Brian M. D’Onofrio

Critical Need for Family-Based, Quasi-Experimental Designs in Integrating Genetic and Social Science Research

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.

All in the Family: Comparing Siblings to Test Causal Hypotheses Regarding Environmental Influences on Behavior

Psychologists in both basic and applied fields are keenly interested in the environmental influences that shape our lives. Therefore, researchers test causal hypotheses to construct models of environmental influences that can withstand attempts at refutation. Randomized experiments provide the strongest tests of causal hypotheses but are not always feasible, and their assumptions cannot always be met. In such cases, a number of quasi-experimental research designs can be used to substantially reduce confounding in tests of causal hypotheses. Sibling-comparison designs provide robust quasi-experimental tests of causal environmental hypotheses, but they are underused in psychology in spite of their power, feasibility, and convenience.

Serious Transport Accidents in Adults With Attention-Deficit/Hyperactivity Disorder and the Effect of Medication: A Population-Based Study

IMPORTANCE Studies have shown that attention-deficit/hyperactivity disorder (ADHD) is associated with transport accidents, but the magnitude of the association remains unclear. Most important, it is also unclear whether ADHD medication reduces this risk. OBJECTIVES To estimate the association between ADHD and the risk of serious transport accidents and to explore the extent to which ADHD medication influences this risk among patients with ADHD. DESIGN, SETTING, AND PARTICIPANTS In total, 17,408 patients with a diagnosis of ADHD were observed from January 1, 2006, through December 31, 2009, for serious transport accidents documented in Swedish national registers. The association between ADHD and accidents was estimated with Cox proportional hazards regression. To study the effect of ADHD medication, we used stratified Cox regression to compare the risk of accidents during the medication period with the risk during the nonmedication period within the same patients. MAIN OUTCOMES AND MEASURES Serious transport accident, identified as an emergency hospital visit or death due to transport accident. RESULTS Compared with individuals without ADHD, male patients with ADHD (adjusted hazard ratio, 1.47; 95% CI, 1.32-1.63) and female patients with ADHD (1.45; 1.24-1.71) had an increased risk of serious transport accidents. In male patients with ADHD, medication was associated with a 58% risk reduction (hazard ratio, 0.42; 95% CI, 0.23-0.75), but there was no statistically significant association in female patients. Estimates of the population-attributable fractions suggested that 41% to 49% of the accidents in male patients with ADHD could have been avoided if they had been receiving treatment during the entire follow-up. CONCLUSIONS AND RELEVANCE Attention-deficit/hyperactivity disorder is associated with an increased risk of serious transport accidents, and this risk seems to be possibly reduced by ADHD medication, at least among male patients. This should lead to increased awareness among clinicians and patients of the association between serious transport accidents and ADHD medication.

Familial Confounding of the Association Between Maternal Smoking During Pregnancy and Offspring Substance Use and Problems

CONTEXT Previous epidemiological, animal, and human cognitive neuroscience research suggests that maternal smoking during pregnancy (SDP) causes increased risk of substance use/problems in offspring. OBJECTIVE To determine the extent to which the association between SDP and offspring substance use/problems depends on confounded familial background factors by using a quasi-experimental design. DESIGN We used 2 separate samples from the United States and Sweden. The analyses prospectively predicted multiple indices of substance use and problems while controlling for statistical covariates and comparing differentially exposed siblings to minimize confounding. SETTING Offspring of a representative sample of women in the United States (sample 1) and the total Swedish population born during the period from January 1, 1983, to December 31, 1995 (sample 2). PATIENTS OR OTHER PARTICIPANTS Adolescent offspring of the women in the National Longitudinal Survey of Youth 1979 (n = 6904) and all offspring born in Sweden during the 13-year period (n = 1,187,360). MAIN OUTCOME MEASURES Self-reported adolescent alcohol, cigarette, and marijuana use and early onset (before 14 years of age) of each substance (sample 1) and substance-related convictions and hospitalizations for an alcohol- or other drug-related problem (sample 2). RESULTS The same pattern emerged for each index of substance use/problems across the 2 samples. At the population level, maternal SDP predicted every measure of offspring substance use/problems in both samples, ranging from adolescent alcohol use (hazard ratio [HR](moderate), 1.32 [95% CI, 1.22-1.43]; HR(high), 1.33 [1.17-1.53]) to a narcotics-related conviction (HR(moderate), 2.23 [2.14-2.31]; HR(high), 2.97 [2.86-3.09]). When comparing differentially exposed siblings to minimize genetic and environmental confounds, however, the association between SDP and each measure of substance use/problems was minimal and not statistically significant. CONCLUSIONS The association between maternal SDP and offspring substance use/problems is likely due to familial background factors, not a causal influence, because siblings have similar rates of substance use and problems regardless of their specific exposure to SDP.

Maternal age at childbirth and offspring disruptive behaviors: testing the causal hypothesis

BACKGROUND Recent studies suggest that the association between maternal age at childbearing (MAC) and childrens disruptive behaviors is the result of family factors that are confounded with both variables, rather than a casual effect of environmental factors specifically related to MAC. These studies, however, relied on restricted samples and did not use the strongest approach to test causal influences. METHODS Using data on 9,171 4-9-year-old and 6,592 10-13-year-old offspring of women from a nationally representative sample of US households, we conducted sibling-comparison analyses. The analyses ruled out all genetic factors that could confound the association, as well as all environmental confounds that differ between unrelated nuclear families, providing a strong test of the causal hypothesis that the environments of children born at different maternal ages influence mother- and self-reported disruptive behaviors. RESULTS When these genetic and environmental confounds were ruled out as alternative explanations, the relation between environments within nuclear families specifically associated with MAC and disruptive behaviors was robust, with the association being stronger for second- and third-born children. CONCLUSIONS Environmental factors specifically associated with early MAC within nuclear families account for increased risk of offspring disruptive behaviors, especially in later-born children.

Using epidemiologic methods to test hypotheses regarding causal influences on child and adolescent mental disorders

Epidemiology uses strong sampling methods and study designs to test refutable hypotheses regarding the causes of important health, mental health, and social outcomes. Epidemiologic methods are increasingly being used to move developmental psychopathology from studies that catalogue correlates of child and adolescent mental health to designs that can test rival hypotheses regarding causal genetic and environmental influences. A two-part strategy is proposed for the next phase of epidemiologic research. First, to facilitate the most informed tests of causal hypotheses, it is necessary to develop and test models of the structure of hypothesized genetic and environmental influences on mental health phenotypes. This will involve testing the related hypotheses that there are both (a) dimensions of psychopathology that are distinct in the sense of having at least some unique genetic and/or environmental influences, and (b) higher-order domains of correlated dimensions that are all apparently influenced in part by the same genetic and/or environmental factors. The resulting causal taxonomy would organize tests of causal hypotheses regarding both factors that may broadly increase risk for multiple dimensions of psychopathology and factors that may specifically increase risk for each individual dimension. Second, it is necessary to make greater use of a number of powerful epidemiologic designs that allow rigorous tests of rival hypotheses regarding genetic and environmental causes.

Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring

Importance Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding. Objective To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems. Design, Setting, and Participants This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations. Exposures Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations. Main Outcomes and Measures Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring. Results Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons. Conclusions and Relevance Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Maternal Stress and Infant Mortality The Importance of the Preconception Period

Although preconception and prenatal maternal stress are associated with adverse outcomes in birth and childhood, their relation to infant mortality remains uncertain. We used logistic regression to study infant mortality risk following maternal stress within a population-based sample of infants born in Sweden between 1973 and 2008 (N = 3,055,361). Preconception (6–0 months before conception) and prenatal (between conception and birth) stress were defined as death of a first-degree relative of the mother. A total of 20,651 offspring were exposed to preconception stress, 26,731 offspring were exposed to prenatal stress, and 8,398 cases of infant mortality were identified. Preconception stress increased the risk of infant mortality independently of measured covariates, and this association was timing specific and robust across low-risk groups. Prenatal stress did not increase risk of infant mortality. These results suggest that the period immediately before conception may be a sensitive developmental period with ramifications for infant mortality risk.

A sibling-comparison study of smoking during pregnancy and childhood psychological traits

Prenatal exposure to substances of abuse is associated with numerous psychological problems in offspring, but quasi-experimental studies controlling for co-occurring risk factors suggest that familial factors (e.g., genetic and environmental effects shared among siblings) confound many associations with maternal smoking during pregnancy (SDP). Few of the quasi-experimental studies in this area have explored normative psychological traits in early childhood or developmental changes across the lifespan, however. The current study used multilevel growth curve models with a large, nationally-representative sample in the United States to investigate for potential effects of SDP on the developmental trajectories of cognitive functioning, temperament/personality, and disruptive behavior across childhood, while accounting for shared familial confounds by comparing differentially exposed siblings and statistically controlling for offspring-specific covariates. Maternal SDP predicted the intercept (but not change over time) for all cognitive and externalizing outcomes. Accounting for familial confounds, however, attenuated the association between SDP exposure and all outcomes, except the intercept (age 5) for reading recognition. These findings, which are commensurate with previous quasi-experimental research on more severe indices of adolescent and adult problems, suggest that the associations between SDP and developmental traits in childhood are due primarily to confounding factors and not a causal association.

Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes

Importance Motor vehicle crashes (MVCs) are a major public health problem. Research has demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to experience MVCs, but the effect of ADHD medication treatment on the risk of MVCs remains unclear. Objective To explore associations between ADHD medication use and risk of MVCs in a large cohort of patients with ADHD. Design, Setting, and Participants For this study, a US national cohort of patients with ADHD (n = 2 319 450) was identified from commercial health insurance claims between January 1, 2005, and December 31, 2014, and followed up for emergency department visits for MVCs. The study used within-individual analyses to compare the risk of MVCs during months in which patients received ADHD medication with the risk of MVCs during months in which they did not receive ADHD medication. Exposures Dispensed prescription of ADHD medications. Main Outcomes and Measures Emergency department visits for MVCs. Results Among 2 319 450 patients identified with ADHD, the mean (SD) age was 32.5 (12.8) years, and 51.7% were female. In the within-individual analyses, male patients with ADHD had a 38% (odds ratio, 0.62; 95% CI, 0.56-0.67) lower risk of MVCs in months when receiving ADHD medication compared with months when not receiving medication, and female patients had a 42% (odds ratio, 0.58; 95% CI, 0.53-0.62) lower risk of MVCs in months when receiving ADHD medication. Similar reductions were found across all age groups, across multiple sensitivity analyses, and when considering the long-term association between ADHD medication use and MVCs. Estimates of the population-attributable fraction suggested that up to 22.1% of the MVCs in patients with ADHD could have been avoided if they had received medication during the entire follow-up. Conclusions and Relevance Among patients with ADHD, rates of MVCs were lower during periods when they received ADHD medication. Considering the high prevalence of ADHD and its association with MVCs, these findings warrant attention to this prevalent and preventable cause of mortality and morbidity.