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3 understanding and applying epidemiology hb lead-conf

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HB Litigation Conferences Lead Litigation 2013

HB Litigation Conferences Lead Litigation 2013

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  • 1. November 14-15, 2013
  • 2. Cris A. Williams, PhD ENVIRON Gary H. Abelson Hiscock & Barclay LLP Nicholas Szokoly Law Offices of Evan K. Thalenberg, P.A. Karl Kieburtz, MD, MPH University of Rochester Medical Center
  • 3. Observational case series – clinical observation ecologic associations – existing data cross sectional (prevalence) – existing/new data case-control – new data cohort – retrospective – existing/new data prospective – new data Interventional non-randomized trial randomized, controlled trials
  • 4. Major: Temporal Biological Plausibility Consistency Alternative Explanations Explored Other: Dose-response Relationship Strength of Association Cessation Effects Gordis 1990
  • 5. Intended to answer the following questions: Does the agent get to where it may exert injury? At a sufficient concentration? In a biologically active form? Does it engage the target of interest? Does it influence downstream biology/pharmacology? At what dose?
  • 6. Studies that are designed to show that an exposure/agent modifies a health state
  • 7. • Randomization • Blinding to treatment Attempts to reduce bias and to improve the quality of evidence.
  • 8. Medicine is always confronted with estimating what the benefits and toxicities of interventions might be in a specific patient, given the evidence available from populations, usually with little data about ‘matched’ individuals
  • 9. Karch and Lasangna Widely used in assessing adversity Uncommon in thinking about benefit Principles are the same
  • 10.        Karl’s topic – Basics of Clinical Trials/How Medicine Looks at Causation Introduction to Epidemiology Epi Study Designs and Strengths/Limitations Karl’s topic – How to Determine Causation in an Individual Lead Studies Overview Lead Studies from the Plaintiffs’ Perspective Lead Studies from the Defense Perspective
  • 11.   Definition – study of occurrence of disease in populations Subtypes according to exposure/agent ◦ Biological – i.e., infectious disease (cholera) ◦ Environmental  Natural environment (radon, asbestos, arsenic, lead)  Man-made or “anthropogenic”, incl. occupational (e.g., benzene but also asbestos, arsenic, lead)
  • 12.  Descriptive studies ◦ For hypothesis generation/identification of risk factors ◦ Use data/information from readily-available sources (census, disease registries, vital stats) ◦ Cannot establish causal associations between exposure and disease ◦ Two subtypes: ecological; cross-sectional  Analytical studies ◦ Hypothesis testing ◦ Quantify relative risk of disease ◦ Can establish causal associations between exposure and disease ◦ Two subtypes: case-control; cohort
  • 13.   Compare outcome frequencies between different groups during the same time period or in the same population at different time periods Example – birth weight distributions in two different regions with different levels of arsenic in drinking water  No information on individuals’ exposure  No control of confounding (e.g., smoking)
  • 14.    Presence or absence of both exposure and outcome are assessed simultaneously; i.e., a “snapshot” Example – study of infertility and psychological stress Cannot distinguish whether exposure preceded outcome
  • 15.  Subjects selected on the basis of whether they have (cases) or don’t have (controls) a specific outcome     Example – study of lung cancer cases and controls and residential radon exposure Good for diseases with long latency periods and for rare diseases Time- and cost-efficient Susceptible to bias ◦ Selection (e.g., hospital admits) ◦ Recall (e.g., regarding exposure)
  • 16.      A group of individuals are defined on the basis of the presence or absence of exposure (e.g., worker studies) Prospective – cohort identified and followed forward in time (exposure has not yet occurred) Retrospective – cohort identified and traced backward in time (exposure had already occurred) Longitudinal – cohort is the same individuals tracked forward or backward Most studies relating lead exposure to IQ are longitudinal retrospective studies
  • 17. Study Type Strengths Limitations Ecological Quick, inexpensive, uses readilyavailable information. No exposure information, doesn’t control for confounding. Cross-sectional Quick, inexpensive, can provide valuable information on health status of a population. Cannot determine whether exposure preceded or resulted from disease. Case-control Good for diseases with long latency periods and for rare disease, time- and cost-efficient, can examine multiple etiologic factors for a single disease. Good for rare diseases, temporal relationship between exposure and disease difficult to establish, results may be biased (selection and recall). Cohort Good for rare exposures, can assess multiple effects of a single exposure and temporal relationship between exposure and disease, minimizes bias, allows for determination of disease incidence rates. Not good for rare diseases, expensive and time-consuming (prospective), requires availability of adequate records (retrospective), susceptible to loss to follow up. Source: Nielsen and Jensen (2005).
  • 18.  Dozens of studies relating blood lead and neurobehavior/cognitive development in humans and animals  Dating from the late 1970’s  Key studies/reviews ◦ Needleman and Gatsonis (1990) – Low-level Lead Exposure and the IQ of Children. A Meta-analysis of Modern Studies (JAMA 263:673-678) ◦ Canfield et al. (2003a) – Intellectual Impairment in Children with Blood Lead Concentrations Below 10 µg per Deciliter (N Engl J Med 348:1517-1526) ◦ Lanphear et al. (2005) – Low-level Environmental Lead Exposure and Children’s Intellectual Function: An International Pooled Analysis (Environ Health Perspect 113:894–899)
  • 19.  Key reviews/commentary ◦ Kaufman (2001a) – Do Low Levels of Lead Produce IQ Loss in Children?: A Careful Examination of the Literature? (Archives of Clinical Neuropsychology 16:303-341) ◦ Needleman and Bellinger (2001) – Studies of Lead Exposure and the Developing Central Nervous System: A Reply to Kaufman (Archives of Clinical Neuropsychology 16:359-374) ◦ Kaufman (2001b) – How Dangerous are Low (Not Moderate or High) Doses of Lead for Children' s Intellectual Development? (Archives of Clinical Neuropsychology 16:403-431)    Early studies – established the effect Later studies – establishing the effect at increasingly lower PbB “Plaintiff” studies and “Defense” studies
  • 20.     The hypothesis that Pb damages children's brains at low doses is widely accepted There is no safe level of PbB/a linear inverse relationship exists between PbB and intelligence test scores (IQ) – i.e., no threshold Correlations between PbB and IQ are socially relevant Correlations between PbB and IQ remain when confounders were considered
  • 21. The hypothesis that Pb affects IQ at low doses is widely accepted (EPA 2013)    12 major prospective studies, 1992-2011 3 cross-sectional studies, 1987-2011 4 “meta” analyses/pooled studies, 19902005
  • 22. There is no safe level of blood lead/a linear inverse relationship exists between PbB and intelligence test scores (IQ) – i.e., no threshold     Boston cohort – PbB = 1-9.3 μg/dL (Schwartz 1994) Rochester cohort – PbB = 0.5-8.4 μg/dL (Canfield et al. 2003b) Mexico City cohort – PbB = 0.8-4.9 μg/dL (Téllez-Rojo 2008) North Carolina cohort – PbB = 2 μg/dL (Miranda et al. 2009)* *EOG (4th grade) as a surrogate for IQ.
  • 23. Correlations between PbB and IQ are socially relevant (Needleman and Bellinger 2001)      shift of IQ scores occurred across entire distribution of IQ scores  shift in median scores of 6 points associated with 4-fold increase in IQ scores <80 5% of population failed to achieve superior IQ scores >125 Exposures in early childhood associated with 7x increase in high school failure and a 6x increase in reading disabilities
  • 24. Correlations between PbB and IQ remain when confounders were considered (Needleman and Bellinger 2001)    Prospective studies controlled for at least some measure of maternal IQ Most studies controlled for at least global measures of SES; in some cases controlled for home environment more specifically (e.g., via HOME, FACES, etc.) Persons administering the IQ tests in most of the studies were adequately trained in psychometrics
  • 25.     The hypothesis that Pb affects IQ at low doses is controversial There is a level of PbB below which effects on IQ are insignificant – i.e., a threshold Correlations between PbB and IQ are not socially relevant Correlations between PbB and IQ largely disappear when confounders were considered
  • 26. The hypothesis that Pb consistently affects IQ at low doses is controversial     Inconsistency in IQ findings both between studies and within studies (Ernhart 1995) Studies purported to be “low-lead” studies in humans (and animals) are actually moderate- to high-lead studies (Kaufman 2001b) Gender-specific effects – some studies showed > effects in girls than boys; others demonstrated the opposite (Hebben 2001) Although many studies report a significant association between lead and IQ, lead tends to account for a very small amount of variance in IQ (Bellinger and Dietrich 1994)
  • 27. There is a level of PbB below which effects on IQ are insignificant – i.e., a threshold   Assumption of PbB/IQ linearity based not on actual data but rather on dubious regression analyses (Kaufman 2001b) EPA’s Integrated Science Assessment for Lead (EPA 2013) ◦ Lack of a reference population (PbB in pre-industrial population) limits ability to identify a threshold ◦ “. . . the current evidence does not preclude the possibility of a threshold for neurodevelopmental effects in children existing with lower blood levels than those currently examined.”
  • 28. Correlations between PbB and IQ are not socially relevant (Kaufman 2001b)    A few IQ points is well within a reasonable band of error around the observed score The usual IQ loss attributed to low PbB is similar in magnitude to the 2- to 3-point mean gender difference (favoring males) IQ score is meaningless without measurement of other aspects of intellectual functioning – e.g., creativity, social intelligence, practical intelligence, adaptive behavior, mechanical ability, etc.
  • 29. Correlations between PbB and IQ largely disappear when confounders were considered (Kaufman 2001a and b)  For the 26 PbB/IQ studies where confounders may have affected the results: ◦ ◦ ◦ ◦ ◦ 12 used only a global assessment of SES 17 used a “poor” or no measure of maternal IQ 24 did not test father’s IQ 24 did not control for persistent otitis media 18 did not control for pregnancy risk factors (e.g., maternal drug use/abuse, smoking)
  • 30. Difference in Maternal IQ Scores Difference in HOME Scores Difference in Parental Years of Education 7.5 3.6 0.75 7.58 9.42 11.27 1.5 9.11 10.96 12.81 2.25 10.65 12.50 14.35 0.75 11.77 13.62 15.46 1.5 13.30 15.15 17.00 2.25 14.84 16.69 18.54 0.75 15.96 17.81 19.65 1.5 17.50 19.34 21.19 2.25 19.03 20.88 22.73 7.2 10.8 15 22.5 Difference in Child IQ Scores Source: Mink et al. (2004).
  • 31.  An additional “threat” to the validity of the Pb/IQ studies are variables associated with intelligence that are either unknown or unmeasurable – the “Flynn effect” (Kaufman 2001a) ◦ 3 point-per-decade gain in IQ beginning in the 1930’s and continuing to this day ◦ Exposure to technology/mass media? ◦ Parenting/increased awareness of importance of providing cognitive stimulation in infancy? ◦ Improved nutrition?
  • 32.         Bellinger, D., and Dietrich, K. N. 1994. Low-level lead exposure and cognitive function in children. Pediatric Annals 23:601-605. Canfield, R.L., Henderson, C.R. Jr., Cory-Slechta, D.A., Cox, C., Jusko, T.A., and Lanphear, B.P. 2003a. Intellectual Impairment in children with blood lead concentrations below 10 µg per deciliter. N Engl J Med 348:1517-1526. Canfield, R.L.., Kreher, D.A., Cornwell, C., and Henderson, C.R., Jr. 2003b. Low-level lead exposure, executive functioning, and learning in early childhood. Child Neuropsychol 9:35-53. EPA. 2013. Integrated Science Assessment for Lead. EPA/600/R-10/075F. Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, NC. Ernhart, C.B. 1995. Inconsistencies in the lead-effects literature exist and cannot be explained by "effect modification". Neurotoxicol Teratol. 17(3):227-233. Hebben, H. 2001. Low lead levels and neuropsychological assessment: Let us not be mislead. Archives of Clinical Neuropsychology 16:353-357. Kaufman, A.S. 2001a. Do low levels of lead produce IQ loss in children?: A careful examination of the literature? Archives of Clinical Neuropsychology 16:303-341. Kaufman, A.S. 2001b. How dangerous are low (not moderate or high) doses of lead for children' s intellectual development? Archives of Clinical Neuropsychology 16:403-431.
  • 33.        Lanphear, B.P., Hornung, R., Khoury, J., Yolton, K., Baghurst, P., Bellinger, D.C., Canfield, R.L., Dietrich, K.N., Bornschein, R., Greene, T., Rothenberg, S.J., Needleman, H.L., Schnaas, L., Wasserman, G., Graziano, J., and Roberts, R. 2005. Low-level environmental lead exposure and children’s intellectual function: An international pooled analysis (Environ Health Perspect 113:894–899. Mink, P.J., Goodman, M., Barraj, L.M., Imrey, H., Kelsh, M.A., and Yager. J. 2004. Evaluation of uncontrolled confounding in studies of environmental exposures and neurobehavioral testing in children. Epidemiology 15(4):385-393. Miranda, M.L., Kim, D., Reiter, J., Overstreet Galeano, MA., and Maxson, P. 2009. Environmental contributors to the achievement gap. Neurotoxicology 30:10191024. Needleman, H.L., and Bellinger, D. 2001. Studies of lead exposure and the developing central nervous system: A reply to Kaufman. Archives of Clinical Neuropsychology 16:359-374. Needleman, H.L., and Gatsonis, C.A. 1990. Low-level lead exposure and the IQ of children. A meta-analysis of modern studies. JAMA 263(5):673-678. Nielsen, J.B. and Jensen, T.K. 2005. Environmental Epidemiology. In: Essentials of Medical Geology – Impacts of the Natural Environment on Public Health. O. Selinus, Ed. Elsevier. Schwartz, J. 1994. Low-level lead exposure and children's IQ: A meta-analysis and search for a threshold. Environ Res 65:42-55..
  • 34.  Téllez-Rojo, M.M., Bellinger, D.C., Arroyo-Quiroz, C., Lamadrid-Figueroa, H., Mercado-Garcia, A., Schnaas-Arrieta, L., Wright, RO., Hernandez-Avila, M., and Hu, H. 2006. Longitudinal associations between blood lead concentrations lower than 10 microg/dL and neurobehavioral development in environmentally exposed children in Mexico City. Pediatrics 118:e323-e330.
  • 35. EPIDEMIOLOGIC STUDIES FOR LEAD WHAT ARE THEY GOOD FOR?
  • 36. • Can epidemiologic studies be used “across the board” to determine whether lead has affected a particular individual?
  • 37. General Causation v. Specific Causation
  • 38. • Population based studies • They were not designed – nor could they be – to determine whether a specific child has been affected by lead exposure
  • 39. Does A equal B? 1. Do all smokers get lung cancer? 2. Do all football players sustain brain injuries?
  • 40. • Epidemiologic Studies may show “general causation” • They cannot, by themselves, get to specific causation in an individual.
  • 41. • Lead and IQ – is there a correlation? 1. Is pre-morbid IQ testing necessary?
  • 42. a. In order to make an intelligent assessment of whether an individual has lost IQ points as a result of exposure to lead there must be a baseline. b.Studies that claim to quantify IQ loss as a result of exposure to lead are speculative.
  • 43. c. Not possible to “assign” a loss of IQ with any elevated lead level – only a comparison between preinjury testing and postinjury assessment can yield a true measure of intellectual change.
  • 44. d. Full scale IQ measure can be unreliable for determining a person’s actual level of cognitive capability. e. Neuropsychological testing is used to test areas involving memory, attention , executive functions, verbal fluency.
  • 45. f. How does an individual test in these areas? Have to look “behind the numbers” g. If a child scores low, medium or high on any test – does not mean they would have scored otherwise had there been no lead exposure
  • 46. • There is no specific/single neuropsychological test or result that allows for the conclusion that a specific child’s lead exposure had any impact.
  • 47. 2. Confounding Variables Significant and wellknown risk factors for the development of cognitive difficulties mirror claims of lead exposure:
  • 48. a. Low birth weight b.Maternal pregnancy issues – drugs/alcohol in utero exposure c. Prenatal smoking
  • 49. d. Parental involvement e. Structured environment/lack thereof f. Abuse issues 1) Mental 2) Physical 3) Sexual
  • 50. h. Potential foster care i. Outside influences j. Drug Use by individuals k. Depression/anxiety
  • 51. • Each individual different – cannot “control” for all variables • Fallacy of argument that confounding factors are being counted twice
  • 52. 3. School Performance a. Attendance – school and specific classes b. Homework completion c. Extra help
  • 53. d. e. f. g. Behavior problems Discipline problems Drug use Frequent changes in school – disruptive learning
  • 54. Conclusion General population studies are just that, not capable of being used to determine that any individual has been affected by alleged exposure to lead.
  • 55.  ONE OF THE LONGEST EPIDEMIOLOGICAL LONGITUDINAL STUDIES! Quit smoking on the advice of your physician?  Epidemiological research. Take Tamiflu in 2009?  Epidemiological research.
  • 56.   Lead is the most well studied toxin in history. International pooled analysis: ◦ Data, not average of averages. ◦ Seven participating sites:         Boston, Mass. Cincinnati, Ohio Cleveland, Ohio Mexico City, Mexico Port Pirie, Australia Rochester, NY Yugoslovia Approximately 1,300 children.
  • 57.  International Pooled Analysis ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ HOME Inventory Sex Birth weight Birth order Maternal education Maternal IQ Maternal age Marital status Prenatal smoking status Prenatal alcohol use
  • 58.  Q And I think you had said it once best, and tell if it sounds -- you said this, but just tell me if you still agree with it, the researchers control for those factors so that the conclusion of their study is specific to what is the measurable effect that lead has on IQ loss? A Correct. Q And that's in the context of the pooled analysis. And for Needleman, it would be the researchers controlled for those factors so the conclusion of their study is specific to what is the measurable effect that lead has on behavior? A Correct. Q And so it's incorrect to assume that in order to reach the opinions you have in this case, that you need administer the HOME test to the plaintiffs to determine whether or not their lead exposure caused them IQ loss? A That's correct. Q It's already been done. That's the point. A Well, and I'm only giving opinions about what IQ loss I would attribute using this type of medical literature to this particular child. Q And I know it sounds pedantic. Just work with me here. But the point that I'm making is that you don't have to go back in the forensic context and control for all these variables again. That's why the researchers did it in the first place? MR. [Lawyer for the Defendant]: Objection.  A           That's correct. Yes. I agree with that.
  • 59.   If only Johnny with his 65 IQ, reading disorder and ADHD wouldn’t have missed 30 days his 4th time in 9th grade, it would have all worked out okay. Hammond et al., May 2007 ◦ Among the top risk factors for dropping out of middle school and high school:  Learning disabled  Low academic achievement  Retention/over-age for grade  Multiple retentions have additive effects, dramatically increasing the risk of dropping out.
  • 60.                 Dr. Cris A. Williams Ph.D., Senior Science Advisor ENVIRON 850.668.3551 cwilliams@environcorp.com Gary Abelson Hiscock & Barclay LLP 585.295.8411 gabelson@hblaw.com Nicholas Szokoly Law Offices of Evan K. Thalenberg, P.A. 410.625.9200 nszokoly@ektlaw.com Dr. Karl Kieburtz MD, MPH University of Rochester Medical Center 585.275.8762 Karl.Kieburtz@chet.rochester.edu