Combining Mendelian randomization with the sibling comparison design.

Mendelian randomization (MR) is a popular epidemiologic study design that uses genetic variants as instrumental variables (IVs) to estimate causal effects, while accounting for unmeasured confounding. The validity of the MR design hinges on certain IV assumptions, which may sometimes be violated due to dynastic effects, population stratification, or assortative mating. Since these mechanisms act through parental factors it was recently suggested that the bias resulting from violations of the IV assumptions can be reduced by combing the MR design with the sibling comparison design, which implicitly controls for all factors that are constant within families. In this article, we provide a formal discussion of this combined MR-sibling design. We derive conditions under which the MR-sibling design is unbiased, and we relate these to the corresponding conditions for the standard MR and sibling comparison designs. We proceed by considering scenarios where all three designs are biased to some extent, and discuss under which conditions the MR-sibling design can be expected to have less bias than the other two designs. We finally illustrate the theoretical results and conclusions with an application to real data, in a study of low-density lipoprotein and diastolic blood pressure using data from the Swedish Twin Registry.

Duration and intensity of being breastfed and educational attainment, income and labour force participation: a prospective cohort and sibling study from Denmark.

OBJECTIVE: Breastfeeding improves cognitive ability in childhood, but the long-term impact on socioeconomic outcomes remains unknown. We examined associations between durations of predominant and any breastfeeding and educational attainment, income, and labor force participation in adulthood, and whether these varied by maternal education. STUDY DESIGN: Prospective cohort study. METHODS: We followed 84,255 individuals born 1959-1967 with prospectively collected information on breastfeeding duration and intensity from the Copenhagen Infant Health Nurse Records. Socioeconomic outcome information came from national registers (1980-2020). Linear and Poisson regression were used, and models were adjusted for prenatal and postnatal variables across three levels of maternal education. RESULTS: Durations of being breastfed exhibited associations with all outcomes, with most being more pronounced among mothers with low education. Compared with infants breastfed <1 month, those breastfed ≥5 months had 0.68 (95% confidence interval: 0.60-0.76), 0.55 (0.45-0.65), and 0.65 (0.46-0.84) additional years of education for infants born to mothers with low, medium, or high education, respectively. Moreover, infants breastfed ≥5 months had 4047, 3713, and 1902 US$ higher annual incomes and were 23% less likely to be outside the labor force at age 50 years. These associations were stronger with longer breastfeeding durations and for predominant than any breastfeeding. CONCLUSIONS: Prolonged and higher breastfeeding intensity consistently exhibited dose-dependent associations with improved socioeconomic indicators in adulthood. Notably, these relationships were more pronounced among individuals whose mothers had lower educational attainment. Consequently, our findings suggest that breastfeeding may have a lasting positive influence on socioeconomic outcomes, particularly for the most disadvantaged infants.

Fatherhood timing and men's midlife earnings: A within-family study of Finnish cohorts born in 1938-50.

Fathers tend to achieve higher earnings than childless men, but there is limited evidence on the associations between fatherhood timing and men's later earnings. Using a longitudinal census-based sample of Finnish men, including a subsample of brothers, we investigated fatherhood timing and men's midlife earnings using both between- and within-family models. Earnings around age 50 were lower among adolescent and young fathers than for men who became fathers at ages 25-29 or later, but these associations became negligible after accounting for measured confounders and unobserved familial confounding. Overall, our findings highlight the important roles of selection into early childbearing and into childlessness. At the population level, early fatherhood was associated with clear negative distributional shifts in fathers' midlife earnings. However, among all men, any influence of fatherhood timing on men's midlife earnings distribution paled in comparison with that of childlessness.

Cancer risk following surgical removal of tonsils and adenoids - a population-based, sibling-controlled cohort study in Sweden.

BACKGROUND: Removal of tonsils and adenoids is among the most common surgical procedures worldwide. Evidence of increased risk of cancer following such surgery is, however, inconclusive. METHODS: We conducted a population-based, sibling-controlled cohort study of 4,953,583 individuals in Sweden with a follow-up during 1980-2016. History of tonsillectomy, adenotonsillectomy, and adenoidectomy was identified from the Swedish Patient Register whereas incident cases of cancer during follow-up were identified from the Swedish Cancer Register. We used Cox models to calculate hazard ratios (HR) with 95% confidence intervals (CI) of cancer in both a population and a sibling comparison. The sibling comparison was used to assess the potential impact of familial confounding, due to shared genetic or non-genetic factors within a family. RESULTS: We found a modestly increased risk for any cancer following tonsillectomy, adenoidectomy, or adenotonsillectomy in both the population (HR 1.10; 95%CI 1.07-1.12) and sibling (HR 1.15; 95%CI 1.10-1.20) comparisons. The association did not differ greatly by type of surgery, age at surgery, or potential indication for surgery, and persisted more than two decades after surgery. An excess risk was consistently observed for cancer of the breast, prostate, thyroid, and for lymphoma in both population and sibling comparisons. A positive association was observed for pancreatic cancer, kidney cancer, and leukemia in the population comparison whereas a positive association was observed for esophageal cancer in the sibling comparison. CONCLUSIONS: Surgical removal of tonsils and adenoids is associated with a modestly increased risk of cancer during the decades following the surgery. The association is unlikely attributed to confounding due to shared genetic or non-genetic factors with a family.

Association of caesarean delivery with offspring health outcomes in full-cohort versus sibling-comparison studies: a comparative meta-analysis and simulation study.

BACKGROUND: Full-cohort and sibling-comparison designs have yielded inconsistent results about the impacts of caesarean delivery on offspring health outcomes, with the effect estimates from the latter being more likely directed towards the null value. We hypothesized that the seemingly conservative results obtained from the sibling-comparison design might be attributed to inadequate adjustment for non-shared confounders between siblings, particularly maternal age at delivery. METHODS: A systematic review and meta-analysis was first conducted. PubMed, Embase, and the Web of Science were searched from database inception to April 6, 2022. Included studies (1) examined the association of caesarean delivery, whether elective or emergency, with offspring health outcomes; (2) simultaneously conducted full-cohort and sibling-comparison analyses; and (3) reported adjusted effect estimates with 95% confidence intervals (95% CIs). No language restrictions were applied. Data were extracted by 2 reviewers independently. Three-level meta-analytic models were used to calculate the pooled odds ratios (ORs) and 95% CIs for caesarean versus vaginal delivery on multiple offspring health outcomes separately for full-cohort and sibling-comparison designs. Subgroup analyses were performed based on the method of adjustment for maternal age at delivery. A simulation study was then conducted. The simulated datasets were generated with some key parameters derived from the meta-analysis. RESULTS: Eighteen studies involving 21,854,828 individuals were included. The outcomes assessed included mental and behavioral disorders; endocrine, nutritional and metabolic diseases; asthma; cardiorespiratory fitness; and multiple sclerosis. The overall pooled OR for estimates from the full-cohort design was 1.14 (95% CI: 1.11 to 1.17), higher than that for estimates from the sibling-comparison design (OR = 1.08; 95% CI: 1.02 to 1.14). Stratified analyses showed that estimates from the sibling-comparison design varied considerably across studies using different methods to adjust for maternal age at delivery in multivariate analyses, while those from the full-cohort design were rather stable: in studies that did not adjust maternal age at delivery, the pooled OR of full-cohort vs. sibling-comparison design was 1.10 (95% CI: 0.99 to 1.22) vs. 1.06 (95% CI: 0.85 to 1.31), in studies adjusting it as a categorical variable, 1.15 (95% CI: 1.11 to 1.19) vs. 1.07 (95% CI: 1.00 to 1.15), and in studies adjusting it as a continuous variable, 1.12 (95% CI: 1.05 to 1.19) vs. 1.12 (95% CI: 0.98 to 1.29). The severe underestimation bias related to the inadequate adjustment of maternal age at delivery in sibling-comparison analyses was fully replicated in the simulation study. CONCLUSIONS: Sibling-comparison analyses may underestimate the association of caesarean delivery with multiple offspring health outcomes due to inadequate adjustment of non-shared confounders, such as maternal age at delivery. Thus, we should be cautious when interpreting the seemingly conservative results of sibling-comparison analyses in delivery-related studies.

Annual Research Review: Towards a deeper understanding of nature and nurture: combining family-based quasi-experimental methods with genomic data.

Distinguishing between the effects of nature and nurture constitutes a major research goal for those interested in understanding human development. It is known, for example, that many parent traits predict mental health outcomes in children, but the causal processes underlying such associations are often unclear. Family-based quasi-experimental designs such as sibling comparison, adoption and extended family studies have been used for decades to distinguish the genetic transmission of risk from the environmental effects family members potentially have on one another. Recently, these designs have been combined with genomic data, and this combination is fuelling a range of exciting methodological advances. In this review we explore these advances - highlighting the ways in which they have been applied to date and considering what they are likely to teach us in the coming years about the aetiology and intergenerational transmission of psychopathology.

Association of severe childhood infections with depression and intentional self-harm in adolescents and young adults.

Early-life infections have been linked with subsequent depression and self-harm. Examination of specific groups of infections and the role of familial factors may elucidate this observed relationship. We addressed these considerations in our investigations of the association of severe childhood infections with the risks of depression and self-harm in adolescence and early-adulthood. This population-based cohort study included all individuals born in Sweden between 1982 and 1996, with follow-up through 2013 (N = 1,506,070). Severe childhood infections were identified using inpatient and outpatient diagnoses from birth through age 12. Any infection as well as specific groups of infections were investigated. We examined diagnoses of depression and self-harm within inpatient and outpatient care and death by self-harm between ages 13 and 31. Cox proportional hazards regression models were used to estimate absolute risks, hazard ratios (HRs), and 95% CIs. When adjusting for sex and birth year, individuals exposed to any childhood infection demonstrated increased absolute risk differences for both outcomes (2.42% [95% CI, 0.41-4.43%] of being diagnosed with depression up until age 31, and 0.73% [-2.05% to 3.51%] of self-harm up until age 31) and increased relative risks (HR, 1.22 [1.20-1.24] for depression and HR, 1.29 [1.25-1.32] for self-harm). When controlling for unmeasured factors shared between family members by comparing discordant siblings, no strong association persisted. Our findings show that childhood infections may not be involved in the etiology of later depression and self-harm, and highlight the importance of identifying these genetic and environmental familial risk factors, which may serve as targets for interventions.

Genetic and psychosocial influence on the association between early childhood infections and later psychiatric disorders.

OBJECTIVE: To evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders METHODS: A case-cohort study including participants from the Danish iPSYCH2012 sample, a case-cohort sample where all cases born between May 1, 1981, and December 31, 2005, diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar affective disorder (BIP), Major Depressive Disorder (MDD) or schizophrenia (SCZ), were identified and pooled with a representative sample (subcohort) of the Danish population. We used Cox proportional hazards regression customized to the case-cohort setup to calculate hazard ratios of outcome with 95% confidence intervals (CIs), following exposure to early childhood infection before the age of 5 years for ADHD and ASD, and before the age of 10 years for BIP, MDD, and SCZ. To evaluate psychosocial confounding we included sex, calendar period, sibling infections, urbanicity, parental socio-economic status, parental mental health information, and polygenic risk scores for all five disorders, as covariates. To estimate how liability for psychiatric disorders measured through the PRS influenced the risk of early childhood infection, we calculated odds ratios (ORs) with 95% CIs, using logistic regression RESULTS: Early childhood infection was associated with ADHD, ASD, MDD, and SCZ with number of childhood infections increasing the hazard. The HR was still significant in the model with full adjustments after 1 infection for ADHD (HR 1.29, 95% CI: 1.19-1.41), ASD (HR 1.28, 95% CI: 1.18-1.40), MDD (HR 1.23, 95% CI: 1.14-1.33), and SCZ (HR 1.21, 95% CI: 1.07-1.36), but not for BIP (HR1.17, 95% CI: 0.96-1.42). Probands exposed to sibling infections, but not own infection had an absolute risk of ADHD, BIP, MDD, and SCZ that closely approached the absolute risk for individuals exposed to own infections. We found evidence of gene-environment correlation with higher PRS of MDD and to some extent SCZ increasing the risk of infections and higher PRS of BIP associated with significantly decreased risk CONCLUSION: Early childhood infection is significantly associated with ADHD, ASD, MDD, and SCZ and not explained by genetic or psychosocial confounding. Although we found evidence of gene-environment correlation, it had minor impact on the results.

Generalizability and effect measure modification in sibling comparison studies.

Sibling comparison studies have the attractive feature of being able to control for unmeasured confounding by factors that are shared within families. However, there is sometimes a concern that these studies may have poor generalizability (external validity) due to the implicit restriction to families that are covariate-discordant, i.e., those families where at least two siblings have different levels of at least one of the covariates (exposure or confounders) under investigation. Even if this selection mechanism has been noted by many authors, previous accounts of the problem tend to be brief. The purpose of this paper is to provide a formal discussion of the implicit restriction to covariate-discordant families in sibling comparison studies. We discuss when and how this restriction may impair the generalizability of the study, and we show that a similar generalizability problem may in fact arise even when all families are covariate-discordant, e.g. even if the exposure is continuous so that all siblings have different exposure levels. We show how this problem can be solved by using a so-called marginal between-within model for estimation of marginal exposure effects. Finally, we illustrate the theoretical conclusions with a simulation study.

Maternal Prenatal Smoking and Autism Spectrum Disorder in Offspring: A California Statewide Cohort and Sibling Study.

We examined associations between maternal smoking and autism spectrum disorder (ASD) in children in a statewide population-based cohort and sibling-comparison design using California birth records (n = 2,015,104) with information on maternal smoking, demographic factors, and pregnancy (2007-2010). ASD cases (n = 11,722) were identified through California Department of Developmental Services records with diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders-IV-TR. We estimated odds ratios for ASD with and without intellectual disability in the full cohort using logistic regression and in a sibling comparison using conditional logistic regression. In the full cohort, the adjusted odds ratio for ASD and maternal smoking 3 months before/during pregnancy compared with nonsmoking was 1.15 (95% confidence interval (CI): 1.04, 1.26), and it was similar in cases with (odds ratio = 1.12, 95% CI: 0.84, 1.49) and without intellectual disability (odds ratio = 1.15, 95% CI: 1.04, 1.27). Heavy prenatal smoking (≥20 cigarettes/day in any trimester) was related to an odds ratio of 1.55 (95% CI: 1.21, 1.98). In the sibling comparison, the odds ratio for heavy smoking was similarly elevated but the confidence interval was wide. Our findings are consistent with an increased risk for ASD in offspring of mothers who smoked ≥20 cigarettes/day during pregnancy; associations with lighter smoking were weaker.

Is association of preterm birth with cognitive-neurophysiological impairments and ADHD symptoms consistent with a causal inference or due to familial confounds?

BACKGROUND: Preterm birth is associated with an increased risk for cognitive-neurophysiological impairments and attention-deficit/hyperactivity disorder (ADHD). Whether the associations are due to the preterm birth insult per se, or due to other risk factors that characterise families with preterm-born children, is largely unknown. METHODS: We employed a within-sibling comparison design, using cognitive-performance and event-related potential (ERP) measures from 104 preterm-born adolescents and 104 of their term-born siblings. Analyses focused on ADHD symptoms and cognitive and ERP measures from a cued continuous performance test, an arrow flanker task and a reaction time task. RESULTS: Within-sibling analyses showed that preterm birth was significantly associated with increased ADHD symptoms (ß = 0.32, p = 0.01, 95% CI 0.05 to 0.58) and specific cognitive-ERP impairments, such as IQ (ß = -0.20, p = 0.02, 95% CI -0.40 to -0.01), preparation-vigilance measures and measures of error processing (ranging from ß = 0.71, -0.35). There was a negligible within-sibling association between preterm birth with executive control measures of inhibition (NoGo-P3, ß = -0.07, p = 0.45, 95% CI -0.33 to 0.15) or verbal working memory (digit span backward, ß = -0.05, p = 0.63, 95% CI -0.30 to 0.18). CONCLUSIONS: Our results suggest that the relationship between preterm birth with ADHD symptoms and specific cognitive-neurophysiological impairments (IQ, preparation-vigilance and error processing) is independent of family-level risk and consistent with a causal inference. In contrast, our results suggest that previously observed associations between preterm birth with executive control processes of inhibition and working memory are instead linked to background characteristics of families with a preterm-born child rather than preterm birth insult per se. These findings suggest that interventions need to target both preterm-birth specific and family-level risk factors.

Stratified analysis of the correlation between gestational weight gain and birth weight for gestational age: a retrospective single-center cohort study in Japan.

BACKGROUND: Japan has an exceptionally high proportion of low-weight births and underweight women. It has been suggested that an appropriate increase in gestational weight gain (GWG) for underweight women will help to prevent low birth weight. The current strategy aims to raise the desired value of GWG equally for all pregnant women within the underweight category. However, it remains elusive whether or not the relationship between GWG and birth weight for gestational age (BW/GA) are uniformly equivalent for all the women. METHODS: We performed a retrospective cohort analysis of women who delivered their newborns at Tokyo Medical and Dental University Hospital from 2013 to 2017. First, in order to examine the direct effect of an increase or decrease in GWG on BW/GA, we analyzed the correlation between inter-pregnancy differences in GWG and BW/GA using a sub-cohort of women who experienced two deliveries during the study period (n = 75). Second, we dichotomized the main cohort (n = 1114) according to BW/GA to verify our hypothesis that the correlation between GWG and BW/GA differs depending on the size of the newborn. RESULTS: The inter-pregnancy difference in BW/GA was not correlated with that of GWG. However, the correlation between BW/GA of siblings was high (r = 0.63, p = 1.9 × 10- 9). The correlation between GWG and BW/GA in women who delivered larger-sized newborns was higher (r = 0.17, p = 4.1 × 10- 5) than that in women who delivered smaller-sized newborns (r = 0.099, p = 1.9 × 10- 2). This disparity did not change after adjustment for pre-pregnancy BMI. The mean birth weight in the dichotomized groups corresponded to percentile 52.0 and 13.4 of the international newborn size assessed by INTERGROWTH-21st standards. CONCLUSIONS: In our study, GWG was positively correlated with BW/GA for heavier neonates whose birth weights were similar to the average neonatal weight according to world standards. However, caution might be required for low-birth-weight neonates because increased GWG does not always result in increased birth weight.

A Family-Based Study of the Association Between Labor Induction and Offspring Attention-Deficit Hyperactivity Disorder and Low Academic Achievement.

The current study examined associations between labor induction and both (1) offspring attention-deficit hyperactivity disorder (ADHD) diagnosis in a Swedish birth cohort born 1992-2005 (n = 1,085,008) and (2) indices of offspring low academic achievement in a sub-cohort born 1992-1997 (n = 489,196). Associations were examined in the entire sample (i.e., related and unrelated individuals) with adjustment for measured covariates and, in order to account for unmeasured confounders shared within families, within differentially exposed cousins and siblings. We observed an association between labor induction and offspring ADHD diagnosis and low academic achievement in the population. However, these associations were fully attenuated after adjusting for measured covariates and unmeasured factors that cousins and siblings share. The results suggest that observed associations between labor induction and ADHD and low academic achievement may be due to genetic and/or shared environmental factors that influence both mothers' risk of labor induction and offspring neurodevelopment.

Age at fatherhood: heritability and associations with psychiatric disorders.

BACKGROUND: Advancing paternal age has been linked to psychiatric disorders. These associations might be caused by the increased number of de novo mutations transmitted to offspring of older men. It has also been suggested that the associations are confounded by a genetic liability for psychiatric disorders in parents. The aim of this study was to indirectly test the confounding hypotheses by examining if there is a genetic component to advancing paternal age and if men with a genetic liability for psychiatric disorders have children at older ages. METHOD: We examined the genetic component to advancing paternal age by utilizing the twin model in a cohort of male twins (N = 14 679). We also studied ages at childbirth in men with or without schizophrenia, bipolar disorder and/or autism spectrum disorder. Ages were examined in: (1) healthy men, (2) affected men, (3) healthy men with an affected sibling, (4) men with healthy spouses, (5) men with affected spouses, and (6) men with healthy spouses with an affected sibling. RESULTS: The twin analyses showed that late fatherhood is under genetic influence (heritability = 0.33). However, affected men or men with affected spouses did not have children at older ages. The same was found for healthy individuals with affected siblings. Instead, these men were generally having children at younger ages. CONCLUSION: Although there is a genetic component influencing late fatherhood, our data suggest that the associations are not explained by psychiatric disorders or a genetic liability for psychiatric disorders in the parent.

Genetic and Environmental Contributions to Associations between Infant Fussy Temperament and Antisocial Behavior in Childhood and Adolescence.

Previous research suggests that fussy temperament in infancy predicts risk for later antisocial behavior (ASB) in childhood and adolescence. It remains unclear, however, to what extent infant fussiness is related to later ASB through causal processes or if they both reflect the same family risk factors for ASB. The current study used two approaches, the comparison of siblings and bivariate biometric modeling, to reduce familial confounding and examine genetic and environmental influences on associations between fussiness in the first 2 years of life and ASB in childhood and late adolescence. Analyses were conducted on data from a prospective cohort (9237 at 4-9 years and 7034 at 14-17 years) who are the offspring of a nationally representative sample of US women. In the full sample, fussiness predicted both child and adolescent ASB to small but significant extents, controlling for a wide range of measured child and family-level covariates. When siblings who differed in their fussiness were compared, fussiness predicted ASB in childhood, but not ASB during adolescence. Furthermore, results from a bivariate Cholesky model suggested that even the association of fussiness with childhood ASB found when comparing siblings is attributable to familial factors. That is, although families with infants who are higher in fussiness also tend to have children and adolescents who engage in greater ASB, the hypothesis that infant fussiness has an environmentally mediated impact on the development of future ASB was not strongly supported.

Maternal Smoking During Pregnancy and Offspring Birth Weight: A Genetically-Informed Approach Comparing Multiple Raters.

Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the fetus. There is considerable debate about the best method of assessing SDP, including birth/medical records, timeline follow-back approaches, multiple reporters, and biological verification (e.g., cotinine). This is particularly salient for genetically-informed approaches where it is not always possible or practical to do a prospective study starting during the prenatal period when concurrent biological specimen samples can be collected with ease. In a sample of families (N = 173) specifically selected for sibling pairs discordant for prenatal smoking exposure, we: (1) compare rates of agreement across different types of report-maternal report of SDP, paternal report of maternal SDP, and SDP contained on birth records from the Department of Vital Statistics; (2) examine whether SDP is predictive of birth weight outcomes using our best SDP report as identified via step (1); and (3) use a sibling-comparison approach that controls for genetic and familial influences that siblings share in order to assess the effects of SDP on birth weight. Results show high agreement between reporters and support the utility of retrospective report of SDP. Further, we replicate a causal association between SDP and birth weight, wherein SDP results in reduced birth weight even when accounting for genetic and familial confounding factors via a sibling comparison approach.

Smoking during pregnancy and ADHD risk: A genetically informed, multiple-rater approach.

Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the developing child, including behavioral outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD). There is substantial interest in understanding the nature of this reported association, particularly in light of more recent genetically informed studies that suggest that the SDP-ADHD link is less clear than once thought. In a sample of families (N = 173) specifically selected for sibling pairs discordant for prenatal smoking exposure, we use a sibling-comparison approach that controls for shared genetic and familial influences to assess the effects of SDP on ADHD symptom dimensions. ADHD was measured by both parent and teacher report on the Conners report forms and the Child Behavior Checklist/Teacher Report Form (CBCL/TRF). Results for the CBCL/TRF Total ADHD score are consistent with prior genetically informed approaches and suggest that previously reported associations between SDP and ADHD are largely due to familial confounding rather than causal teratogenic effects. However, results from the Conners parent report suggest a potentially causal effect of SDP on hyperactive/impulsive and, to a lesser extent, total ADHD symptoms; SDP results in increased parent-reported hyperactive/impulsive and total ADHD symptoms even after accounting for genetic and familial confounding factors. This suggests that the Conners assessment (parent-report) may provide a sensitive measure for use in studies examining child specific SDP effects on continuous and dimensional aspects of ADHD. © 2016 Wiley Periodicals, Inc.

Missouri Mothers and Their Children: A Family Study of the Effects of Genetics and the Prenatal Environment.

The Missouri Mothers and Their Children Study (MO-MATCH) was specifically designed to critically investigate prenatal environmental influences on child attention problems and associated learning and cognitive deficits. The project began as a pilot study in 2004 and was formally launched in 2008. Participants in the study were initially identified via the Department of Vital Statistics birth record (BR) database. Interview and lab-based data were obtained from: (1) mothers of Missouri-born children (born 1998-2005), who smoked during one pregnancy but not during another pregnancy; (2) biological fathers when available; and (3) the children (i.e., full sibling pairs discordant for exposure to maternal smoking during pregnancy (SDP). This within-mother, between-pregnancy contrast provides the best possible methodological control for many stable maternal and familial confounding factors (e.g., heritable and socio-demographic characteristics of the mother that predict increased probability of SDP). It also controls for differences between mothers who do and do not smoke during pregnancy, and their partners, that might otherwise artifactually create, or alternatively mask, associations between SDP and child outcomes. Such a design will therefore provide opportunities to determine less biased effect sizes while also allowing us to investigate (on a preliminary basis) the possible contribution of paternal or other second-hand smoke exposure during the pre, peri, and postnatal periods to offspring outcome. This protocol has developed a cohort that can be followed longitudinally through periods typically associated with increased externalizing symptoms and substance used initiation.

Exploring the relationship between depression and delinquency: a sibling comparison design using the NLSY.

Relative to the general population, adolescents with psychiatric disorders such as major depression disorder are incarcerated (and reincarcerated) at higher rates. Current research is mixed on whether this association is a cause, consequence, or the product of selection. For example, aggression can lead to more depressive symptoms, yet depression is associated with antisocial behaviors (e.g., delinquency). To better understand the relationship between depression and delinquent behavior, we used the discordant kinship model to examine data from sibling pairs in the National Longitudinal Surveys of Youth 1979, a nationally representative study. By explicitly modeling within- and between-family variance, we reduced the influence of genetic and shared-environmental confounds on our analysis. Our results suggest that the relationship between depression and delinquency is not causal, but rather a product of selection.

Impact of traumatic brain injury on risk for schizophrenia and bipolar disorder.

The impact of traumatic brain injury (TBI) on subsequent risk of schizophrenia (SCZ) or bipolar disorder (BD) remains contested. Possible genetic and environmental confounding effects have also been understudied. Therefore, we aim to investigate the impact of TBI on the risk of SCZ and BD and whether the effect varies by injury severity, age at injury, and sex. We identified 4,184 SCZ and 18,681 BD cases born between 1973 and 1998 in the Swedish National Registers. Case-control samples matched (1:5) on birth year, sex, and birthplace were created along with a family design study, with cases matched to non-case full siblings. TBI was associated with higher risk of SCZ and BD (IRR=1.33 for SCZ, IRR=1.78 for BD). The association remained significant in the sibling comparison study. Moderate or severe TBI was associated with higher risk for both SCZ and BD compared to mild TBI. Older age at injury was associated with higher risk of SCZ and BD, and the effect of TBI was stronger in women than men. Findings indicate that TBI is a risk factor for both SCZ and BD with differential impact by age, severity and sex and that this association cannot be explained by familial confounding alone.