Schachtman Law » Scientific Evidence

TORTINI

For your delectation and delight, desultory dicta on the law of delicts.

Demonstration of Frye Gatekeeping in Pennsylvania Birth Defects Case

October 6th, 2015

Michael D. Freeman is a chiropractor and self-styled “forensic epidemiologist,” affiliated with Departments of Public Health & Preventive Medicine and Psychiatry, Oregon Health & Science University School of Medicine, in Portland, Oregon. His C.V. can be found here. Freeman has an interesting publication in press on his views of forensic epidemiology. Michael D. Freeman & Maurice Zeegers, “Principles and applications of forensic epidemiology in the medico-legal setting,” Law, Probability and Risk (2015); doi:10.1093/lpr/mgv010. Freeman’s views on epidemiology did not, however, pass muster in the courtroom. Porter v. Smithkline Beecham Corp., Phila. Cty. Ct. C.P., Sept. Term 2007, No. 03275. Slip op. (Oct. 5, 2015).

In Porter, plaintiffs sued Pfizer, the manufacturer of the SSRI antidepressant Zoloft. Plaintiffs claimed the mother plaintiff’s use of Zoloft during pregnancy caused her child to be born with omphalocele, a serious defect that occurs when the child’s intestines develop outside his body. Pfizer moved to exclude plaintiffs’ medical causation expert witnesses, Dr. Cabrera and Dr. Freeman. The trial judge was the Hon. Mark I. Bernstein, who has written and presented frequently on expert witness evidence.[1] Judge Bernstein held a two day hearing in September 2015, and last week, His Honor ruled that the plaintiffs’ expert witnesses failed to meet Pennsylvania’s Frye standard for admissibility. Judge Bernstein’s opinion reads a bit like a Berenstain Bear book on how not to use epidemiology.

GENERAL CAUSATION SCREW UPS

Proper Epidemiologic Method

First, Find An Association

Dr. Freeman has a methodologic map that included Bradford Hill criteria at the back end of the procedure. Dr. Freeman, however, impetuously forgot that before you get to the back end, you must traverse the front end:

“Dr. Freemen agrees that he must, and claims he has, applied the Bradford Hill Criteria to support his opinion. However, the starting procedure of any Bradford-Hill analysis is ‘an association between two variables’ that is ‘perfectly clear-cut and beyond what we would care to attribute to the play of chance’.³⁵ Dr. Freeman testified that generally accepted methodology requires a determination, first, that there’s evidence of an association and, second, whether chance, bias and confounding have been accounted for, before application of the Bradford-Hill criteria.³⁶ Because no such association has been properly demonstrated, the Bradford Hill criteria could not have been properly applied.”

Slip op. at 12-13. In other words, don’t go rushing to the Bradford Hill factors until and unless you have first shown an association; second, you have shown that it is “clear cut,” and not likely the result of bias or confounding; and third, you have ruled out the play of chance or random variability in explaining the difference between the observed and expected rates of disease.

Proper epidemiologic method requires surveying the pertinent published studies that investigate whether there is an association between the medication use and the claimed harm. The expert witnesses must, however, do more than write a bibliography; they must assess any putative associations for “chance, confounding or bias”:

“Proper epidemiological methodology begins with published study results which demonstrate an association between a drug and an unfortunate effect. Once an association has been found, a judgment as whether a real causal relationship between exposure to a drug and a particular birth defect really exists must be made. This judgment requires a critical analysis of the relevant literature applying proper epidemiologic principles and methods. It must be determined whether the observed results are due to a real association or merely the result of chance. Appropriate scientific studies must be analyzed for the possibility that the apparent associations were the result of chance, confounding or bias. It must also be considered whether the results have been replicated.”

Slip op. at 7.

Then Rule Out Chance

So if there is something that appears to be an association in a study, the expert epidemiologist must assess whether it is likely consistent with a chance association. If we flip a fair coin 10 times, we “expect” 5 heads and 5 tails, but actually the probability of not getting the expected result is about three times greater than obtaining the expected result. If on one series of 10 tosses we obtain 6 heads and 4 tails, we would certainly not reject a starting assumption that the expected outcome was 5 heads/ 5 tails. Indeed, the probability of obtaining 6 heads / 4 tails or 4 heads /6 tails is almost double that of the probability of obtaining the expected outcome of equal number of heads and tails.

As it turned out in the Porter case, Dr. Freeman relied rather heavily upon one study, the Louik study, for his claim that Zoloft causes the birth defect in question. See Carol Louik, Angela E. Lin, Martha M. Werler, Sonia Hernández-Díaz, and Allen A. Mitchell, “First-Trimester Use of Selective Serotonin-Reuptake Inhibitors and the Risk of Birth Defects,” 356 New Engl. J. Med. 2675 (2007). The authors of the Louik study were quite clear that they were not able to rule out chance as a sufficient explanation for the observed data in their study:

“The previously unreported associations we identified warrant particularly cautious interpretation. In the absence of preexisting hypotheses and the presence of multiple comparisons, distinguishing random variation from true elevations in risk is difficult. Despite the large size of our study overall, we had limited numbers to evaluate associations between rare outcomes and rare exposures. We included results based on small numbers of exposed subjects in order to allow other researchers to compare their observations with ours, but we caution that these estimates should not be interpreted as strong evidence of increased risks.²⁴”

Slip op at 10 (quoting from Louik study).

Judge Bernstein thus criticized Freeman for failing to account for chance in explaining his putative association between maternal Zoloft use and infant omphalocele. The appropriate and generally accepted methodology for accomplishing this step of evaluating a putative association is to consider whether the association is statistically significant at the conventional level.

In relying heavily upon the Louik study, Dr. Freeman opened himself up to serious methodological criticism. Judge Bernstein’s opinion stands for the important proposition that courts should not be unduly impressed with nominal statistical significance in the presence of multiple comparisons and very broad confidence intervals:

“The Louik study is the only study to report a statistically significant association between Zoloft and omphalocele. Louik’s confidence interval which ranges between 1.6 and 20.7 is exceptionally broad. … The Louik study had only 3 exposed subjects who developed omphalocele thus limiting its statistical power. Studies that rely on a very small number of cases can present a random statistically unstable clustering pattern that may not replicate the reality of a larger population. The Louik authors were unable to rule out confounding or chance. The results have never been replicated concerning omphalocele. Dr. Freeman’s testimony does not explain, or seemingly even consider these serious limitations.”

Slip op. at 8. Statistical precision in the point estimate of risk, which includes assessing the outcome in the context of whether the authors conducted multiple comparisons, and whether the observed confidence intervals were very broad, is part of the generally accepted epidemiologic methodology, which Freeman flouted:

“Generally accepted methodology considers statistically significant replication of study results in different populations because apparent associations may reflect flaws in methodology.”

Slip op. at 9. The studies that Freeman cited and apparently relied upon failed to report statistically significant associations between sertraline (Zoloft) and omphalocele. Judge Bernstein found this lack to be a serious problem for Freeman and his epidemiologic opinion:

“While non-significant results can be of some use, despite a multitude of subsequent studies which isolated omphalocele, there is no study which replicates or supports Dr. Freeman’s conclusions.”

Slip op. at 10. The lack of statistical significance, in the context of repeated attempts to find it, helped sink Freeman’s proffered testimony.

Then Rule Out Bias and Confounding

As noted, Freeman relied heavily upon the Louik study, which was the only study to report a nominally statistically significant risk ratio for maternal Zoloft use and infant omphalocele. The Louik study, by its design, however, could not exclude chance or confounding as full explanation for the apparent association, and Judge Bernstein chastised Dr. Freeman for overselling the study as support for the plaintiffs’ causal claim:

“The Louik authors were unable to rule out confounding or chance. The results have never been replicated concerning omphalocele. Dr. Freeman’s testimony does not explain, or seemingly even consider these serious limitations.”

Slip op. at 8.

And Only Then Consider the Bradford Hill Factors

Even when an association is clear cut, and beyond what we can likely attribute to chance, generally accepted methodology requires the epidemiologist to consider the Bradford Hill factors. As Judge Bernstein explains, generally accepted methodology for assessing causality in this area requires a proper consideration of Hill’s factors before a conclusion of causation is reached:

“As the Bradford-Hill factors are properly considered, causality becomes a matter of the epidemiologist’s professional judgment.”

Slip op. at 7.

Consistency or Replication

The nine Hill factors are well known to lawyers because they have been stated and discussed extensively in Hill’s original article, and in references such as the Reference Manual on Scientific Evidence. Not all the Hill factors are equally important, or important at all, but one that is consistency or concordance of results among the available epidemiologic studies. Stated alternatively, a clear cut association unlikely to be explained by chance is certainly interesting and probative, but it raises an important methodological question — can the result be replicated? Judge Bernstein restated this important Hill factor as an important determinant of whether a challenged expert witness employed a generally accepted method:

“Generally accepted methodology considers statistically significant replication of study results in different populations because apparent associations may reflect flaws in methodology.”

Slip op. at 10.

“More significantly neither Reefhuis nor Alwan reported statistically significant associations between Zoloft and omphalocele. While non-significant results can be of some use, despite a multitude of subsequent studies which isolated omphalocele, there is no study which replicates or supports Dr. Freeman’s conclusions.”

Slip op. at 10.

Replication But Without Double Dipping the Data

Epidemiologic studies are sometimes updated and extended with additional follow up. An expert witness who wished to skate over the replication and consistency requirement might be tempted, as was Dr. Freeman, to count the earlier and later iteration of the same basic study to count as “replication.” The Louik study was indeed updated and extended this year in a published paper by Jennita Reefhuis and colleagues.[2] Proper methodology, however, prohibits double dipping data to count the later study that subsumes the early one as a “replication”:

“Generally accepted methodology considers statistically significant replication of study results in different populations because apparent associations may reflect flaws in methodology. Dr. Freeman claims the Alwan and Reefhuis studies demonstrate replication. However, the population Alwan studied is only a subset of the Reefhuis population and therefore they are effectively the same.”

Slip op. at 10.

The Lumping Fallacy

Analyzing the health outcome of interest at the right level of specificity can sometimes be a puzzle and a challenge, but Freeman generally got it wrong by opportunistically “lumping” disparate outcomes together when it helps him get a result that he likes. Judge Bernstein admonishes:

“Proper methodology further requires that one not fall victim to the … the ‘Lumping Fallacy’. … Different birth defects should not be grouped together unless they a part of the same body system, share a common pathogenesis or there is a specific valid justification or necessity for an association²⁰ and chance, bias, and confounding have been eliminated.”

Slip op. at 7. Dr. Freeman lumped a lot, but Judge Bernstein saw through the methodological ruse. As Judge Bernstein pointed out:

“Dr. Freeman’s analysis improperly conflates three types of data: Zoloft and omphalocele, SSRI’s generally and omphalocele, and SSRI’s and gastrointestinal and abdominal malformations.”

Slip op. at 8. Freeman’s approach, which sadly is seen frequently in pharmaceutical and other products liability cases, is methodologically improper:

“Generally accepted causation criteria must be based on the data applicable to the specific birth defect at issue. Dr. Freeman improperly lumps together disparate birth defects.”

Slip op. at 11.

Class Effect Fallacy

Another kind of improper lumping results from treating all SSRI antidepressants the same to either lump them together, or to pick and choose from among all the SSRIs, the data points that are supportive of the plaintiffs’ claims (while ignoring those SSRI data points not supportive of the claims). To be sure, the SSRI antidepressants do form a “class,” in that they all have a similar pharmacologic effect. The SSRIs, however, do not all achieve their effect in the serotonergic neurons the same way; nor do they all have the same “off-target” effects. Treating all the SSRIs as interchangeable for a claimed adverse effect, without independent support for this treatment, is known as the class effect fallacy. In Judge Bernstein’s words:

“Proper methodology further requires that one not fall victim to the ‘Class Effect Fallacy’ … . A class effect cannot be assumed. The causation conclusion must be drug specific.”

Slip op. at 7. Dr. Freeman’s analysis improperly conflated Zoloft data with SSRI data generally. Slip op. at 8. Assuming what you set out to demonstrate is, of course, a fine way to go methodologically into the ditch:

“Without significant independent scientific justification it is contrary to generally accepted methodology to assume the existence of a class effect. Dr. Freeman lumps all SSRI drug results together and assumes a class effect.”

Slip op. at 10.

SPECIFIC CAUSATION SCREW UPS

Dr. Freeman was also offered by plaintiffs to provide a specific causation opinion – that Mrs. Porter’s use of Zoloft in pregnancy caused her child’s omphalocele. Freeman claimed to have performed a differential diagnosis or etiology or something to rule out alternative causes.

Genetics

In the field of birth defects, one possible cause looming in any given case is an inherited or spontaneous genetic mutation. Freeman purported to have considered and ruled out genetic causes, which he acknowledged to make up a substantial percentage of all omphalocele cases. Bo Porter, Mrs. Porter’s son, was tested for known genetic causes, and Freeman argued that this allowed him to “rule out” genetic causes. But the current state of the art in genetic testing allowed only for identifying a small number of possible genetic causes, and Freeman failed to explain how he might have ruled out the as-of-yet unidentified genetic causes of birth defects:

“Dr. Freeman fails to properly rule out genetic causes. Dr. Freeman opines that 45-49% of omphalocele cases are due to genetic factors and that the remaining 50-55% of cases are due to non-genetic factors. Dr. Freeman relies on Bo Porter’s genetic testing which did not identify a specific genetic cause for his injury. However, minor plaintiff has not been tested for all known genetic causes. Unknown genetic causes of course cannot yet be tested. Dr. Freeman has made no analysis at all, only unwarranted assumptions.”

Slip op. at 15-16. Judge Bernstein reviewed Freeman’s attempted analysis and ruling out of potential causes, and found that it departed from the generally accepted methodology in conducting differential etiology. Slip op. at 17.

Timing Errors

One feature of putative terotogenicity is that an embryonic exposure must take place at a specific gestational developmental time in order to have its claimed deleterious effect. As Judge Bernstein pointed out, omphalocele results from an incomplete folding of the abdominal wall during the third to fifth weeks of gestation. Mrs. Porter, however, did not begin taking Zoloft until her seventh week of pregnancy, which left Dr. Freeman opinion-less as to how Zoloft contributed to the claimed causation of the minor plaintiff’s birth defect. Slip op. at 14. This aspect of Freeman’s specific causation analysis was glaringly defect, and clearly not the sort of generally accepted methodology of attributing a birth defect to a teratogen.

******************************************************

All in all, Judge Bernstein’s opinion is a tour de force demonstration of how a state court judge, in a so-called Frye jurisdiction, can show that failure to employ generally accepted methods renders an expert witness’s opinions inadmissible. There is one small problem in statistical terminology.

Statistical Power

Judge Bernstein states, at different places, that the Louik study was and was not statistically significant for Zoloft and omphalocele. The court’s opinion ultimately does explain that the nominal statistical significance was vitiated by multiple comparisons and an extremely broad confidence interval, which more than justified its statement that the study was not truly statistically significant. In another moment, however, the court referred to the problem as one of lack of statistical power. For some reason, however, Judge Bernstein chose to explain the problem with the Louik study as a lack of statistical power:

“Equally significant is the lack of power concerning the omphalocele results. The Louik study had only 3 exposed subjects who developed omphalocele thus limiting its statistical power.”

Slip op. at 8. The adjusted odds ratio for Zoloft and omphalocele, was 5.7, with a 95% confidence interval of 1.6 – 20.7. Power was not the issue because if the odds ratio were otherwise credible, free from bias, confounding, and chance, the study had the power to observe an increased risk of close to 500%, which met the pre-stated level of significance. The problem, however, was multiple testing, fragile and imprecise results, and inability to evaluate the odds ratio fully for bias and confounding.

[1] Mark I. Bernstein, “Expert Testimony in Pennsylvania,” 68 Temple L. Rev. 699 (1995); Mark I. Bernstein, “Jury Evaluation of Expert Testimony under the Federal Rules,” 7 Drexel L. Rev. 239 (2014-2015).

[2] Jennita Reefhuis, Owen Devine, Jan M Friedman, Carol Louik, Margaret A Honein, “Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports,” 351 Brit. Med. J. (2015).

Posted in Causation, Frye, Scientific Evidence | Comments Off on Demonstration of Frye Gatekeeping in Pennsylvania Birth Defects Case

Clinical Trials and Epidemiologic Studies Biased by False and Misleading Data From Research Participants

October 2nd, 2015

Many legal commentators erroneously refer to epidemiologic studies as “admitted” into evidence.[1] These expressions are sloppy, and unfortunate, because they obscure the tenuousness of study validity, and the many hearsay levels that are represented by an epidemiologic study. Rule 702 permits expert witness opinion that has an epistemic basis, and Rule 703 allows expert witnesses to rely upon otherwise inadmissible facts and data, as long as real experts in the field would reasonably rely upon such facts and data. Nothing in Rule 702 or 703 make an epidemiologic study itself admissible. And the general inadmissibility of the studies themselves is a good thing, given that they will be meaningless to the trier of fact without the endorsements, qualifications, and explanations of an expert witness, and given that many studies are inaccurate, invalid, and lack data integrity to boot.

Dr. Frank Woodside was kind enough to call my attention to an interesting editorial piece in the current issue of the New England Journal of Medicine, which reinforced the importance of recognizing that epidemiologic studies and clinical trials are inadmissible in themselves. The editorial, by scientists from the National Institute of Environmental Health Studies and the National Institute on Drug Abuse, calls out the problem of study participants who lie, falsify, fail to disclose, and exaggerate important aspects of their medical histories as well as their data. See David B. Resnik & David J. McCann, “Deception by Research Participants,” 373 New Engl. J. Med. 1192 (2015). The editorial is an important caveat for those who would glibly describe epidemiologic studies and clinical trials as “admissible.”

As a reminder of the autonomy of those who participate in clinical trials and studies, we now refer to individuals in a study as “participants,” and not “subjects.” Resnik and McCann remind us, however, that notwithstanding their importance, study participants can bias a study in important ways. Citing other recent papers,[2] the editorialists note that clinical trials offer financial incentives to participants, which may lead to exaggeration of symptoms to ensure enrollment, to failure to disclose exclusionary medical conditions and information, and to withholding of embarrassing or inculpatory information. Although fabrication or falsification of medical history and data by research participants is not research misconduct by the investigators, the participants’ misconduct can seriously bias and undermine the validity and integrity of a study.

Resnik and McCann’s concerns about the accuracy and truthfulness of clinical trial participant medical data and information can mushroom exponentially in the context of observational studies that involve high-stakes claims for compensation and vindication on medical causation issues. Here are a couple of high-stakes examples.

The Brinton Study in Silicone Gel Breast Implant Litigation

In the silicone gel breast implant litigation, claimants looked forward to a study by one of their champions, Dr. Louis Brinton, of the National Cancer Institute (NCI). Brinton had obtained intramural funding to conduct a study of women who had had silicone gel breast implants and their health outcomes. To their consternation, the defendants in that litigation learned of Dr. Brinton’s close ties with plaintiffs’ counsel, plaintiffs’ support groups, and other advocates. Further investigation, including Freedom of Information Act requests to the NCI led to some disturbing and startling revelations.

In October 1996, a leading epidemiologist wrote a “concerned citizen” letter to Dr. Joseph Fraumeni, who was then the director of Epidemiology and Genetics at the NCI. The correspondent wrote to call Dr. Fraumeni’s attention to severe bias problems in Dr. Brinton’s pending study of disease and symptom outcomes among women who had had silicone breast implants. Dr. Brinton had written to an Oregon attorney (Michael Williams) to enlist him to encourage his clients to participate in Brinton’s NCI study. Dr. Brinton had also written to a Philadelphia attorney (Steven Sheller) to seek permission to link potential study subjects to the global settlement database of information on women participating in the settlement. Perhaps most egregiously, Dr. Brinton and others had prepared a study Question & Answer sheet, from the National Institutes of Health, which ended with a ringing solicitation of “The study provides an opportunity for women who may be suffering as a result of implants to be heard. Now is your chance to make a major contribution to women’s health by supporting this essential research.” Dr. Brinton apparently had not thought of appealing to women with implants who did not have health problems.

Dr. Brinton’s methodology doomed her study from the start. Without access to the background materials, such as the principal investigator’s correspondence file, or the recruitment documents used to solicit participation of ill women in the study, the scientific community, and the silicone litigation defendants would not have had the important insights into serious bias and flaws of Brinton’s study.

The Racette-Scruggs’ Study in Welding Fume Litigation

The welding fume litigation saw its version of a study corrupted by the participation of litigants and potential litigants. Richard (Dickie) Scruggs and colleagues funded some neurological researchers to travel to Alabama and Mississippi to “screen” plaintiffs and potential plaintiffs in litigation for over claims of neurological injury and disease from welding fume exposure. The plaintiffs’ lawyers rounded up the research subjects (a.k.a. clients and potential clients), talked to them before the medical evaluations, and administered the study questionnaires. Clearly the study subjects were aware of Scruggs’ “research” hypothesis. The plaintiffs’ lawyers then invited researchers who saw the welding tradesmen, using a novel videotaping methodology, to evaluate the workers for parkinsonism.

After their sojourn, at Scruggs’ expense to Alabama and Mississippi, the researchers wrote up their results, with little or no detail of the circumstances of how they had acquired their research “participants,” or those participants’ motives to give accurate or inaccurate medical and employment history information. See Brad A. Racette, S.D. Tabbal, D. Jennings, L. Good, J.S. Perlmutter, and Brad Evanoff, “Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders,” 64 Neurology 230 (2005); Brad A. Racette, et al., “A rapid method for mass screening for parkinsonism,” 27 Neurotoxicology 357 (2006) (a largely duplicative report of the Alabama welders study).

Defense counsel directed subpoenas to both Dr. Racette and his institution, Washington University St. Louis, for the study protocol, underlying data, data codes, and statistical analyses. After a long discovery fight, the MDL court largely enforced the subpoenas. See, e.g., In re Welding Fume Prods. Liab. Litig., MDL 1535, 2005 WL 5417815 (N.D. Ohio Oct. 18, 2005) (upholding defendants’ subpoena for protocol, data, data codes, statistical analyses, and other things from Dr. Racette’s Alabama study on welding and parkinsonism). After the defense had the opportunity to obtain and analyze the underlying data in the Scruggs-Racette study, the welding plaintiffs largely retreated from their epidemiologic case. The Racette Alabama study faded into the background of the trials.

Both the Brinton and the Racette studies are painful reminders of the importance of assessing the motives of the study participants in observational epidemiologic studies, and the participants’ ability to undermine data integrity. If the financial motives identified by Resnik and McCann are sufficient to lead participants to give false information, or to fail to disclose correct information, we can only imagine how powerful are the motives created by the American tort litigation system among actual and potential claimants when they participate in epidemiologic studies. Resnik and McCann may be correct that fabrication or falsification of medical history and data by research participants is not research misconduct by the investigators themselves, but investigators who turn a blind eye to the knowledge, intent, and motives of their research participants may be conducting studies that are doomed from the outset.

[1] Michael D. Green, D. Michal Freedman, Leon Gordis, “Reference Guide on Epidemiology 549, 551,” in Reference Manual on Scientific Evidence (3d ed. 2011) ( “Epidemiologic studies have been well received by courts deciding cases involving toxic substances. *** Well-conducted studies are uniformly admitted.) (citing David L. Faigman et al. eds., 3 Modern Scientific Evidence: The Law and Science of Expert Testimony § 23.1, at 187 (2007–08)).

[2] Eric Devine, Megan Waters, Megan Putnam, et al., “Concealment and fabrication by experienced research subjects,” 20 Clin. Trials 935 (2013); Rebecca Dresser, “Subversive subjects: rule-breaking and deception in clinical trials,” 41 J. Law Med. Ethics 829 (2013).

Posted in Data Sharing, Rule 702, Scientific Evidence, Scientific Misconduct, Underlying Data | Comments Off on Clinical Trials and Epidemiologic Studies Biased by False and Misleading Data From Research Participants

The C-8 (Perfluorooctanoic Acid) Litigation Against DuPont, part 1

September 27th, 2015

The first plaintiff has begun her trial against E.I. Du Pont De Nemours & Company (DuPont), for alleged harm from environmental exposure to perfluorooctanoic acid or its salts (PFOA). Ms. Carla Bartlett is claiming that she developed kidney cancer as a result of drinking water allegedly contaminated with PFOA by DuPont. Nicole Hong, “Chemical-Discharge Case Against DuPont Goes to Trial: Outcome could affect thousands of claims filed by other U.S. residents,” Wall St. J. (Sept. 13, 2015). The case is pending before Chief Judge Edmund A. Sargus, Jr., in the Southern District of Ohio.

PFOA is not classified as a carcinogen in the Integrated Risk Information System (IRIS), of the U.S. Environmental Protection Agency (EPA). In 2005, the EPA Office of Pollution Prevention and Toxics submitted a “Draft Risk Assessment of the Potential Human Health Effects Associated With Exposure to Perfluorooctanoic Acid and Its Salts (PFOA),” which is available at the EPA’s website. The draft report, which is based upon some epidemiology and mostly animal toxicology studies, stated that there was “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.”

In 2013, The Health Council of the Netherlands evaluated the PFOA cancer issue, and found the data unsupportive of a causal conclusions. The Health Council of the Netherlands, “Perfluorooctanoic acid and its salts: Evaluation of the carcinogenicity and genotoxicity” (2013) (“The Committee is of the opinion that the available data on perfluorooctanoic acid and its salts are insufficient to evaluate the carcinogenic properties (category 3)”).

Last year, the World Health Organization (WHO) through its International Agency for Research on Cancer (IARC) reviewed the evidence on the alleged carcinogenicity of PFOA. The IARC, which has fostered much inflation with respect to carcinogenicity evaluations, classified as PFOA as only possibly carcinogenic. See News, “Carcinogenicity of perfluorooctanoic acid, tetrafl uoroethylene, dichloromethane, 1,2-dichloropropane, and 1,3-propane sultone,” 15 The Lancet Oncology 924 (2014).

Most independent reviews also find the animal and epidemiologic unsupportive of a causal conclusion between PFOA and any human cancer. See, e.g., Thorsten Stahl, Daniela Mattern, and Hubertus Brunn, “Toxicology of perfluorinated compounds,” 23 Environmental Sciences Europe 38 (2011).

So you might wonder how DuPont lost its Rule 702 challenges in such a case, which it surely did. In re E. I. du Pont de Nemours & Co. C-8 Pers. Injury Litig., Civil Action 2:13-md-2433, 2015 U.S. Dist. LEXIS 98788 (S.D. Ohio July 21, 2015). That is a story for another day.

Posted in Causation, Expert Witnesses, Rule 702, Scientific Evidence, Uncategorized | Comments Off on The C-8 (Perfluorooctanoic Acid) Litigation Against DuPont, part 1

David Faigman’s Critique of G2i Inferences at Weinstein Symposium

September 25th, 2015

The DePaul Law Review’s 20th Annual Clifford Symposium on Tort Law and Social Policy is an 800-plus page tribute in honor of Judge Jack Weinstein. 64 DePaul L. Rev. (Winter 2015). There are many notable, thought-provoking articles, but my attention was commanded by the contribution on Judge Weinstein’s approach to expert witness opinion evidence. David L. Faigman & Claire Lesikar, “Organized Common Sense: Some Lessons from Judge Jack Weinstein’s Uncommonly Sensible Approach to Expert Evidence,” 64 DePaul L. Rev. 421 (2015) [cited as Faigman].

Professor Faigman praises Judge Jack Weinstein for his substantial contributions to expert witness jurisprudence, while acknowledging that Judge Weinstein has been a sometimes reluctant participant and supporter of judicial gatekeeping of expert witness testimony. Professor Faigman also uses the occasion to restate his own views about the so-called “G2i” problem, the problem of translating general knowledge that pertains to groups to individual cases. In the law of torts, the G2i problem arises from the law’s requirement that plaintiffs show that they were harmed by defendants’ products or environmental exposures. In the context of modern biological “sufficient” causal set principles, this “proof” requirement entails that the product or exposure can cause the specified harms in human beings generally (“general causation”) and that the product or exposure actually played a causal role in bringing about plaintiffs’ specific harms.

Faigman makes the helpful point that courts initially and incorrectly invoked “differential diagnosis,” as the generally accepted methodology for attributing causation. In doing so, the courts extrapolated from the general acceptance of differential diagnosis in the medical community to the courtroom testimony about etiology. The extrapolation often glossed over the methodological weaknesses of the differential approach to etiology. Not until 1995 did a court wake to the realization that what was being proffered was a “differential etiology,” and not a differential diagnosis. McCullock v. H.B. Fuller Co., 61 F.3d 1038, 1043 (2d Cir. 1995). This realization, however, did not necessarily stimulate the courts’ analytical faculties, and for the most part, they treated the methodology of specific causal attribution as general acceptance and uncontroversial. Faigman’s point that the courts need to pay attention to the methodological challenges to differential etiological analysis is well taken.

Faigman also claims, however, that in advancing “differential etiologies, expert witnesses were inventing wholesale an approach that had no foundation or acceptance in their scientific disciplines:

“Differential etiology is ostensibly a scientific methodology, but one not developed by, or even recognized by, physicians or scientists. As described, it is entirely logical, but has no scientific methods or principles underlying it. It is a legal invention and, as such, has analytical heft, but it is entirely bereft of empirical grounding. Courts and commentators have so far merely described the logic of differential etiology; they have yet to define what that methodology is.”

Faigman at 444.[1] Faigman is correct that courts often have left unarticulated exactly what the methodology is, but he does not quite make sense when he writes that the method of differential etiology is “entirely logical,” but has no “scientific methods or principles underlying it.” Afterall, Faigman starts off his essay with a quotation from Thomas Huxley that “science is nothing but trained and organized common sense.”[2] As I have written elsewhere, the form of reasoning involved in differential diagnosis is nothing other than the iterative disjunctive syllogism.[3] Either-or reasoning occurs throughout the physical and biological sciences; it is not clear why Faigman declares it un- or extra-scientific.

The strength of Faigman’s claim about the made-up nature of differential etiology appears to be undermined and contradicted by an example that he provides from clinical allergy and immunology:

“Allergists, for example, attempt to identify the etiology of allergic reactions in order to treat them (or to advise the patient to avoid what caused them), though it might still be possible to treat the allergic reactions without knowing their etiology.”

Faigman at 437. Of course, not only allergists try to determine the cause of an individual patient’s disease. Psychiatrists, in the psychoanalytic tradition, certain do so as well. Physicians who use predictive regression models use group data, in multivariate analyses, to predict outcomes, risk, and mortality in individual patients. Faigman’s claim is similarly undermined by the existence of a few diseases (other than infectious diseases) that are defined by the causative exposure. Silicosis and manganism have played a large role in often bogus litigation, but they represent instances in which a differential diagnosis and puzzle may also be an etiological diagnosis and puzzle. Of course, to the extent that a disease is defined in terms of causative exposures, there may be serious and even intractable problems caused by the lack of specificity and accuracy in the diagnostic criteria for the supposedly pathognomonic disease.

As for whether the concept of “differential etiology” is ever used in the sciences themselves, a few citations for consideration follow.

Kløve & D. Doehring, “MMPI in epileptic groups with differential etiology,” 18 J. Clin. Psychol. 149 (1962)

Kløve & C. Matthews, “Psychometric and adaptive abilities in epilepsy with differential etiology,” 7 Epilepsia 330 (1966)

Teuber & K. Usadel, “Immunosuppression in juvenile diabetes mellitus? Critical viewpoint on the treatment with cyclosporin A with consideration of the differential etiology,” 103 Fortschr. Med. 707 (1985)

G.May & W. May, “Detection of serum IgA antibodies to varicella zoster virus (VZV)–differential etiology of peripheral facial paralysis. A case report,” 74 Laryngorhinootologie 553 (1995)

Alan Roberts, “Psychiatric Comorbidity in White and African-American Illicity Substance Abusers” Evidence for Differential Etiology,” 20 Clinical Psych. Rev. 667 (2000)

Mark E. Mullinsa, Michael H. Leva, Dawid Schellingerhout, Gilberto Gonzalez, and Pamela W. Schaefera, “Intracranial Hemorrhage Complicating Acute Stroke: How Common Is Hemorrhagic Stroke on Initial Head CT Scan and How Often Is Initial Clinical Diagnosis of Acute Stroke Eventually Confirmed?” 26 Am. J. Neuroradiology 2207 (2005)

Qiang Fua, et al., “Differential Etiology of Posttraumatic Stress Disorder with Conduct Disorder and Major Depression in Male Veterans,” 62 Biological Psychiatry 1088 (2007)

Jesse L. Hawke, et al., “Etiology of reading difficulties as a function of gender and severity,” 20 Reading and Writing 13 (2007)

Mastrangelo, “A rare occupation causing mesothelioma: mechanisms and differential etiology,” 105 Med. Lav. 337 (2014)

[1] See also Faigman at 448 (“courts have invented a methodology – differential etiology – that purports to resolve the G2i problem. Unfortunately, this method has only so far been described; it has not been defined with any precision. For now, it remains a highly ambiguous idea, sound in principle, but profoundly underdefined.”).

[2] Thomas H. Huxley, “On the Education Value of the Natural History Sciences” (1854), in Lay Sermons, Addresses and Reviews 77 (1915).

[3] See, e.g., “Differential Etiology and Other Courtroom Magic” (June 23, 2014) (collecting cases); “Differential Diagnosis in Milward v. Acuity Specialty Products Group” (Sept. 26, 2013).

Posted in Causation, Expert Witnesses, Rule 702, Scientific Evidence | Comments Off on David Faigman’s Critique of G2i Inferences at Weinstein Symposium

Seventh Circuit Affirms Exclusion of Expert Witnesses in Vinyl Chloride Case

August 30th, 2015

Last week, the Seventh Circuit affirmed a federal district court’s exclusion of plaintiffs’ expert witnesses in an environmental vinyl chloride exposure case. Wood v. Textron, Inc., No. 3:10 CV 87, 2014 U.S. Dist. LEXIS 34938 (N.D. Ind. Mar. 17, 2014); 2014 U.S. Dist. LEXIS 141593, at *11 (N.D. Ind. Oct. 3, 2014), aff’d, Slip op., No. 14-3448, 20125 U.S. App. LEXIS 15076 (7th Cir. Aug. 26, 2015). Plaintiffs, children C.W. and E.W., claimed exposure from Textron’s manufacturing facility in Rochester, Indiana, which released vinyl chloride as a gas that seeped into ground water, and into neighborhood residential water wells. Slip op. at 2-3. Plaintiffs claimed present injuries in the form of “gastrointestinal issues (vomiting, bloody stools), immunological issues, and neurological issues,” as well as future increased risk of cancer. Importantly, the appellate court explicitly approved the trial court’s careful reading of relied upon studies to determine whether they really did support the scientific causal claims made by the expert witnesses. Given the reluctance of some federal district judges to engage with the studies actually cited, this holding is noteworthy.

To support their claims, plaintiffs offered the testimony from three familiar expert witnesses:

(1) Dr. James G. Dahlgren;

(2) Dr. Vera S. Byers; and

(3) Dr. Jill E. Ryer-Powder.

Slip op. at 5. This gaggle offered well-rehearsed but scientifically unsound arguments in place of actual evidence that the children were hurt, or would be afflicted, as a result of their claimed exposures:

(a) extrapolation from high dose animal and human studies;

(b) assertions of children’s heightened vulnerability;

(c) differential etiology;

(d) temporality; and

(e) regulatory exposure limits.

On appeal, a panel of the Seventh Circuit held that the district court had properly conducted “an in-depth review of the relevant studies that the experts relied upon to generate their differential etiology,” and their general causation opinions. Slip op. at 13-14 (distinguishing other Seventh Circuit decisions that reversed district court Rule 702 rulings, and noting that the court below followed Joiner’s lead by analyzing the relied-upon studies to assess analytical gaps and extrapolations). The plaintiffs’ expert witnesses simply failed in analytical gap bridging, and dot connecting.

Extrapolation

The Circuit agreed with the district court that the extrapolations asserted were extreme, and that they represented “analytical gaps” too wide to be permitted in a courtroom. Slip op. at 15. The challenged expert witnesses extrapolated between species, between exposure levels, between exposure duration, between exposure circumstances, and between disease outcomes.

The district court faulted Dahlgren for relying upon articles that “fail to establish that [vinyl chloride] at the dose and duration present in this case could cause the problems that the [p]laintiffs have experienced or claim that they are likely to experience.” C.W. v. Textron, 2014 U.S. Dist. LEXIS 34938, at *53, *45 (N.D. Ind. Mar. 17, 2014) (finding that the analytical gap between the cited studies and Dahlgren’s purpose in citing the studies was an unbridged gap, which Dahlgren had failed to explain). Slip op. at 8.

Byers, for instance, cited one study[1] that involved exposure for five years, at an average level that was over 1,000 times higher than the children’s alleged exposure levels, which lasted less than 17 and 7 months, each. Perhaps even more extreme were the plaintiffs’ expert witnesses’ attempted extrapolations from animal studies, which the district court recognized as “too attenuated” from plaintiffs’ case. Slip op. at 14. The Seventh Circuit rejected plaintiffs’ alleged error that the district court had imposed a requirement of “absolute precision,” in holding that the plaintiffs’ expert witnesses’ analytical gaps (and slips) were too wide to be bridged. The Circuit provided a colorful example of a study on laboratory rodents, pressed into service for a long-term carcinogenetic assay, which found no statistically significant increase in tumors fed 0.03 milligrams vinyl chloride per kilogram of bodyweight, (0.03 mg/kg), for 4 to 5 days each week, for 59 weeks, compared to control rodents fed olive oil.[2] Slip op. at 14-15. This exposure level in this study of 0.03 mg/kg was over 10 times the children’s exposure, as estimated by Ryer-Powder. The 59 weeks of study exposure represents the great majority of the rodents’ adult years, which greatly exceeds the children’s exposure was took place over several months of their lives. Slip op. at 15.

The Circuit held that the district court was within its discretion in evaluating the analytical gaps, and that the district court was correct to look at the study details to exercise its role as a gatekeeper under Rule 702. Slip op. at 15-17. The plaintiffs’ expert witnesses failed to explain their extrapolations, which was made their opinions suspect. As the Circuit court noted, there is a methodology by which scientists sometimes attempt to model human risks from animal evidence. Slip op. at 16-17, citing Bernard D. Goldtsein & Mary Sue Henifin, “Reference Guide on Toxicology,” in Federal Manual on Scientific Evidence 646 (3d ed. 2011) (“The mathematical depiction of the process by which an external dose moves through various compartments in the body until it reaches the target organ is often called physiologically based pharmokinetics or toxicokinetics.”). Given the abject failures of plaintiffs’ expert witnesses to explain their leaps of faith, the appellate court had no occasion to explore the limits of risk assessment outside regulatory contexts.

Children’s Vulnerability

Plaintiffs’ expert witness asserted that children are much more susceptible than adult workers, and even laboratory rats. As is typical in such cases, these expert witnesses had no evidence to support their assertions, and they made no effort even to invoke models that attempted reasonable risk assessments of children’s risk.

Differential Etiology

Dahlgren and Byers both claimed that they reached individual or specific causation conclusions based upon their conduct of a “differential etiology.” The trial and appellate court both faulted them for failing to “rule in” vinyl chloride for plaintiffs’ specific ailments before going about the business of ruling out competing or alternative causes. Slip op. at 6-7; 9-10; 20-21.

The courts also rejected Dahlgren’s claim that he could rule out all potential alternative causes by noting that the children’s treating physicians had failed to identify any cause for their ailments. So after postulating a limited universe of alternative causes of “inheritance, allergy, infection or another poison,” Dahlgren ruled all of them out of the case, because these putative causes “would have been detected by [the appellants’] doctors and treated accordingly.” Slip op. at 7, 18. As the Circuit court saw the matter:

“[T]his approach is not the stuff of science. It is based on faith in his fellow physicians—nothing more. The district court did not abuse its discretion in rejecting it.”

Slip op. at 18. Of course, the court might well have noted that physicians are often concerned exclusively with identifying effective therapy, and have little or nothing to offer on actual causation.

The Seventh Circuit panel did fuss with dicta in the trial court’s opinion that suggested differential etiology “cannot be used to support general causation.” C.W. v. Textron, 2014 U.S. Dist. LEXIS 141593, at *11 (N.D. Ind. Oct. 3, 2014). Elsewhere, the trial court wrote, in a footnote, that “[d]ifferential [etiology] is admissible only insofar as it supports specific causation, which is secondary to general causation … .” Id. at *12 n.3. Curiously the appellate court characterized these statements as “holdings” of the trial court, but disproved their own characterization by affirming the judgment below. The Circuit court countered with its own dicta that

“there may be a case where a rigorous differential etiology is sufficient to help prove, if not prove altogether, both general and specific causation.”

Slip op. at 20 (citing, in turn, improvident dicta from the Second Circuit, in Ruggiero v. Warner-Lambert Co., 424 F.3d 249, 254 (2d Cir. 2005) (“There may be instances where, because of the rigor of differential diagnosis performed, the expert’s training and experience, the type of illness or injury at issue, or some other … circumstance, a differential diagnosis is sufficient to support an expert’s opinion in support of both general and specific causation.”).

Regulatory Pronouncements

Dahlgren based his opinions upon the children’s water supply containing vinyl chloride in excess of regulatory levels set by state and federal agencies, including the U.S. Environmental Protection Agency (E.P.A.). Slip op. at 6. Similarly, Ryer-Powder relied upon exposure levels’ exceeding regulatory permissible limits for her causation opinions. Slip op. at 10.

The district court, with the approval now of the Seventh Circuit would have none of this nonsense. Exceeding governmental regulatory exposure limits does not prove causation. The con-compliance does not help the fact finder without knowing “the specific dangers” that led the agency to set the permissible level, and thus the regulations are not relevant at all without this information. Even with respect to specific causation, the regulatory infraction may be weak or null evidence for causation. Slip op. at 18-19 (citing Cunningham v. Masterwear Corp., 569 F.3d 673, 674–75 (7th Cir. 2009).

Temporality

Byers and Dahlgren also emphasized that the children’s symptoms began after exposure and abated after removal from exposure. Slip op. at 9, 6-7. Both the trial and appellate courts were duly unimpressed by the post hoc ergo propter hoc argument. Slip op. at 19, citing Ervin v. Johnson & Johnson, 492 F.3d 901, 904-05 (7th Cir. 2007) (“The mere existence of a temporal relationship between taking a medication and the onset of symptoms does not show a sufficient causal relationship.”).

Increased Risk of Cancer

The plaintiffs’ expert witnesses offered opinions about the children’s future risk of cancer that were truly over the top. Dahlgren testified that the children were “highly likely” to develop cancer in the future. Slip op. at 6. Ryer-Powder claimed that the children’s exposures were “sufficient to present an unacceptable risk of cancer in the future.” Slip op. at 10. With no competence evidence to support their claims of present or past injury, these opinions about future cancer were no longer relevant. The Circuit thus missed an opportunity to comment on how meaningless these opinions were. Most people will develop a cancer at some point in their lifetime, and we might all agree that any risk is unacceptable, which is why medical research continues into the causes, prevention, and cure of cancer. An unquantified risk of cancer, however, cannot support an award of damages even if it were a proper item of damages. See, e.g., Sutcliffe v. G.A.F. Corp., 15 Phila. 339, 1986 Phila. Cty. Rptr. LEXIS 22, 1986 WL 501554 (1986). See also “Back to Baselines – Litigating Increased Risks” (Dec. 21, 2010).

[1] Steven J. Smith, et al., “Molecular Epidemiology of p53 Protein Mutations in Workers Exposed to Vinyl Chloride,” 147 Am. J. Epidemiology 302 (1998) (average level of workers’ exposure was 3,735 parts per million; children were supposedly exposed at 3 ppb). This study looked only at a putative biomarker for angiosarcoma of the liver, not at cancer risk.

[2] Cesare Maltoni, et al., “Carcinogenity Bioassays of Vinyl Chloride Monomer: A Model of Risk Assessment on an Experimental Basis, 41 Envt’l Health Persp. 3 (1981).

Posted in Causation, Rule 702, Scientific Evidence | Comments Off on Seventh Circuit Affirms Exclusion of Expert Witnesses in Vinyl Chloride Case

Time to Retire Ancient Documents As Hearsay Exception

August 23rd, 2015

The Committee on Rules of Practice and Procedure of the Judicial Conference of the United States has prepared a Preliminary Draft of Proposed Amendments to the Federal Rules of Bankruptcy Procedure and the Federal Rules of Evidence (Aug. 2015). The Committee seeks approval of proposed amendments to Bankruptcy Rules 1001 and 1006, and to Federal Rules of Evidence Rules 803 (16)and 902. See Debra Cassens Weiss, “Federal judiciary considers dumping ‘ancient documents’ rule,” ABA Journal Online (Aug. 19, 2015).

Rule 803(16) of the Federal Rules of Evidence is the so-called ancient document exception to the rule against hearsay. The proposed amendment would abolish this hearsay exception.

The Federal Rules of Evidence, as well as most state rules and common law, allow for the authentication of ancient documents, by showing just three things:

(A) is in a condition that creates no suspicion about its authenticity;

(B) was in a place where, if authentic, it would likely be; and

(C) is at least 20 years old when offered.

Federal Rule of Evidence 902(8) (“Evidence About Ancient Documents or Data Compilations”). Rule 803(16) goes beyond the authentication to permit the so-called ancient document, more than 20-years old, appearing to be authentic, to be admitted for its truth. The Committee is seeking the abrogation of Rule 803(16), the ancient documents exception to the hearsay rule. The proposal is based upon an earlier report of the Advisory Committee on Evidence Rules. See Hon. William K. Sessions, III, Chair, Report of the Advisory Committee on Evidence Rules (May 7, 2015).

The requested change is based upon the Committee’s understanding that the exception is rarely used, and upon the development of electronic documents, which makes the exception unneccessary because so-called ancient documents would usually be admissible under the business records or the residual hearsay exceptions. Comments can be submitted online or in writing, by February 16, 2016.

The fact that a document is old may perhaps add to its authenticity, but in many technical, scientific, and medical contexts, the “ancient” provenance actually makes the content unlikely to be true. The pace of change of technical and scientific opinion and understanding is too fast to indulge this exception that permits false statements of doubtful validity to confuse the finder of fact. The rule as currently in effect is thus capable of a good deal of mischief. With respect to statements or claims to scientific knowledge, the Federal Rules of Evidence has evolved towards a system of evidence-based opinion, and away from naked opinion based upon the apparent authority or prestige of the speaker. Similarly, the age of the speaker or of the document provides no warrant for the truth of the document’s content. Of course, the statements in authenticated ancient documents remain relevant to the declarant’s state of mind, and nothing in the proposed amendment would affect this use of the document. As for the contested truth of the document’s content, there will usually be better, more recent, and sounder scientific evidence to support the ancient document’s statements if those statements are indeed correct. In the unlikely instance that more recent, more exacting evidence is unavailable, and the trustworthiness of the ancient document’s statements can be otherwise established, then the statements would probably be admissible pursuant to other exceptions to the rule against hearsay, as noted by the Committee.

Posted in Scientific Evidence, Trial Procedure | Comments Off on Time to Retire Ancient Documents As Hearsay Exception

Publication of Two Symposia on Scientific Evidence in the Law

August 2nd, 2015

The Journal of Philosophy, Science & Law bills itself as an on-line journal for the interdisciplinary exploration of philsophy, science, and law. This journal has just made its “Daubert Special” issue available at its website:

Jason Borenstein and Carol Henderson, “Reflections on Daubert: A Look Back at the Supreme Court’s Decision,” 15 J. Philos., Sci. & Law 1 (2015)

Mark Amadeus Notturno, “Falsifiability Revisited: Popper, Daubert, and Kuhn,” 15 J. Philos., Sci. & Law 5 (2015)

Tony Ward, “An English Daubert? Law, Forensic Science and Epistemic Deference,” 15 J. Philos., Sci. & Law 26 (2015)

Daniella McCahey & Simon A. Cole, “Human(e) Science? Demarcation, Law, and ‘Scientific Whaling’ in Whaling in the Antarctic” 15 J. Philos., Sci. & Law 37 (2015)

Back in January 30 – 31, 2015, the Texas Law Review called for a Conference on Science Challenges for Law and Policy, to focus on issues arising at intersection of science and law, with particular focus on issues arising in criminal justice, bioethics, and the environment. The Conference schedule is still available here. Conference papers addressed the nature of scientific disputes, the role of expertise in resolving such disputes, and the legal implementation and management of scientific knowledge. Some of the Conference papers are now available in the symposium issue of the 2015 Texas Law Review:

Rebecca Dresser, “The ‘Right to Try’ Investigational Drugs: Science and Stories in the Access Debate,” 93 Tex. L. Rev. 1631

David L. Faigman, “Where Law and Science (and Religion?) Meet,” 93 Tex. L. Rev. 1659 (2015)

Jennifer E. Laurin, “Criminal Law’s Science Lag: How Criminal Justice Meets Changed Scientific Understanding,” 93 Tex. L. Rev. 1751 (2015)

Elizabeth Fisher, Pasky Pascual & Wendy Wagner, “Rethinking Judicial Review of Expert Agencies,” 93 Tex. L. Rev. 1681 (2015)

Sheila Jasanoff, “Serviceable Truths: Science for Action in Law and Policy,” 93 Tex. L. Rev. 1723 (2015)

Thomas O. McGarity, “Science and Policy in Setting National Ambient Air Quality Standards: Resolving the Ozone Enigma,” 93 Tex. L. Rev. 1783 (2015)

Jennifer L. Mnookin, “Constructing Evidence and Educating Juries: The Case for Modular, Made-In-Advance Expert Evidence About Eyewitness Identifications and False Confessions,” 93 Tex. L. Rev. 1811 (2015)

Posted in Expert Witnesses, Rule 702, Scientific Evidence | Comments Off on Publication of Two Symposia on Scientific Evidence in the Law

Events, Outcomes, and Effects – Media Responsibility to Be Accurate

July 29th, 2015

Thanks to Dr. David Schwartz for the pointer to a story, by a Bloomberg, Reuters health reporter, on a JAMA online-first article on drug “side effects.” See David Schwartz, “Lack of compliance on ADR Reporting: Some serious drug side effects not told to FDA within 15 days” (July 29, 2015).

The reporter, Lisa Rapaport, wrote about an in-press article in JAMA Internal Medicine, about delays in drug company mandatory reporting. Lisa Rapaport, “Some serious drug side effects not told to FDA within 15 days,” (July 27, 2015). The article that gave rise to this media coverage, however, was not about side effects, or direct effects, for that matter; it was about adverse events. See Paul Ma, Iván Marinovic, and Pinar Karaca-Mandic, “Drug Manufacturers’ Delayed Disclosure of Serious and Unexpected Adverse Events to the US Food and Drug Administration,” JAMA Intern. Med. (published online July 27, 2015) (doi:10.1001/jamainternmed.2015.3565).

The word “effect[s]” occurs 10 times in Rapaport’s news item; and yet, that word does not appear at all in the JAMA article, except in a footnote that points to a popular media article. And Reuters is the source of the footnoted popular media article.[1] Apparently, Reuter’s reporters are unaware of the difference between an event and an effect. The companies’ delay in reporting apparently made up 10% of all adverse event reports, but spinning the story as though it were about adverse effects makes the story seem more important and the delays more nefarious.

Why would a reporter covering a medical journal article not be familiar with the basic terminology and concepts at issue? The FDA’s description of its adverse event system makes clear that adverse events have nothing to do with “effects.” The governing regulations for post-marketing reporting of adverse drug experiences are even more clear that adverse events or experiences are not admissions or conclusions of causality. 21 C.F.R. 314.80(a), (k). See also ICH Harmonised Tripartite Guideline for Good Clinical Practice E6(R1) (10 June 1996).

Perhaps this is an issue with which Sense about Science USA can help? Located in the brain basket of America – Brooklyn, NY – Sense about Science is:

“a non-profit, non-partisan American branch of the British charitable trust, Sense About Science, which was founded in 2003 and which grew to play a pivotal role in promoting scientific understanding and defending scientific integrity in the UK and Europe.”

One of the organization’s activities is offering media help in understanding scientific and statistical issues. Let’s hope that they take the help being offered.

[1] S. Heavey, “FDA warns Pfizer for not reporting side effects” (June 10, 2010).

Posted in Causation, Scientific Evidence | Comments Off on Events, Outcomes, and Effects – Media Responsibility to Be Accurate

California Actos Decision Embraces Relative-Risk-Greater-Than-Two Argument

July 28th, 2015

A recent decision of the California Court of Appeal, Second District, Division Three, continues the dubious state and federal practice of deciding important issues under cover of unpublished opinions. Cooper v. Takeda Pharms. America, Inc., No. B250163, 2015 Cal. App. Unpub. LEXIS 4965 (Calif. App., 2nd Dist., Div. 3; July 16, 2015). In Cooper, plaintiff claimed that her late husband’s bladder cancer was caused by defendant’s anti-diabetic medication, Actos (pioglitazone). The defendant moved to strike the expert witness testimony in support of specific causation. The trial judge expressed serious concerns about the admissibility of plaintiff’s expert witnesses on specific causation, but permitted the trial to go forward. After a jury returned its verdict in favor of plaintiff, the trial court entered judgment for the defendants, on grounds that the plaintiff lacked admissible expert witness testimony.

Although a recent, large, well-conducted study[1] failed to find any meaningful association between pioglitazone and bladder cancer, there were, at the time of trial, several studies that suggested an association. Plaintiff’s expert witnesses, epidemiologist Dr. Alfred Neugut and bladder oncologist Dr. Norm Smith interpreted the evidence to claim a causal association, but both conceded that there were no biomarkers that allowed them to attribute Cooper’s cancer to pioglitazone. The plaintiff also properly conceded that identifying a cause of the bladder cancer was irrelevant to treating the disease. Cooper, 2015 Cal. App. Unpub. LEXIS 4965, at *13. Specific causation was thus determined by the so-called process of differential etiology, with the ex ante existence of risk substituting for cause, and using risk exposure in the differential analysis.

The trial court was apparently soured on Dr. Smith’s specific causation assessment because of his poor performance at deposition, in which he demonstrated a lack of understanding of Cooper’s other potential exposures. Smith’s spotty understanding of Cooper’s actual and potential exposures and other risks made any specific causation assessment less than guesswork. By the time of trial, Dr. Smith and plaintiff’s counsel had backfilled the gaps, and Smith presented a more confident analysis of Cooper’s exposures and potentially competing risks.

Cooper had no family history of bladder cancer, no alcohol consumption, and no obvious exposure to occupational bladder carcinogens. His smoking history would account for exposure to a known bladder carcinogen, cigarette smoke, but Cooper’s documented history was of minor tobacco use, and remote in time. Factually, Cooper’s history was suspect and at odds with his known emphysema. Based upon this history, along with their causal interpretation of the Actos bladder cancer association, and their quantitative assessment that the risk ratio for bladder cancer from Actos was 7.0 or higher for Mr. Cooper (controlled for covariate, potential confounders), the plaintiff’s expert witnesses opined that Actos was probably a substantial factor in causing Mr. Cooper’s bladder cancer. The court did not examine the reasonableness of Dr. Smith’s risk ratios, which seem exorbitant in view of several available meta-analyses.[2]

The court stated that under the applicable California law of “substantial factor,” the plaintiff’s expert witness, in conducting a differential diagnosis, need not exclude every other possible cause of plaintiff’s disease “with absolute certainty.” Cooper, at *41-42. This statement leaves unclear and ambiguous whether the plaintiff’s expert witness must (and did in this case) rule out other possible causes with some level of certitude less than “absolute certainty,” such as reasonable medical certainty, or perhaps reasonable probability. Dr. Smith’s testimony, as described, did not attempt to go so far as to rule out smoking as “a cause” of Cooper’s bladder cancer; only that the risk from smoking was a lower order of magnitude than that for Actos. In Dr. Smith’s opinion, the discrepancy in magnitude between the risk ratios for smoking and Actos allowed him to state confidently that Actos was the most substantial risk.

Having estimated the smoking-related increased risk to somewhere between 0 and 100%, with the Actos increased risk at 600% or greater, Dr. Smith was able to present an admissible opinion that Actos was a substantial factor. Of course, this all turns on the appellate court’s acceptance of risk, of some sufficiently large magnitude, as evidence of specific causation. In the Cooper court’s words:

“The epidemiological studies relied on by Dr. Smith indicated exposure to Actos® resulted in hazard ratios for developing bladder cancer ranging from 2.54 to 6.97.¹⁸ By demonstrating a relative risk greater than 2.0 that a product causes a disease, epidemiological studies thereby become admissible to prove that the product at issue was more likely than not responsible for causing a particular person’s disease. “When statistical analyses or probabilistic results of epidemiological studies are offered to prove specific causation . . . under California law those analyses must show a relative risk greater than 2.0 to be ‘useful’ to the jury. Daubert v. Merrell Dow Pharmaceuticals Inc., 43 F.3d 1311, 1320 (9th Cir.), cert. denied 516 U.S. 869 (1995) [Daubert II]. This is so, because a relative risk greater than 2.0 is needed to extrapolate from generic population-based studies to conclusions about what caused a specific person’s disease. When the relative risk is 2.0, the alleged cause is responsible for an equal number of cases of the disease as all other background causes present in the control group. Thus, a relative risk of 2.0 implies a 50% probability that the agent at issue was responsible for a particular individual’s disease. This means that a relative risk that is greater than 2.0 permits the conclusion that the agent was more likely than not responsible for a particular individual’s disease. [Reference Manual on Scientific Evidence (Federal Judicial Center 2d ed. 2000) (“Ref. Manual”),] Ref. Manual at 384, n. 140 (citing Daubert II).” (In re Silicone Gel Breast Implant Prod. Liab. Lit. (C.D. Cal. 2004) 318 F.Supp.2d 879, 893; italics added.) Thus, having considered and ruled out other background causes of bladder cancer based on his medical records, Dr. Smith could conclude based on the studies that it was more likely than not that Cooper’s exposure to Actos® caused his bladder cancer. In other words, because the studies, to varying degrees, adjusted for race, age, sex, and smoking, as well as other known causes of bladder cancer, Dr. Smith could rely upon those studies to make his differential diagnosis ruling in Actos®—as well as smoking—and concluding that Actos® was the most probable cause of Cooper’s disease.”

Cooper, at *78-80 (emphasis in the original).

Of course, the epidemiologic studies themselves are not admissible, regardless of the size of the relative risk, but the court was, no doubt, speaking loosely about the expert witness opinion testimony that was based upon the studies with risk ratios greater than two. Although the Cooper case does not change California law’s facile acceptance of risk as a substitute for cause, the case does base its approval of plaintiff’s expert witness’s attribution as turning on the magnitude of the risk ratio, adjusted for confounders, as having exceeded two. The Cooper case leaves open what happens when the risk that is being substituted for cause is a ratio ≤ 2.0. Some critics of the risk ratio > 2.0 inference have suggested that risk ratios greater than two would lead to directed verdicts for plaintiffs in all cases, but this suggestion requires demonstrations of both the internal and external validity of the studies that measure the risk ratio, which in many cases is in doubt. In Cooper, the plaintiff’s expert witnesses’ embrace of a high, outlier risk ratio for Actos, while simultaneously downplaying competing risks, allowed them to make out their specific causation case.

[1] James D. Lewis, Laurel A. Habel, Charles P. Quesenberry, Brian L. Strom, Tiffany Peng, Monique M. Hedderson, Samantha F. Ehrlich, Ronac Mamtani, Warren Bilker, David J. Vaughn, Lisa Nessel, Stephen K. Van Den Eeden, and Assiamira Ferrara, “Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes,” 314 J. Am. Med. Ass’n 265 (2015) (adjusted hazard ratio 1.06, 95% CI, 0.89-1.26).

[2] See, e.g., R.M. Turner, et al., “Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis,” 78 Brit. J. Clin. Pharmacol. 258 (2014) (OR = 1.51, 95% CI 1.26-1.81, for longest cumulative duration of pioglitazone use); M. Ferwana, et al., “Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies,” 30 Diabet. Med. 1026 (2013) (based upon 6 studies, with median follow-up of 44 months, risk ratio = 1.23; 95% CI 1.09-1.39); Cristina Bosetti, “Cancer Risk for Patients Using Thiazolidinediones for Type 2 Diabetes: A Meta-Analysis,” 18 The Oncologist 148 (2013) (RR = 1.64 for longest exposure); Shiyao He, et al., “Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis,” 35 Tumor Biology 2095 (2014) (pooled hazard ratio = 1.67 (95% C.I., 1.31 – 2.12).

Posted in Causation, Expert Witnesses, Risk and Risk Factor, Rule 702, Scientific Evidence | Comments Off on California Actos Decision Embraces Relative-Risk-Greater-Than-Two Argument

Canadian Judges’ Reference Manual on Scientific Evidence

July 24th, 2015

I had some notion that there was a Canadian version of the Reference Manual on Scientific Evidence in the works, but Professor Greenland’s comments in a discussion over at Deborah Mayo’s blog drew my attention to the publication of the Science Manual for Canadian Judges [Manual]. See “‘Statistical Significance’ According to the U.S. Dept. of Health and Human Services (ii),” Error Statistics Philosophy (July 17, 2015).

The Manual is the product of the Canadian National Judicial Institute (NJI), which is an independent, not-for-profit group that is committed to educating Canadian judges. The NJI’s website describes the Manual:

“Without the proper tools, the justice system can be vulnerable to unreliable expert scientific evidence.

* * *

The goal of the Science Manual is to provide judges with tools to better understand expert evidence and to assess the validity of purportedly scientific evidence presented to them. …”

The Chief Justice of Canada, Hon. Beverley M. McLachlin, contributed an introduction to the Manual, which was notable for its frank admission that:

“[w]ithout the proper tools, the justice system is vulnerable to unreliable expert scientific evidence.

****

Within the increasingly science-rich culture of the courtroom, the judiciary needs to discern ‘good’ science from ‘bad’ science, in order to assess expert evidence effectively and establish a proper threshold for admissibility. Judicial education in science, the scientific method, and technology is essential to ensure that judges are capable of dealing with scientific evidence, and to counterbalance the discomfort of jurists confronted with this specific subject matter.”

Manual at 14. These are laudable goals, indeed.

The first chapter of the Manual is an overview of Canadian law of scientific evidence, “The Legal Framework for Scientific Evidence,” by Canadian law professors Hamish Stewart (University of Toronto), and Catherine Piché (University of Montreal). Several judges served as peer reviewers.

The second chapter, “Science and the Scientific Method,” contains the heart of what judges supposedly should know about scientific and statistical matters to serve as effective “gatekeepers.” Like the chapters in the Reference Manual on Scientific Evidence, this chapter was prepared by a scientist author (Scott Findlay, Ph.D., Associate Professor of Biology, University of Ottawa) and a lawyer author (Nathalie Chalifour, Associate Professor of Law, University of Ottawa). Several judges, and Professor Brian Baigrie (University of Toronto, Victoria College, and the Institute for the History and Philosophy of Science and Technology) provided peer review. The chapter attempts to cover the demarcation between science and non-science, and between scientific and other expert witness opinion. The authors describe “the” scientific method, hypotheses, experiments, predictions, inference, probability, statistics and statistical hypothesis testing, data reliability, and related topics. A subsection of chapter two is entitled “Normative Issues in Science – The Myth of Scientific Objectivity,” which suggests a Feyerabend, post-modernist influence at odds with the Chief Justice’s aspirational statement of goals in her introduction to the Manual.

Greenland noted some rather cavalier statements in Chapter two that suggest that the conventional alpha of 5% corresponds to a “scientific attitude that unless we are 95% sure the null hypothesis is false, we provisionally accept it.” And he pointed elsewhere where the chapter seems to suggest that the coefficient of confidence that corresponds to an alpha of 5% “constitutes a rather high standard of proof,” thus confusing and conflating probability of random error with posterior probabilities. Some have argued that these errors are simply an effort to make statistical concepts easier to grasp for lay people, but the statistics chapter in the FJC’s Reference Manual shows that accurate exposition of statistical concepts can be made understandable. The Canadian Manual seems in need of some trimming with Einstein’s razor, usually paraphrased as “Everything should be made as simple as possible, but no simpler.”[1] The razor should certainly applied to statistical concepts, with the understanding that pushing to simplify too aggressively can sometimes result in simplistic, and simply wrong, exposition.

Chapter 3 returns to more lawyerly matters, “Managing and Evaluating Expert Evidence in the Courtroom,” prepared and peer-reviewed by prominent Canadian lawyers and judges. The final chapter, “Ethics of the Expert Witness,” should be of interest to lawyers and judges in the United States, where the topic is largely ignored. The chapter was prepared by Professor Adam Dodek (University of Ottawa), along with several writers from the National Judicial Institute, the Canadian Judicial Council, American College of Trial Lawyers, Environment Canada, and notably, Joe Cecil & the Federal Judicial Center.

Weighing in at 228 pages, the Science Manual for Canadian Judges is much shorter than the Federal Judicial Center’s Reference Manual on Scientific Evidence. Unlike the FJC’s Reference Manual, which is now in its third edition, the Canadian Manual has no separate chapters on regression, DNA testing and forensic evidence, clinical medicine and epidemiology. The coverage of statistical inference is concentrated in chapter two, but that chapter has no discussion of meta-analysis, systematic review, evidence-based medicine, confounding, and the like. Perhaps there will soon be a second edition of the Science Manual for Canadian Judges.

[1] See Albert Einstein, “On the Method of Theoretical Physics; The Herbert Spencer Lecture,” delivered at Oxford (10 June 1933), published in 1 Philosophy of Science 163 (1934) (“It can scarcely be denied that the supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience.”).

Posted in Expert Witnesses, Rule 702, Scientific Evidence, statistical evidence, Trial Procedure | Comments Off on Canadian Judges’ Reference Manual on Scientific Evidence