifically, are doctors finding more cases of melanoma nowadays because they’re looking harder or are they finding more cases of melanoma because something else, maybe increased UV radiation, is causing more people to get it? Those are the questions raised by this New York Times article. Something similar happened with prostate cancer and something similar will likely happen in the future once methods of detecting cancers like mesothelioma and leukemia very early in the disease process are developed.

A Cup of Bifidobacterium Animalis Strain DN-173 010, Please

If you watch TV you’ll have noticed celebrities eager to tell you about their “digestive health”. They attribute their well being to regularity and their regularity to eating probiotics, which are live bacteria. The NYTimes also noticed and reported on the issue today. Especially of note to lawyers is the discussion of the $35 million Dannon, maker of probiotic product Activia, has agreed to pay to settle claims of mislabeling and deceptive marketing.

Interestingly, Dannon has agreed to “increase the visibility of the scientific names of the unique strains of probiotics that are in each of these products”. Pity the poor consumer who has enough trouble understanding the nutritional data already on food products – “hmmm, should I buy the yogurt with streptococcus thermophilus, lactobacillus acidophilus and a generic bifidobacterium or the one with just bifidobacterium regluaris?”

Then there’s the law of unintended consequences. The idea that certain strains of bacteria have been essentially domesticated and can be turned loose in the gut to work their magic without fear that they might mutate or disrupt an already balanced system seems overly hopeful. While the milk intolerant have been happily ingesting lactobacillus acidophilus for years and research on certain species of lactobacillus seems to support the theory that these “good” bacteria wage war in your guts against “bad” cancer-causing bacteria both directly and indirectly (e.g. by inducing intestinal epithelial cells to shore up their defenses) one wonders how long it will be before a good strain goes bad, a good strain is unmasked as a double agent or a good strain is demonstrated to have a dark side.

Specific Causation

I was part of a panel discussion last week in San Francisco about what we in the law call "specific causation" - essentially the determination, in an individual case of causal attribution, when the disease in question has been associated with certain risk factors in the general population.  It is, I think, a distinction without a difference but until courts move past 20th century science (epidemiology) and on to 21st century science (molecular biology) it's one we'll have to talk about.  Here's my PowerPoint from the seminar.


Is Soda Raising Blood Pressure in Middle-Aged Men?

Diets high in foods with large amounts of fructose sugar such as sweetened soft drinks increased blood pressure in men, according to a study presented September 23rd that also found that a drug for gout blocked the effect. Most sugar consumption in the U.S. comes from sweetened drinks and foods high in sugar or high fructose corn syrup.  Fructose is the only common sugar known to increase uric acid levels. 

Men in the study who ate a high-fructose diet had their blood pressure rise about 5 percent after two weeks, while those who also were given a gout treatment increased less than 1 percent. Eating great amounts of fructose without the treatment also raised the risk of developing metabolic syndrome, a risk factor associated with the development of heart disease and diabetes.  The gout treatment lowered the body’s uric acid that is linked at elevated levels to high blood pressure, diabetes and heart disease.  So, it’s possible that lowering uric acid levels could become a routine practice in the future, much like lowering cholesterol.

My blood pressure was perfect until middle age when it ticked up a bit and I've not had a sugary soda in many years. The same is true for many men. Thus, I'm betting on correlation rather than causation on this one. Well, correlation and a statin that is ...

The Causes of Autism

Here's a paper that reviews current knowledge regarding the causes of autism. Note the concerns about Vitamin D deficiency. Could it be that decades of sun-o-phobia has led to more than just increases in rickets and a host of cancers?

Every Puff You Take

What is it in cigarette smoke that causes lung cancer? Tar? PNAHs? Exotic isotopes? What about bacteria and fungi? What if they're in part responsible for chronic inflammation associated with lung cancer? It turns out that when you inhale cigarette smoke you invite into your lungs a swarm of nasty germs. Here's a new article that'll introduce you to the issue and lay out the evidence.

Wouldn't it be interesting if there were similar microbes living in and on asbestos fibers? Actually ....

The 411 On An Old Health Scare Revived by Congress

Senator Tom Harkin (D-IA), the new head of the Senate Committee on Health, Education, Labor and Pensions promised on Monday to probe deeply into any potential links between cell phone use and cancer. This issue has been extensively studied, particularly in Scandinavian countries where cell phone manufacturers such as Nokia and Ericson are headquartered. Each study to date has found no statistically significant association between cell phone use and cancer, including brain cancer.

However, there are still some who attribute brain cancer to cell phones on the theory that radio waves, a form of radiation, damage brain cells. The debate comes on the heels of the 1980's and 1990's controversy regarding the potential adverse health effects of electromagnetic fields EMFs emanating from power lines. While studies cleared EMFs they implicated population mixing likely via some sub-clinical infection as a cause of cancer in children. More on population mixing to come.

Sugar Pills More Potent Than Ever

Wired has a new article about the placebo effect and evidence that placebos are becoming more increasingly more potent.

Years ago I was thinking about going to medical school and so hung on every word from a friend's father when he talked about what he did for a living. I remembered being fascinated by his stories about sugar pills and the patients to whom he prescribed them. He said that he'd learned years before that for some patients, the ones without any objective signs of treatable illness, he did his best work by being part priest and part witch doctor.

He'd listen to their stories, affirm their suffering, advise them to live better, forgive them their faults and prescribe powerful new magic - "penta-methyl-tri-something-or-another-cis-this-and-that". And it worked. He and his pharmacist friend had to be creative though as patients would compare pills and often return to demand stronger magic citing a neighbor's far milder symptoms. So they wound up having a number of different sugar pills in varying shapes and sizes. I don't recall him saying much about color other than that one lady, upon discovering that she'd been prescribed a very large red and white pill, returned to the office to say that she wasn't nearly as sick as the doctor apparently thought she was.

So what does this have to do with mass torts? Well, particularly in the realm of adverse effects from the use of psychotropic drugs, there's a huge risk of (or opportunity for) getting the causation arrow pointed in the wrong direction especially when so little is known about the causes of mental and emotional disorders and the mechanisms by which they are alleviated. After all, trial lawyers thrive in conditions of uncertainty.

Diagnosing Mesothelioma

Distinguishing a mesothelioma from a lung adenocarcinoma is critical in asbestos malignancies. Over time, diagnoses made on the basis of morphology and the presence of asbestos bodies gave way to immunohistochemistry. Immunohistochemical staining panels keep changing and debates often rage over whether say a positive calretinen, etc. and negative CEA, etc. is enough or whether they merely show for example an adenoma of mesothelial origin. Now there's a new paper out discussing the use of epigenetic (your genes aren't so deterministic after all) profiles. Its title is "Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles" and you can buy a copy of it there.

Of course all these new methodologies raise the obvious question of "What happens when you try to draw causal inferences about a case diagnosed today from epidemiological research conducted at a time long before these diagnostic techniques existed?" Will these then be, at least with regard to the litigation, distinctions without a difference?