gwern branwen
Partagé en mode public -How much of health and diet science is junk because it relies on epidemiological correlations and a denial that anything important is heritable? Looks like the ill effects of smoking during pregnancy may be a good example.
We all know correlation!=causation, but nevertheless it seems like common sense that if you find women who smoke while pregnant have more aggressive kids or with birth defects or cognitive problems that you should jump to ' #smoking while pregnant is evil'. Except you didn't measure all variables, not even close to it, and you omitted huge confounds like genetics and family factors. Thus it is we come to a paper like this:
D'Onofrio BM, Lahey BB, Turkheimer E, Lichtenstein P. "Critical need for family-based, quasi-experimental designs in integrating genetic and social science research"; excerpts:
"Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses.
We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles.
SDP [maternal smoking during pregnancy] is associated with increased likelihood of various offspring problems, including preterm birth and low birth weight, 13 infant mortality, 14 cognitive deficits, 15,16 obesity, 17 and social and behavioral difficulties (e.g., childhood conduct problem, adolescent delinquency, and substance use problems). 18,19 Several literature reviews have concluded that fetal exposure to maternal SDP causes these problems 13,18,19 because the statistical associations are well-replicated, robust to the use of statistical controls for measured confounds, and consistent with basic research on SDP conducted in animals. 20,21 Other researchers have hypothesized mechanisms through which maternal SDP influences offspring outcomes. 22 For instance, researchers have postulated that maternal SDP alters the development of brain systems responsible for stress reactivity, 23 reward sensitivity, 19,24 and decision-making, 25 which subsequently influence behavior and substance use problems. However, all of the analytic models used to study mediating variables, including developmental cascade models, are based on strong causal assumptions. 26 In particular, the models assume that there are no other causes of the associations among initial risks, the mediating variables, and the outcome of interest. It is clear, however, that maternal SDP is correlated with numerous environmental risks across multiple domains (e.g., maternal and paternal intellectual abilities, psychiatric problems, substance use problems, socioeconomic status, etc.) that also predict offspring problems. 27 In addition, maternal SDP is influenced by genetic factors, 28-- 30 with the genetic risk being correlated with both women's liability for nicotine dependence problems 29 and criminality, 30 consistent with the finding that genetic factors often influence multiple behavioral traits. 31,32 The fact that genetic factors influence SDP, therefore, means that genetic confounding factors could account for the association between SDP and offspring health and behavior problems. 33,34 Given the inability of human research to adequately account for all environmental and genetic selection factors, numerous researchers have cautioned against drawing causal inferences regarding maternal SDP 18,28,35-37 or, for that matter, all prenatal risks. 38,39
Correctly identifying the processes through which genetic and environmental factors interact, therefore, requires that researchers appropriately rule out environmental and genetic confounds of the causal relation. The assumptions concerning causal inferences have profound implications for studies that explore G·E of SDP with measured genotypes, 40,41 because all models assume that the putative environmental factor reflects purely environmental processes. 9,42,43 Researchers must rule out genetic confounding of environmental variables when conducting G·E studies, because genetic selection factors caused by gene-environment correlations (rGE; a related but distinct set of mechanisms we describe in the following section) can confound the study of G·E. 44,45
Family-based, quasi-experiments use "natural experiments" based on family relationships. When a study includes multiple family relationships that differ in their environmental exposure and genetic risk, quantitative genetic models can specifically test competing causal hypotheses. 28,53-55
Sibling-Comparison Designs:
Comparisons of differentially exposed siblings can help account for certain types of confounding. Comparisons of siblings raised in the same family automatically exclude confounding of the exposure with all environmental factors that are shared in common by the siblings. Comparisons of siblings can also help rule out genetic confounding. 59-61
Sibling-comparison studies of SDP [maternal smoking during pregnancy] and childhood conduct and oppositional problems, 76,82 attention or impulsivity problems, 76,86 intellectual abilities, 16,82 academic achievement or grades, 15,77,82 psychological functioning during adolescence, 75,87 suicidal behavior, 88 substance use and substance problems, 83 adolescent antisocial behavior, 89 and adolescent and young adult criminal convictions 87,89 have all reached the opposite conclusion-familial selection factors account for all of the associations. Although there is a robust correlation between maternal SDP and behavioral outcomes in between-family studies, differentially exposed siblings do not differ in the measured behaviors. Although there were concerns about the measurement of child functioning in some early sibling-comparison studies, 60,90 all published sibling-comparison studies of behavioral outcomes to date, including studies predicting normative traits, have concluded that familial selection factors, not exposure to maternal SDP, account for the associations.
This conclusion is reinforced by the fact that bidirectional case-cross studies 67 of intellectual abilities 16 suggest that some assumptions inherent in the sibling-comparison design (e.g., carry-over effects) were not violated and do not account for the findings. Recent studies combined different quasi-experimental designs to test other assumptions in sibling comparisons and helped identify the confounded selection factors that actually account for the association between maternal SDP and offspring psychosocial or cognitive problems. In a study that included half- and full-siblings, as well as half- and full-cousins, the authors found that confounded genetic influences accounted for part of the association between SDP and offspring intellectual abilities and academic achievement. 77 IVF studies likewise suggested that genetic factors passed down from women accounted for the statistical associations of SDP with offspring conduct problems 84 and attention deficit or hyperactivity problems. 85 Those results were also consistent with an offspring of twins study of SDP and offspring attention deficit or hyperactivity problems. 91 Finally, a recent study that combined sibling comparisons with an offspring of siblings design found that genetic liability shared by parents and offspring accounted for the association between SDP and offspring stress-coping. 75 The results of the quasi-experimental research was further supported by studies comparing unrelated individuals that included strong measured covariates in the analyses 36,92 or propensity score matching. 93 The converging evidence from studies using multiple designs, therefore, provides strong evidence that selection factors, including genetic confounds, account for the statistical associations between SDP and offspring psychosocial or cognitive problems.
- 15: Lambe M, Hultman C, Torrang MacCabe J, Cnattingius S. "Maternal smoking during pregnancy and school performance at age 15" https://pdf.yt/d/MSa3v_0EE3aCYN-c / https://dl.dropboxusercontent.com/u/243666993/2006-lambe.pdf . Epidemiology. 2006;17(5):524---530. - 16: Lundberg F, Cnattingius S, D'Onofrio B, et al. "Maternal smoking during pregnancy and intellectual performance in young adult Swedish male offspring" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653250/ . Paediatr Perinat Epidemiol. 2010;24(1):79---87. - 36: Silberg JL, Parr T, Neale MC, M, Angold A, Eaves LJ. "Maternal smoking during pregnancy and risk to boys' conduct disturbance: an examination of the causal hypothesis" http://www.vipbg.vcu.edu/vipbg/Articles/biopsychiatry-maternal-2003.pdf . Biol Psychiatry. 2003;53(2):130---135. - 60: Rutter M. "Proceeding from observed correlation to causal inference: the use of natural experiments" http://psych.colorado.edu/~willcutt/pdfs/rutter_2007.pdf . Perspect Psychol Sci. 2007;2(4):377---395. - 67: Meyer KA, Williams P, Hernandez-Diaz S, Cnattingius S. "Smoking and the risk of oral clefts: exploring the impact of study designs" https://pdf.yt/d/EHvJOOIx5FynCeeo / https://dl.dropboxusercontent.com/u/243666993/2004-meyer.pdf . Epidemiology. 2004;15(6): 671---678. - 75: Kuja-Halkola R, D'Onofrio BM, Illiadou A, Pawitan Y, Langstrom N, Lichtenstein P. "Prenatal smoking exposure and offspring stress coping in late adolescence: no causal link" http://ije.oxfordjournals.org/content/39/6/1531.full . Int J Epidemiol. 2010;39 (6):1531---1540. - 76: D'Onofrio BM, Van Hulle CA, Waldman ID, et al. "Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737574/ . Dev Psychopathol. 2008;20(1):139---164. - 77: D'Onofrio BM, Singh AL, Iliadou A, et al. "A quasi-experimental study of maternal smoking during pregnancy and offspring academic achievement" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656473/ . Child Dev. 2010;81(1):80---100. - 82: Gilman SE, Gardener H, Buka SL. "Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor?" http://aje.oxfordjournals.org/content/168/5/522.full.pdf Am J Epidemiol. 2008;168(5):522---531. - 83: D'Onofrio BM, Rickert ME, Långström N, et al. "Familial Confounding of the Association Between Maternal Smoking during Pregnancy and Offspring Substance Use and Problems: Converging Evidence Across Samples and Measures" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622274/ . Arch Gen Psychiatry. 2012;69(11):1140---1150. - 84: Rice F, Harold GT, Boivin J, Hay DF, Van den Bree M, Thapar A. "Disentangling prenatal and inherited influences in humans with an experimental design" http://www.pnas.org/content/106/7/2464.full . Proc Natl Acad Sci U S A. 2009;106(7):2464---2467. - 85: Thapar A, Rice F, Hay D, et al. "Prenatal smoking might not cause attention-deficit/hyperactivity disorder. Evidence from a novel design" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756407/ . Biol Psychiatry. 2009;66(8):722---727. - 86: Obel C, Olsen J, Henriksen TB, et al. "Is maternal smoking during pregnancy a risk factor for hyperkinetic disorder? - findings from a sibling design" http://ije.oxfordjournals.org/content/40/2/338.full . Int J Epidemiol. 2011;40(2):338---345. - 87: D'Onofrio BM, Singh AL, Iliadou A, et al. "Familial confounding of the association between maternal smoking during pregnancy and offspring criminality: a population-based study in Sweden" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644552/ . Arch Gen Psychiatry. 2010;67(5):529---538. - 88: Cnattingius S, Svensson T, Granath F, Iliadou A. "Maternal smoking during pregnancy and risks of suicidal acts in young offspring" http://hal.archives-ouvertes.fr/docs/00/67/16/53/PDF/PEER_stage2_10.1007%252Fs10654-011-9556-7.pdf . Eur J Epidemiol. 2011;26(6):485---492. - 89: D'Onofrio BM, Van Hulle CA, Goodnight JA, Rathouz PJ, Lahey BB. "Is maternal smoking during pregnancy a causal environmental risk factor for adolescent antisocial behavior? Testing etiological theories and assumptions" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605718/ . Psychol Med. 2012;42(7): 1535---1545. - 90: Talati A, Weissman MM. "In utero smoking exposure warrants further investigation". Letter, Arch Gen Psychiatry. 2010;67 (10):1094.
- 91: Knopik VS, Sparrow EP, Madden PAF, et al. "Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study" https://pdf.yt/d/pTtGDFoKVQGBvBPl /https://dl.dropboxusercontent.com/u/243666993/2005-knopik.pdf . Psychol Med. 2005;35(5):625---635. - 92: Batty GD, Der G, Deary IJ. "Effect of maternal smoking during pregnancy on offspring's cognitive ability: empirical evidence for complete confounding in the US National Longitudinal Survey of Youth" https://pdf.yt/d/bU37WJKvOAHjGP7W / https://dl.dropboxusercontent.com/u/243666993/2005-batty.pdf . Pediatrics 2006;118(3):943---950. - 93: Boutwell BB, Beaver KM. "Maternal cigarette smoking during pregnancy and offspring externalizing behavioral problems: a propensity score matching analysis" http://www.mdpi.com/1660-4601/7/1/146/pdf . Int J Environ Res Public Health. 2010;7 (1):146---163."
#hereditary #statistics #genetics
We all know correlation!=causation, but nevertheless it seems like common sense that if you find women who smoke while pregnant have more aggressive kids or with birth defects or cognitive problems that you should jump to ' #smoking while pregnant is evil'. Except you didn't measure all variables, not even close to it, and you omitted huge confounds like genetics and family factors. Thus it is we come to a paper like this:
D'Onofrio BM, Lahey BB, Turkheimer E, Lichtenstein P. "Critical need for family-based, quasi-experimental designs in integrating genetic and social science research"; excerpts:
"Researchers have identified environmental risks that predict subsequent psychological and medical problems. Based on these correlational findings, researchers have developed and tested complex developmental models and have examined biological moderating factors (e.g., gene-environment interactions). In this context, we stress the critical need for researchers to use family-based, quasi-experimental designs when trying to integrate genetic and social science research involving environmental variables because these designs rigorously examine causal inferences by testing competing hypotheses.
We argue that sibling comparison, offspring of twins or siblings, in vitro fertilization designs, and other genetically informed approaches play a unique role in bridging gaps between basic biological and social science research. We use studies on maternal smoking during pregnancy to exemplify these principles.
SDP [maternal smoking during pregnancy] is associated with increased likelihood of various offspring problems, including preterm birth and low birth weight, 13 infant mortality, 14 cognitive deficits, 15,16 obesity, 17 and social and behavioral difficulties (e.g., childhood conduct problem, adolescent delinquency, and substance use problems). 18,19 Several literature reviews have concluded that fetal exposure to maternal SDP causes these problems 13,18,19 because the statistical associations are well-replicated, robust to the use of statistical controls for measured confounds, and consistent with basic research on SDP conducted in animals. 20,21 Other researchers have hypothesized mechanisms through which maternal SDP influences offspring outcomes. 22 For instance, researchers have postulated that maternal SDP alters the development of brain systems responsible for stress reactivity, 23 reward sensitivity, 19,24 and decision-making, 25 which subsequently influence behavior and substance use problems. However, all of the analytic models used to study mediating variables, including developmental cascade models, are based on strong causal assumptions. 26 In particular, the models assume that there are no other causes of the associations among initial risks, the mediating variables, and the outcome of interest. It is clear, however, that maternal SDP is correlated with numerous environmental risks across multiple domains (e.g., maternal and paternal intellectual abilities, psychiatric problems, substance use problems, socioeconomic status, etc.) that also predict offspring problems. 27 In addition, maternal SDP is influenced by genetic factors, 28-- 30 with the genetic risk being correlated with both women's liability for nicotine dependence problems 29 and criminality, 30 consistent with the finding that genetic factors often influence multiple behavioral traits. 31,32 The fact that genetic factors influence SDP, therefore, means that genetic confounding factors could account for the association between SDP and offspring health and behavior problems. 33,34 Given the inability of human research to adequately account for all environmental and genetic selection factors, numerous researchers have cautioned against drawing causal inferences regarding maternal SDP 18,28,35-37 or, for that matter, all prenatal risks. 38,39
Correctly identifying the processes through which genetic and environmental factors interact, therefore, requires that researchers appropriately rule out environmental and genetic confounds of the causal relation. The assumptions concerning causal inferences have profound implications for studies that explore G·E of SDP with measured genotypes, 40,41 because all models assume that the putative environmental factor reflects purely environmental processes. 9,42,43 Researchers must rule out genetic confounding of environmental variables when conducting G·E studies, because genetic selection factors caused by gene-environment correlations (rGE; a related but distinct set of mechanisms we describe in the following section) can confound the study of G·E. 44,45
Family-based, quasi-experiments use "natural experiments" based on family relationships. When a study includes multiple family relationships that differ in their environmental exposure and genetic risk, quantitative genetic models can specifically test competing causal hypotheses. 28,53-55
Sibling-Comparison Designs:
Comparisons of differentially exposed siblings can help account for certain types of confounding. Comparisons of siblings raised in the same family automatically exclude confounding of the exposure with all environmental factors that are shared in common by the siblings. Comparisons of siblings can also help rule out genetic confounding. 59-61
Sibling-comparison studies of SDP [maternal smoking during pregnancy] and childhood conduct and oppositional problems, 76,82 attention or impulsivity problems, 76,86 intellectual abilities, 16,82 academic achievement or grades, 15,77,82 psychological functioning during adolescence, 75,87 suicidal behavior, 88 substance use and substance problems, 83 adolescent antisocial behavior, 89 and adolescent and young adult criminal convictions 87,89 have all reached the opposite conclusion-familial selection factors account for all of the associations. Although there is a robust correlation between maternal SDP and behavioral outcomes in between-family studies, differentially exposed siblings do not differ in the measured behaviors. Although there were concerns about the measurement of child functioning in some early sibling-comparison studies, 60,90 all published sibling-comparison studies of behavioral outcomes to date, including studies predicting normative traits, have concluded that familial selection factors, not exposure to maternal SDP, account for the associations.
This conclusion is reinforced by the fact that bidirectional case-cross studies 67 of intellectual abilities 16 suggest that some assumptions inherent in the sibling-comparison design (e.g., carry-over effects) were not violated and do not account for the findings. Recent studies combined different quasi-experimental designs to test other assumptions in sibling comparisons and helped identify the confounded selection factors that actually account for the association between maternal SDP and offspring psychosocial or cognitive problems. In a study that included half- and full-siblings, as well as half- and full-cousins, the authors found that confounded genetic influences accounted for part of the association between SDP and offspring intellectual abilities and academic achievement. 77 IVF studies likewise suggested that genetic factors passed down from women accounted for the statistical associations of SDP with offspring conduct problems 84 and attention deficit or hyperactivity problems. 85 Those results were also consistent with an offspring of twins study of SDP and offspring attention deficit or hyperactivity problems. 91 Finally, a recent study that combined sibling comparisons with an offspring of siblings design found that genetic liability shared by parents and offspring accounted for the association between SDP and offspring stress-coping. 75 The results of the quasi-experimental research was further supported by studies comparing unrelated individuals that included strong measured covariates in the analyses 36,92 or propensity score matching. 93 The converging evidence from studies using multiple designs, therefore, provides strong evidence that selection factors, including genetic confounds, account for the statistical associations between SDP and offspring psychosocial or cognitive problems.
- 15: Lambe M, Hultman C, Torrang MacCabe J, Cnattingius S. "Maternal smoking during pregnancy and school performance at age 15" https://pdf.yt/d/MSa3v_0EE3aCYN-c / https://dl.dropboxusercontent.com/u/243666993/2006-lambe.pdf . Epidemiology. 2006;17(5):524---530. - 16: Lundberg F, Cnattingius S, D'Onofrio B, et al. "Maternal smoking during pregnancy and intellectual performance in young adult Swedish male offspring" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653250/ . Paediatr Perinat Epidemiol. 2010;24(1):79---87. - 36: Silberg JL, Parr T, Neale MC, M, Angold A, Eaves LJ. "Maternal smoking during pregnancy and risk to boys' conduct disturbance: an examination of the causal hypothesis" http://www.vipbg.vcu.edu/vipbg/Articles/biopsychiatry-maternal-2003.pdf . Biol Psychiatry. 2003;53(2):130---135. - 60: Rutter M. "Proceeding from observed correlation to causal inference: the use of natural experiments" http://psych.colorado.edu/~willcutt/pdfs/rutter_2007.pdf . Perspect Psychol Sci. 2007;2(4):377---395. - 67: Meyer KA, Williams P, Hernandez-Diaz S, Cnattingius S. "Smoking and the risk of oral clefts: exploring the impact of study designs" https://pdf.yt/d/EHvJOOIx5FynCeeo / https://dl.dropboxusercontent.com/u/243666993/2004-meyer.pdf . Epidemiology. 2004;15(6): 671---678. - 75: Kuja-Halkola R, D'Onofrio BM, Illiadou A, Pawitan Y, Langstrom N, Lichtenstein P. "Prenatal smoking exposure and offspring stress coping in late adolescence: no causal link" http://ije.oxfordjournals.org/content/39/6/1531.full . Int J Epidemiol. 2010;39 (6):1531---1540. - 76: D'Onofrio BM, Van Hulle CA, Waldman ID, et al. "Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737574/ . Dev Psychopathol. 2008;20(1):139---164. - 77: D'Onofrio BM, Singh AL, Iliadou A, et al. "A quasi-experimental study of maternal smoking during pregnancy and offspring academic achievement" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656473/ . Child Dev. 2010;81(1):80---100. - 82: Gilman SE, Gardener H, Buka SL. "Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor?" http://aje.oxfordjournals.org/content/168/5/522.full.pdf Am J Epidemiol. 2008;168(5):522---531. - 83: D'Onofrio BM, Rickert ME, Långström N, et al. "Familial Confounding of the Association Between Maternal Smoking during Pregnancy and Offspring Substance Use and Problems: Converging Evidence Across Samples and Measures" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622274/ . Arch Gen Psychiatry. 2012;69(11):1140---1150. - 84: Rice F, Harold GT, Boivin J, Hay DF, Van den Bree M, Thapar A. "Disentangling prenatal and inherited influences in humans with an experimental design" http://www.pnas.org/content/106/7/2464.full . Proc Natl Acad Sci U S A. 2009;106(7):2464---2467. - 85: Thapar A, Rice F, Hay D, et al. "Prenatal smoking might not cause attention-deficit/hyperactivity disorder. Evidence from a novel design" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756407/ . Biol Psychiatry. 2009;66(8):722---727. - 86: Obel C, Olsen J, Henriksen TB, et al. "Is maternal smoking during pregnancy a risk factor for hyperkinetic disorder? - findings from a sibling design" http://ije.oxfordjournals.org/content/40/2/338.full . Int J Epidemiol. 2011;40(2):338---345. - 87: D'Onofrio BM, Singh AL, Iliadou A, et al. "Familial confounding of the association between maternal smoking during pregnancy and offspring criminality: a population-based study in Sweden" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644552/ . Arch Gen Psychiatry. 2010;67(5):529---538. - 88: Cnattingius S, Svensson T, Granath F, Iliadou A. "Maternal smoking during pregnancy and risks of suicidal acts in young offspring" http://hal.archives-ouvertes.fr/docs/00/67/16/53/PDF/PEER_stage2_10.1007%252Fs10654-011-9556-7.pdf . Eur J Epidemiol. 2011;26(6):485---492. - 89: D'Onofrio BM, Van Hulle CA, Goodnight JA, Rathouz PJ, Lahey BB. "Is maternal smoking during pregnancy a causal environmental risk factor for adolescent antisocial behavior? Testing etiological theories and assumptions" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605718/ . Psychol Med. 2012;42(7): 1535---1545. - 90: Talati A, Weissman MM. "In utero smoking exposure warrants further investigation". Letter, Arch Gen Psychiatry. 2010;67 (10):1094.
- 91: Knopik VS, Sparrow EP, Madden PAF, et al. "Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study" https://pdf.yt/d/pTtGDFoKVQGBvBPl /https://dl.dropboxusercontent.com/u/243666993/2005-knopik.pdf . Psychol Med. 2005;35(5):625---635. - 92: Batty GD, Der G, Deary IJ. "Effect of maternal smoking during pregnancy on offspring's cognitive ability: empirical evidence for complete confounding in the US National Longitudinal Survey of Youth" https://pdf.yt/d/bU37WJKvOAHjGP7W / https://dl.dropboxusercontent.com/u/243666993/2005-batty.pdf . Pediatrics 2006;118(3):943---950. - 93: Boutwell BB, Beaver KM. "Maternal cigarette smoking during pregnancy and offspring externalizing behavioral problems: a propensity score matching analysis" http://www.mdpi.com/1660-4601/7/1/146/pdf . Int J Environ Res Public Health. 2010;7 (1):146---163."
#hereditary #statistics #genetics
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