Discretizations
Pro/Pre/Pharma-biotics: from skepticism to conversion.
Our modern comforts and conveniences also provide significant health benefits.
If there are zombie ants and zombie mice why can't there be ....?
Discretizations
Would-be Technocrats: don't forget sovereign immunity!
Ovarian cancer and asbestos: causation or misdiagnosis?
Selenium deficiency may enable food-borne bacteria.
Genetic determinism takes hit after hit. (h/t MarginalRevolution)
The more modern type of drug designer says "I don't see the use of this molecule in the body; let us clear it away". h/t Megan McArdle for the idea
Curcumin Against Mesothelioma
For decades researchers have been trying potential chemopreventives on members of the Tyler Asbestos Workers cohort; so far without success. Nether beta-carotene, diet nor vitamins have held off the ravages of cancer inflicted by these men's work at the Unibestos facility in Tyler, TX where amosite insulation for nuclear reactors aboard submarines and aircraft carriers was made in the 1960s.
The idea has been to find something with antioxidant properties that might protect workers from the slowly dissolving amphibole fibers in their lungs that are thought to continuously produce free radicals. So far, no luck. But here's a new study from Michigan suggesting that a potent anti-cancer supplement, curcumin, may in fact restart the body's defense mechanisms against malignant pleural mesothelioma (MPM): "Curcumin Suppresses Growth of Mesothelioma Cells In Vitro and In Vivo, in Part, by Stimulating Apoptosis".
Curcumin, like rapamycin, is a very big deal these days. Drop either word into the search window at www.pubmed.gov and you'll see what I mean. After so many false dawns in the war against cancer it's hard not to assume that this isn't another one. Yet somehow, for these two antibiotics, the evidence has piled up to a point where many are starting to think they see some light on the horizon.
Stray Thought: Cancer Fighting Genes As The Targets of Virulence Factors
Some bacteria produce toxins, others hijack cells from the host and drive them around the body to more hospitable climes, yet others make chemical signals that disrupt host immune defenses. But why would bacteria impair tumor suppressor genes? To prevent apoptosis in damaged or infected cells? Maybe, but how about in order to propel the infection behind a vanguard of invasive cancer cells? Don't know but the evidence for p53 modification by h. pylori can be found (free) in "Helicobacter Pylori Cytotoxin-Associated Gene A (CagA) Subverts the Apoptosis-Stimulating Protein of p53 (ASPP2) Tumor Suppressor Pathway of the Host".
The Linear No Threshold Hypothesis: Battling Risks Already Below Background
If the (hypothetical) risk posed by radiation from drinking water is already less than the (hypothetical) risk posed by radiation exposure from the earth's crust, cosmic rays, etc does it make any sense to spend a lot of time and money worrying about it? Only if you're hoping to gain power or money by leading to safety a "populace alarmed ... by an endless series of hobgoblins ..." And when it comes to instigating and propagating public health panics two things work best when conjuring hobgoblins: 1) recasting one side of a normal distribution of disease into a "disease cluster"; and, 2) the linear no threshold (LNT) hypothesis.
As we recently noted, there's a bill in Congress that rejects (or perhaps implicitly repeals) the stochastic nature of biochemistry and aims for a future in which every community has either average or above average health outcomes. The bill is a response to the fact that none of the hundreds of cancer cluster investigations, conducted at enormous expense, have produced evidence to support the charges brought against the various industrial chemical hobgoblins claimed to have been responsible. About the only cluster to actually be a non-random event, that of childhood leukemia in Fallon, NV, turned out to be due to a virus. Outraged activists are lobbying hard to ensure that nothing other than putatively man-made causes can be investigated in the future.
A similar codification of the LNT hypothesis may be needed to rescue it from obsolescence. Not only is the hypothesis wholly evidence-free, there's sound evidence to support the claim that in the case of radiation low levels cause adaptive responses that make you less likely to develop cancer. An excellent summary of the evidence against LNT and for adaptation is available free online in "Human Health and the Biological Effects of Tritium in Drinking Water: Prudent Policy Through Science - Addressing the ODWAC New Recommendation". It's a discussion about whether or not people ought to worry about tritium in drinking water that produces less radiation than the ground on which we walk and the buildings in which we live. The answer is "no". To paraphrase one of my son's favorite Chuck Norris jokes (don't know how or why these suddenly became popular) 'before getting in bed, hobgoblins check their closets for Canadian health scientists'.
The Differential-Diagnosis "Methodology"
The case of Pluck v. BP Oil Pipeline Company, decided last week by the U.S. Sixth Circuit, turned on whether the opinions of plaintiffs' expert were properly excluded as unreliable and on whether his attempt to salvage them, by subsequently filing a supplemental report stating that upon using the court-approved "differential-diagnosis methodology" the identical evidence-free opinions had (not surprisingly) been reached, was timely. The court answered "yes" and "no", respectively.
Along the way to reaching its decision the court restated its view of the soundness of the differential-diagnosis methodology in deciding the cause of a individual's illness. Lots of courts have been saying the same thing of late. But all they're really saying is that using a decision tree to make a decision is OK. That's like saying that using a digital calculator to calculate the length of the hypotenuse of a right triangle is OK. It doesn't, however, say anything about about whether the data used was accurate nor even about whether the determinative quantities had been measured in the first place.
When we think about differential diagnosis we ought to be thinking of something like this excellent example from Baylor College of Medicine's Radiology Club. Working from a variety of well established causes of a liver mass and precisely measured tests for the presence of each the physicians were able to rule in cholangiocarcinoma while methodically ruling out a variety of other potential causes. We'll save for another day the question of whether or not such a methodology was ever intended to, or is any more capable than cast dice or chicken entrails of, identifying heretofore unrecognized causes of a particular illness a la Milward.
Instead, here's what can happen when a court is satisfied with the utterance of the magic phrase "I used the differential-diagnosis method" and decides it's up to the jury to determine whether the expert's rulings-in and rulings-out are sound. We'll change the facts to those of a well-known example to protect the innocent and to keep us out of trouble with a certain court.
Consider the following, modified from "Judgment Under Uncertainty: Heuristics and Biases". The known, possible causes of plaintiff's illness are either "genes" or "tetramethyl-death". Bad genes account for 85% of all cases while "tetramethyl-death" is only rarely indicted, accounting for just 15% of the cases. Plaintiff's expert says that plaintiff was exposed to "tetramethyl-death" and didn't have the bad genes. The court believes (perhaps because plaintiff's expert has made the mistake of going out on a Bayesian limb and giving an estimate of his faith in his estimation, hint, hint) that 80% of the time plaintiff's expert is able to accurately distinguish between cases caused by "tetramethyl-death" and those caused by bad genes. What then are the odds that plaintiff's illness was indeed caused by the chemical exposure rather than his genes?
Significantly less than 50%.
So the question becomes, essentially, should a verdict finding that one and one sums to three be upheld assuming the parties had a full and fair opportunity to cross examine the purveyor of such nonsense? A surprising number of jurists say "yes". That's what happens when you don't examine the alleged support for each branch of the decision tree; and that's what happens when you don't "get" percentages.
The Evidence Mounts: The Role of Bacteria and Viruses in Autism
Wakefield's fraud wasn't in suggesting that the gut had something to do with autism; that's just hypothesis formation - and in his case, maybe a good one. No, what got him in trouble was suggesting that he had confirmation/verification (that empiricism business we've been writing about) of the cause advocated by his plaintiff lawyer backers. Too bad. The cause may not be vaccines but there's growing evidence that disruption of the microbes with whom we share this life may in fact be at the heart of the matter. For more see:
"State of the Art: Microbiology in Health and Disease. Intestinal Bacterial Flora in Autism" ; then see; Desulfovibrio Species are Potentially Important in Regressive Autism" followed by "Gastrointestinal Flora and Gastrointestinal Status in Children with Autism -- Comparisons to Typical Children and Correlation with Autism Severity" and then finish it off with "Secrets of the MMR Scare. How the Vaccine Crisis Was Meant to Make Money".
Sadly, rather than working to uncover the cause of human suffering we seemingly spend most of our energy trying to determine to whom we ought to assign blame - first for the illness and then for the false claims of causality. For whatever reason we seem, collectively, more interested in rooting out any possible nefarious human agency rather than in solving, engineer-style, the problem at hand. So, perhaps, back to one of our first posts - "It Takes a Villain". If someone can somehow be blamed for the naughtiness of microbes perhaps we can makes some rapid progress on these matters. Pity the victims but after all every Dark Age, even the mini-version through which we're passing, demands its witches.
Community Health and the Lake Wobegon Effect
It would be nice if every community could have above average health. The problem of course is that it's not possible - by definition. But that may not stop Congress from decreeing that whenever "a greater-than-expected number of cases within a group of individuals, a geographical area, or a period of time" is found or just suspected something ought to be done about it. OK, not doable but maybe worthwhile, right?
It's only worthwhile if you really want to find the answer. Unfortunately, the "Strengthening Protections for Children and Communities From Disease Clusters Act" doesn't want to find the answer. It only wants to find a particular answer. And that answer is, "using health protective" science, limited to alleged toxins and pollutants.
The attempt to codify ours as the Third Age of the Epidemiologic Transition, one in which man-made illnesses are allegedly our primary source of woe and the only ones for which interventions will work, is especially appalling given the staggering amount of evidence that disease clusters are almost never the result of exposure to chemicals and that infectious diseases are, as ever, the real culprits. To get some idea of just how fast and how often emergent infectious processes may set off illness (including cancer) within a community see "Truly Emerging - A New Disease Caused by a Novel Virus"
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:
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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.
Deconstructing Milward (part III)
When we first wrote about Milward we said it got causation wrong. The second time we wrote about it we took issue with the opinion for calling paid-for induction the scientific method. Now we address why we deem the opinion radical.
Should an educated guess, a hunch, especially one that's unverified and worse yet unverifiable, be admissible under Rule 702 of the Federal Rules of Evidence? Not if you're a fan of the Enlightenment and of the empiricism running from the likes of Bacon, Locke, Berekely and Hume to the Framers of our Consitution and all the way to Daubert. The idea that someone could be deprived of life, liberty or property on the basis of a mere guess, however impressive the credentials of the guesser, would we think shock the conscience of most Americans. But embracing without saying so the opposite of empiricism, something between Romanticism and and postmodernism, the First Circuit has said it's A-OK. That's pretty radical.
Defenders of the opinion might object to our claim that the opinion of Milward's expert was nothing but an unsupported and unsupportable conjecture. Didn't he offer five pieces of evidence after all? It depends on what you call evidence.
We all know what evidence for a theory looks like in the hard sciences. Albert Einstein makes a prediction about gravity and thereafter other scientists carry out experiments to see if the prediction pans out. Sometimes the answer comes in quickly and sometimes it takes a little longer but ultimately the conjecture stands or falls not on the reputation of the man but on the ability of his theory to withstand all attempts to refute it. Those attempts at refutation that instead confirm a theory's predictions are one form of evidence. In the somewhat softer science of biology including the study of human diseases such evidence tends to be harder to come by largely because biological systems are made up of so many different parts; the existence and complete function of many of which are still largely unknown.
That doesn't, however, mean that theories about biological function can't be tested. Lab animals as proxies for humans can be exposed to suspected carcinogens; their genes can even be manipulated to see if effects observed are the result of some interaction between agent and genome. Randomized controlled trials are the gold standard of drug testing evidence and though you can't experiment on humans by exposing them to known toxins you can certainly compare the outcomes of those exposed in the past to those not exposed to see if there's an association and if so how strong it is. So what sort of evidence did Milward's expert have to offer?
He offered five "bodies of evidence". First, he said that benzene is a known cause of AML. Ok, but plaintiff had APL. Just as the old expert witness canard "cancer is cancer" retreated to "blood cancer is blood cancer", the claim that all forms of AML are different but really the same when it comes to causation is, as the National Academy of Sciences has said, an assertion for which there is no evidence and one which seems odd given the fact that the various forms of AML have unique presentations, treatments and outcomes.
Second, he said that a particular mutation "is often in part" due to a chromosomal translocation in a precursor cell that can lead to all types of AML, that CML (which is almost certainly not caused by benzene) "often in part" has the same mutation and that APL and other AML subtypes with the mutation share "common genetic susceptibility factors", risk factors and incidence (after age 20). Therefore, they all share a common etiology. Hmmm. Well, ask Bruce Ames if all mutagens are carcinogens. And is there any evidence of causation beyond an association that a translocation "often in part" coincides that the mutation? No. Finally, sharing some risk factors some of the time during a certain period of life doesn't get you anywhere because risk factors after all are themselves nothing but reported associations. What we're left with then is as follows: APL shares some common characteristics with other subsets of AML and sometimes they have a common mutation which mutation is "often in part" caused by a translocation which may be caused by benzene. Thus, while "all AMLs have a common etiology" is an hypothesis that can be formed from such bits it's one for which no confirmatory evidence currently exists.
Third, benzene can cause damage to the chromosomes of stem cells in the bone marrow and that "leukemia cases associated with benzene exposure are more likely to contain clonal chromosome aberrations than leukemias arising in the general population." Presumably, though the opinion doesn't say so, benzene is at least sometimes associated with the translocation that "often in part" causes the mutation that supposedly causes APL. Good. At last something testable. If benzene is a potent APL-agen then people exposed to benzene ought to be at a much greater risk of APL.
Fourth, two benzene metabolites are topo II inhibitors and some topo II inhibitors cause so-called secondary APL cases. Fine. Benzene can be broken down into some things that act like other things that can cause APL. Good for hypothesis generation but where's the evidence that the two benzene metabolites survive to reach and act upon stem cells like chemotherapeutic drugs? Indeed Milward's expert admits that he has merely suggested a plausible mechanism.
Finally, there's a small increase in risk of APL (e.g. RR of 1.4) in one epidemiological study and a few others which which do not refute the notion that benzene may have something to do with APL because there isn't a complete absence of APL among those exposed to benzene. Well, here we are at the lick-log and there's nothing here but a proclamation that at least his hypothesis hasn't been refuted. Worst of all, Milward's expert claims that his theory isn't even testable, saying that the rarity of APL "makes it nearly impossible to perform a large enough study" to answer the question of whether or not benzene causes APL.
So that's it. The only test, an epidemiological study of people exposed to benzene, that could possibly refute his theory that benzene causes APL has produced results that are at best equivocal. Oh, and by the way, a test that would actually answer the question is impossible to do. The trial court concluded that without evidence from a test of his theory that verified its prediction (exposure to benzene causes more cases of APL than would otherwise occur) the expert had nothing more than a hypothesis. The First Circuit took a different view.
When we think of the scientific method we think about something very much like this chart. From the green box on down it's all about empiricism, testing, about "bending over backwards to show how you are maybe wrong" and about always publishing the results of any test of one's theory "whichever way it comes out." The First Circuit has however adopted a very different sort of view of the scientific method - one that stops at the yellow box, one that dispenses with the need for proof. One that trades verification for belief.
It's one thing to hold the philosophical view that there is something oppressive about the scientific method. It does, after all, have the well deserved reputation of going about willy-nilly stomping on all manner of cherished beliefs (e.g. the sun revolves around the earth, stress causes peptic ulcers - sorry A.B. Hill, vaccines produce autism, etc.). It's something else entirely though to let an unverified and unverifiable belief, pseudoscience in fact, be the basis upon which a citizen may lawfully be relieved of his hard-earned cash. Yet the view that objective truth does not exist, that fervent belief by a well-credentialed expert originating from nothing more than his subjective weighing of whatever he thinks relevant is enough and that testability, the demarcation between science and pseudoscience, is not a minimum requirement for the belief to be admissible has now made it from comment c, section 28 of the Restatement (Third) of Torts: Liability for Physical Harm to the First Circuit. Now that's radical.
Tort Reform Bills Pending in the Texas Legislature
ASBESTOS AND SILICA LITIGATION.
HB 2034 by Rep. Doug Miller, R-New Braunfels and SB 1202 by Sen. Dan Patrick, R-Houston.
These bills would allow the judge assigned to the asbestos or silica MDL docket to dismiss without prejudice the tens of thousands of cases that have been pending for years without any action because the claimants have not shown medical impairment. It also would prevent "double dipping" by plaintiffs who apply to asbestos bankruptcy trusts only after trial against solvent defendants as a way of avoiding "settlement offsets."
TRESPASSER LIABILITY.
SB 1160 by Sen. Kel Seliger, R-Amarillo and HB 1971 by Rep. Jim Jackson, R-Carrollton.
Texas common law provides that a property owner owes no duty of care to a trespasser, except in very narrow and well-defined circumstances. These bills would codify these traditional common law rules to preempt courts from adopting liberal provisions of the new Restatement Third of Torts, which would dramatically expand trespasses’ rights to sue landowners and impose costly burdens on property owners.
ELIMINATING THE RESPONSIBLE THIRD PARTY PRACTICE.
HB 1427 by Rep. Tryon Lewis, R-Odessa
This bill would repeal Section 33.004(e) of the Civil Practice and Remedies Code as it is used to provide a means to circumvent limitations periods.
Low-Salt Mandates: Who Pays for the Damages?
By now you've probably read "Low-Salt Diet Ineffective, Study Finds. Disagreement Abounds" by Gina Kolata of the NYTimes. She's reporting on "Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion" published this week in JAMA. The big news is that lowering salt in healthy adults was associated with an increased risk of death from cardiovascular disease (CVD). Meanwhile, those subjects in the same study on significantly higher sodium diets were much less likely than those on low-sodium diets to die over the years of follow-up (a median of 7.9yrs for the 3681 members of the cohort).
What you might not have read though are the numerous articles coming to similar conclusions. Take for example last fall's "Low-salt Diet Increases Insulin Resistance in Healthy Subjects". Insulin resistance is a big risk factor for diabetes and diabetes is a big risk factor for CVD.
So what to make of the efforts of the low-salt advocates to subject all Americans to what amounts to a mass uncontrolled experiment without their consent (informed or otherwise) and without the oversight of an ethics review board that might otherwise be charged with safeguarding the public? And what to make of the absence of the Precautionary Principle typically unfurled before our self-styled public health advocates march us out to face nature's cannons? Apparently "caring" means never having to say you're sorry.
But should Uncle Sam have to say he's sorry and pay for the tens of thousands of unnecessary deaths that would occur annually if the findings of these new studies are indeed predictive of what would happen if low-salt diets were forced upon (nudged upon) the entire unwitting populace? If the asbestos story is any indication then the food and beverage industry needs to prepare to be thrown under the bus at the earliest sign that the central low-salt diet plan has not survived first contact with the Law of Unintended Consequences. Because that's exactly what the government that stockpiled asbestos and specified its use did to those whom it directed to stockpile and produce it when asbestos hit the fan nearly 40 years ago.
More on that, plus an old depo of a government witness or two, later.
