Mental Health in Mothers of Autistic Children with a Medical Home: The Potentially Mechanistic Roles of Coping and Social Support.

Mothers of autistic children often report poor mental health outcomes. One established risk factor for these outcomes is the child having a medical home. This study examined possible mediating variables (coping, social support) in this relationship in 988 mothers of autistic children from the 2017/2018 National Survey of Children's Health (NSCH). The results of the multiple mediation model suggest the relationship between having a medical home and maternal mental health is largely explained by indirect associations with coping and social support. These findings suggest that clinical interventions for coping and social support provided by the medical home for mothers of autistic children may improve maternal mental health outcomes over and above implementation of a medical home.

Study protocol to quantify the genetic architecture of sonographic cervical length and its relationship to spontaneous preterm birth.

INTRODUCTION: A short cervix (cervical length <25 mm) in the midtrimester (18-24 weeks) of pregnancy is a powerful predictor of spontaneous preterm delivery. Although the biological mechanisms of cervical change during pregnancy have been the subject of extensive investigation, little is known about whether genes influence the length of the cervix, or the extent to which genetic factors contribute to premature cervical shortening. Defining the genetic architecture of cervical length is foundational to understanding the aetiology of a short cervix and its contribution to an increased risk of spontaneous preterm delivery. METHODS/ANALYSIS: The proposed study is designed to characterise the genetic architecture of cervical length and its genetic relationship to gestational age at delivery in a large cohort of Black/African American women, who are at an increased risk of developing a short cervix and delivering preterm. Repeated measurements of cervical length will be modelled as a longitudinal growth curve, with parameters estimating the initial length of the cervix at the beginning of pregnancy, and its rate of change over time. Genome-wide complex trait analysis methods will be used to estimate the heritability of cervical length growth parameters and their bivariate genetic correlation with gestational age at delivery. Polygenic risk profiling will assess maternal genetic risk for developing a short cervix and subsequently delivering preterm and evaluate the role of cervical length in mediating the relationship between maternal genetic variation and gestational age at delivery. ETHICS/DISSEMINATION: The proposed analyses will be conducted using deidentified data from participants in an IRB-approved study of longitudinal cervical length who provided blood samples and written informed consent for their use in future genetic research. These analyses are preregistered with the Center for Open Science using the AsPredicted format and the results and genomic summary statistics will be published in a peer-reviewed journal.

Patterns of bi-directional relations across alcohol use, religiosity, and self-control in adolescent girls.

Examining predictors of alcohol use among adolescent girls is increasingly important to enhance prevention efforts, given that the gender gap in alcohol use is steadily closing. While both religiosity and self-control have been independently associated with decreased alcohol use, little research has explored 1) whether religiosity and self-control are reciprocally related and 2) whether the reciprocal association between these constructs may indicate different patterns in the development of alcohol use. As such, this study examined whether there are multiple patterns of reciprocal relationships across religiosity, self-control, and alcohol use among adolescent girls. Latent variable mixture modeling was combined with an autoregressive cross-lagged panel model to identify discrete, prototypical patterns of longitudinal associations (i.e., subgroups) across religiosity, self-control, and alcohol use among 2,122 girls ages 13-17. Psychosocial covariates (e.g., conduct problems) were examined as predictors of each subgroup. Two subgroups were identified. Self-control was associated with reduced alcohol use in both the majority (87.56% of the sample) and minority (12.44% of the sample) subgroups, but only the majority subgroup also demonstrated associations between religiosity, self-control, and alcohol use. Religiosity may predict lower alcohol use in a majority of adolescent girls but this association may not be present among all girls, suggesting that there is a qualitative difference in how religiosity is associated with self-control and alcohol use between subgroups. Results also suggest that higher levels of conduct problems may predict which girls are more likely to demonstrate associations between only self-control and alcohol use, and demonstrate no significant associations with religiosity.

Replicated umbilical cord blood DNA methylation loci associated with gestational age at birth.

DNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation.

The Pediatric Inventory for Parents: Development of a short-form in fathers of children with type 1 diabetes (T1D).

BACKGROUND: The Pediatric Inventory for Parents (PIP) is a 42-item measure of paediatric parenting stress that results in 84 responses. Although this measure has been extensively validated, the number of items in the instrument may hinder clinical applicability. METHODS: The current study reports on the development of a short-form of the PIP using data from 344 fathers of children with type 1 diabetes. Recommendations for short-form development as well as item response theory (IRT) were used to construct a 13-item PIP Short-Form that results in 26 responses. RESULTS: The retained items were chosen to reflect the content domains of the original form of the PIP and demonstrated acceptable item fit under the partial credit model (PCM; Infit and Outfit indices closest to one and items with thresholds across the span of the latent trait). CONCLUSIONS: The PIP Short-Form may allow health care professionals to more feasibly assess paediatric parenting stress among parents of children with chronic health conditions. Future studies are needed to validate this new short-form.

Factor Structure and Further Validation of the 20-Item Short Form of the Obsessive Beliefs Questionnaire.

A 44-item version of the Obsessive Beliefs Questionnaire (OBQ-44) put forward by the Obsessive Compulsive Cognitions Working Group remains the most widely used version of the OBQ, despite research casting doubt on its factorial validity and the existence of a short form (i.e., OBQ-20). In a large sample of undergraduate students (n = 1,210), a bifactor model of the OBQ-20, consisting of a general factor and four specific factors (threat, responsibility, importance/control of thoughts, perfectionism/certainty), was supported as the best-fitting model. None of the examined OBQ-44 models provided adequate fit. The bifactor model of the OBQ-20 was retained in two independent samples (n = 1,342 community adults, n = 319 undergraduate students). The incremental validity of the specific factors of the OBQ-20 beyond the general factor was evidenced across multiple criterion indices, including obsessive-compulsive symptom measures and reactions to a thought-induction task. Results further support use of the OBQ-20.

Stressful life events influence transitions among latent classes of alcohol use.

Stressful life events (SLEs) have been associated with an increased risk of heavy drinking, suggesting individuals may use alcohol to cope with negative life events. However, little research has explored the extent to which SLEs have different effects on later alcohol use based on one's current alcohol use pattern. We replicated prototypical patterns of alcohol use via latent class analysis at Waves 2, 3, and 4 of the National Longitudinal Study of Adolescent to Adult Health (n = 4,569). Latent transition analysis was then used to examine the extent to which SLEs influenced the likelihood of stability or change in class membership from adolescence to early adulthood. Results suggested that adolescents were more likely to transition into different patterns of alcohol use as they entered early adulthood but were more likely to retain the same drinking pattern once in early adulthood. Among those who typically abstained, experiencing SLEs was associated with greater odds of transitioning to heavier drinking or problematic patterns of alcohol use. However, among those who had heavy or problematic alcohol use patterns, SLEs were associated with greater odds of decreasing alcohol use to either heavy or abstaining levels. Results suggest those who previously abstained may begin to use alcohol as a coping mechanism following stressful events, whereas those who drank heavily may decrease or abstain from alcohol use following life stress as a means of enacting positive life changes. The results encourage further study into factors that differentiate changes in alcohol use among light drinkers following SLEs. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Prospective longitudinal study of the pregnancy DNA methylome: the US Pregnancy, Race, Environment, Genes (PREG) study.

PURPOSE: The goal of the Pregnancy, Race, Environment, Genes study was to understand how social and environmental determinants of health (SEDH), pregnancy-specific environments (PSE) and biological processes influence the timing of birth and account for the racial disparity in preterm birth. The study followed a racially diverse longitudinal cohort throughout pregnancy and included repeated measures of PSE and DNA methylation (DNAm) over the course of gestation and up to 1 year into the postpartum period. PARTICIPANTS: All women were between 18 and 40 years of age with singleton pregnancies and no diagnosis of diabetes or indication of assisted reproductive technology. Both mother and father had to self-identify as either African-American (AA) or European-American (EA). Maternal peripheral blood samples along with self-report questionnaires measuring SEDH and PSE factors were collected at four pregnancy visits, and umbilical cord blood was obtained at birth. A subset of participants returned for two additional postpartum visits, during which additional questionnaires and maternal blood samples were collected. The pregnancy and postpartum extension included n=240 (AA=126; EA=114) and n=104 (AA=50; EA=54), respectively. FINDINGS TO DATE: One hundred seventy-seven women (AA=89, EA=88) met full inclusion criteria out of a total of 240 who were initially enrolled. Of the 63 participants who met exclusion criteria after enrolment, 44 (69.8%) were associated with a medical reason. Mean gestational age at birth was significantly shorter for the AA participants by 5.1 days (M=272.5 (SD=10.5) days vs M=277.6 (SD=8.3)). FUTURE PLANS: Future studies will focus on identifying key environmental factors that influence DNAm change across pregnancy and account for racial differences in preterm birth.

Critical Issues in the Inclusion of Genetic and Epigenetic Information in Prevention and Intervention Trials.

Human genetic research in the past decade has generated a wealth of data from the genome-wide association scan era, much of which is catalogued and freely available. These data will typically test the relationship between a single nucleotide variant or polymorphism (SNP) and some outcome, disease, or trait. Ongoing investigations will yield a similar wealth of data regarding epigenetic phenomena. These data will typically test the relationship between DNA methylation at a single genomic location/region and some outcome. Most of these findings will be the result of cross-sectional investigations typically using ascertained cases and controls. Consequently, most methodological consideration focuses on methods appropriate for simple case-control comparisons. It is expected that a growing number of investigators with longitudinal experimental prevention or intervention cohorts will also measure genetic and epigenetic indicators as part of their investigations, harvesting the wealth of information generated by the genome-wide association study (GWAS) era to allow for targeted hypothesis testing in the next generation of prevention and intervention trials. Herein, we discuss appropriate quality control and statistical modelling of genetic, polygenic, and epigenetic measures in longitudinal models. We specifically discuss quality control, population stratification, genotype imputation, pathway approaches, and proper modelling of an interaction between a specific genetic variant and an environment variable (GxE interaction).

Prior Delinquency and Depression Differentially Predict Conditional Associations Between Discrete Patterns of Adolescent Religiosity and Adult Alcohol Use Patterns.

Prior research has demonstrated that adolescent delinquency and depression are prospectively related to adult alcohol use and that adolescent religiosity may influence these relationships. However, such associations have not been investigated using person-centered approaches that provide nuanced explorations of these constructs. Using data from the National Longitudinal Study of Adolescent to Adult Health, we examined whether adolescent delinquency and depression differentiated typologies of adult alcohol users and whether these relationships varied across religiosity profiles. Three typologies of self-identified Christian adolescents and 4 types of adult alcohol users were identified via latent profile analysis. Delinquency and depression were related to increased likelihood of membership in heavy drinking or problematic alcohol use profiles, but this relationship was most evident among those likely to be involved in religious practices. These results demonstrate the importance of person-centered approaches in characterizing the influences of internalizing and externalizing behaviors on subsequent patterns of alcohol use.

Parental Monitoring and Alcohol Use Across Adolescence in Black and White Girls: A Cross-Lagged Panel Mixture Model.

BACKGROUND: The link between parental monitoring and adolescent alcohol use is well established, but the directionality of this relationship is somewhat elusive. The literature suggests that parental engagement serves a protective function with respect to alcohol use, but that parental monitoring may also diminish in response to recurrent risk behavior. The lower rate of alcohol use despite evidence of lower levels of parental monitoring in Black versus White youth raises the question of for whom and under what conditions parental monitoring and alcohol use are associated. METHODS: Data were drawn from a community sample of 1,634 female adolescents (954 Black, 680 White) from 4 age cohorts, assessed annually in an accelerated longitudinal design. This study uses data spanning ages 12 to 17; parental monitoring and alcohol use were assessed via self-report, while demographic and adolescent psychosocial risk factors were derived from parent reports when the girls were age 12. An autoregressive cross-lagged panel mixture model was used to identify discrete patterns of parental monitoring and alcohol use associations across adolescence, and psychosocial factors that differentiate between them. RESULTS: Two discrete patterns of codeveloping alcohol use and parental monitoring emerged: one with stable bidirectional and autoregressive links (79%) and another differing from the majority profile in terms of the absence (alcohol use to parental monitoring) and direction (parental monitoring to alcohol use) of cross-construct influences (21%). Those in the minority profile were, at age 12, more likely to have received public assistance, resided in single-parent households, reached puberty, and manifest more severe conduct problems. CONCLUSIONS: Identifying subgroups of girls with distinct patterns of codeveloping alcohol use and parental monitoring is particularly relevant to the development and implementation of family-level interventions, both in terms of targeting those with known demographic risk factors, and tailoring programs to address behavioral correlates, such as conduct problems.

Dimensionality and Genetic Correlates of Problem Behavior in Low-Income African American Adolescents.

Researchers have long observed that problem behaviors tend to cluster together, particularly among adolescents. Epidemiological studies have suggested that this covariation is due, in part, to common genetic influences, and a number of plausible candidates have emerged as targets for investigation. To date, however, genetic association studies of these behaviors have focused mostly on unidimensional models of individual phenotypes within European American samples. Herein, we compared a series of confirmatory factor models to best characterize the structure of problem behavior (alcohol and marijuana use, sexual behavior, and disruptive behavior) within a representative community-based sample of 592 low-income African American adolescents (50.3% female), ages 13 to 18. We further explored the extent to which 3 genes previously implicated for their role in similar behavioral dimensions (CHRM2, GABRA2, and OPRM1) independently accounted for variance within factors specified in the best-fitting model. Supplementary analyses were conducted to derive comparative estimates for the predictive utility of these genes in more traditional unidimensional models. Findings provide initial evidence for a bifactor structure of problem behavior among African American adolescents and highlight novel genetic correlates of specific behavioral dimensions otherwise undetected in an orthogonal syndromal factor. Implications of this approach include increased precision in the assessment of problem behavior, with corresponding increases in the reliability and validity of identified genetic associations. As a corollary, the comparison of primary and supplementary association analyses illustrates the potential for overlooking and/or overinterpreting meaningful genetic effects when failing to adequately account for phenotypic complexity.

Posttraumatic stress disorder and alcohol dependence: Epidemiology and order of onset.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and alcohol dependence (AD) frequently co-occur; however, epidemiologic studies of temporal associations between PTSD and AD are limited. The aims of this study were (a) to investigate the bidirectional associations between PTSD and AD and (b) to examine demographic and clinical correlates of order-of-onset among individuals with PTSD and AD. METHOD: Participants were 11,103 adults (60.6% women; Mage = 48.7 years, SD = 15.9) from the National Epidemiologic Survey on Alcohol and Related Conditions who endorsed lifetime alcohol consumption and DSM-IV PTSD Criterion A trauma exposure (American Psychiatric Association, 2000). Cox proportional hazards models with time-dependent covariates were used to evaluate bidirectional associations between PTSD and AD. Sex differences were assessed using stratified analyses. RESULTS: After adjusting for demographic, trauma, and alcohol characteristics, PTSD was associated with greater likelihood of subsequent AD (hazard ratio [HR] = 1.359, 95% CI = 1.357-1.362), and AD was associated with greater likelihood of subsequent PTSD (HR = 1.274, 95% CI = 1.271-1.277). Bidirectional associations between PTSD and AD were stronger for women compared with men. Among individuals with PTSD and AD, initial onset of PTSD was associated with younger age of first potentially traumatic event. Initial onset of AD was associated with earlier initiation of alcohol use, earlier onset of heavy alcohol use, family history of alcohol problems, and history of generalized anxiety disorder and social anxiety disorder for women but not men. Initial AD was associated with lifetime panic disorder for men and women. CONCLUSIONS: Etiology of PTSD and AD is heterogeneous, and order of onset may reflect differing risk pathways. (PsycINFO Database Record

Associations Between Gestational Age at Birth and Alcohol Use in the Avon Longitudinal Study of Parents and Children.

BACKGROUND: The relationship between gestational age at birth (GA) and alcohol use measures in early adulthood was examined in a large U.K. community-based birth cohort (Avon Longitudinal Study of Parents and Children). METHODS: A series of linear and logistic regression models were used to test for main effects of a continuous measure of GA on a range of alcohol use measures, and moderation of these associations by sex. In addition, mediation analyses assessed the extent to which significant associations between GA and alcohol use operated indirectly, through influences of the parental environment and/or childhood measures of emotional and behavioral health (EBH). RESULTS: Earlier GA significantly predicted never drinking by age 18, but was not associated with other measures of alcohol use behavior among young adult drinkers (i.e., Self-Rating of the Effects of Alcohol, Alcohol Use Disorders Identification Test, or DSM-IV-TR Criteria for Alcohol Dependence). The association between earlier GA and never drinking by age 18 was moderated by sex, such that females born early were less likely to have ever had a drink by age 18. In the full sample, childhood measures of EBH were found to mediate the association between earlier GA and never drinking by age 18. This association was not mediated by parenting factors. CONCLUSIONS: Earlier GA is associated with never drinking alcohol in early adulthood, in females. Emotional and behavioral difficulties experienced in early childhood may mediate the relationship between earlier GA and never drinking by age 18.

Genes involved in stress response and alcohol use among high-risk African American youth.

BACKGROUND: Genetic and environmental factors influence substance use behaviors in youth. One of the known environmental risk factors is exposure to life stressors. The aim of this project is to study the interaction between NR3C1 and CRHBP, genes thought to be involved in stress pathways, exposure to stressful life events, and adolescent alcohol use/misuse. METHODS: The sample included 541 African American individuals (ages 13-18) from the Genes, Environment, and Neighborhood Initiative, a subset of the Mobile Youth Survey sample from whom DNA and more extensive phenotypic data were collected. Participants were selected from high-poverty neighborhoods in Mobile, Alabama, with potential exposure to a variety of extreme life stressors. RESULTS: A measure of stressful life events was significantly predictive of alcohol use/misuse. In addition, this association was significantly dependent upon the number of putative risk variants at rs1715749, a single-nucleotide polymorphism (SNP) in CRHBP (P ≤ .006). There was no significant interaction between NR3C1 and stressful life events with respect to alcohol use/misuse, after taking into account multiple testing. CONCLUSIONS: These findings suggest that CRHBP variants are potentially relevant for adolescent alcohol use/misuse among African American youth populations being reared within the context of stressful life events and warrant replication.

Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial.

Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era.

Examining the latent class structure of CO2 hypersensitivity using time course trajectories of panic response systems.

BACKGROUND AND OBJECTIVES: Carbon dioxide (CO2) hypersensitivity is hypothesized to be a robust endophenotypic marker of panic spectrum vulnerability. The goal of the current study was to explore the latent class trajectories of three primary response systems theoretically associated with CO2 hypersensitivity: subjective anxiety, panic symptoms, and respiratory rate (fR). METHODS: Participants (n = 376; 56% female) underwent a maintained 7.5% CO2 breathing task that included three phases: baseline, CO2 air breathing, and recovery. Growth mixture modeling was used to compare response classes (1…n) to identify the best-fit model for each marker. Panic correlates also were examined to determine class differences in panic vulnerability. RESULTS: For subjective anxiety ratings, a three-class model was selected, with individuals in one class reporting an acute increase in anxiety during 7.5% CO2 breathing and a return to pre-CO2 levels during recovery. A second, smaller latent class was distinguished by elevated anxiety across all three phases. The third class reported low anxiety reported during room air, a mild increase in anxiety during 7.5% CO2 breathing, and a return to baseline during recovery. Latent class trajectories for fR yielded one class whereas panic symptom response yielded two classes. LIMITATIONS: This study examined CO2 hypersensitivity in one of the largest samples to date, but did not ascertain a general population sample thereby limiting generalizability. Moreover, a true resting baseline measure of fR was not measured. CONCLUSIONS: Two classes potentially representing different risk pathways were observed. Implications of results will be discussed in the context of panic risk research.

Childhood internalizing symptoms are negatively associated with early adolescent alcohol use.

BACKGROUND: The relationship between childhood internalizing problems and early adolescent alcohol use has been infrequently explored and remains unclear. METHODS: We employed growth mixture modeling of internalizing symptoms for a large, population-based sample of U.K. children (the Avon Longitudinal Study of Parents and Children Cohort) to identify trajectories of childhood internalizing symptoms from age 4 through age 11.5. We then examined the relationship between membership in each trajectory and alcohol use in early adolescence (reported at age 13.8). RESULTS: Overall, children experiencing elevated levels of internalizing symptoms were less likely to use alcohol in early adolescence. This finding held true across all internalizing trajectories; that is, those exhibiting increasing levels of internalizing symptoms over time, and those whose symptoms desisted over time, were both less likely to use alcohol than their peers who did not exhibit internalizing problems. CONCLUSIONS: We conclude that childhood internalizing symptoms, unlike adolescent symptoms, are negatively associated with early adolescent alcohol experimentation. Additional studies are warranted to follow up on our preliminary evidence that symptoms of phobia and separation anxiety drive this effect.

Effect of OPRM1 and stressful life events on symptoms of major depression in African American adolescents.

BACKGROUND: In a community sample of low-income African American adolescents, we tested the interactive effects of variation in the mu 1 opioid receptor (OPRM1) gene and the occurrence of stressful life events on symptoms of depression. METHOD: Interactive effects of 24 OPRM1 simple nucleotide polymorphisms (SNP) and adolescent report of stressful life events on depression were tested using multilevel regressions. SNPs were dummy coded to test both additive and dominate forms of coding. RESULTS: Five OPRM1 SNPs showed significant evidence of interaction with stressful life events to alter depression risk (or symptoms) after adjusting for multiple testing and the correlated nature of the SNPs. Follow-up analyses showed significant differences based on OPRM1 genotype at both lower and higher frequencies of stressful life events, suggesting that participants with a copy of the minor allele on OPRM1 SNPs rs524731, rs9478503, rs3778157, rs10485057, and rs511420 have fewer symptoms in low stress conditions but more symptoms in high stress conditions compared to major allele homozygotes. LIMITATIONS: The genetic variants associated with depression in African American adolescents may not translate to other ethnic groups. This study is also limited in that only one gene that functions within a complex biological system is addressed. CONCLUSIONS: This current study is the first to find an interaction between OPRM1 and life stress that is associated with depression. It also addressed an understudied population within the behavioral genetics literature. Further research should test additional genes involved in the opioid system and expand the current findings to more diverse samples.

Testing for measured gene-environment interaction: problems with the use of cross-product terms and a regression model reparameterization solution.

The study of gene-environment interaction (G × E) has garnered widespread attention. The most common way to assess interaction effects is in a regression model with a G × E interaction term that is a product of the values specified for the genotypic (G) and environmental (E) variables. In this paper we discuss the circumstances under which interaction can be modeled as a product term and cases in which use of a product term is inappropriate and may lead to erroneous conclusions about the presence and nature of interaction effects. In the case of a binary coded genetic variant (as used in dominant and recessive models, or where the minor allele occurs so infrequently that it is not observed in the homozygous state), the regression coefficient corresponding to a significant interaction term reflects a slope difference between the two genotype categories and appropriately characterizes the statistical interaction between the genetic and environmental variables. However, when using a three-category polymorphic genotype, as is commonly done when modeling an additive effect, both false positive and false negative results can occur, and the nature of the interaction can be misrepresented. We present a reparameterized regression equation that accurately captures interaction effects without the constraints imposed by modeling interactions using a single cross-product term. In addition, we provide a series of recommendations for making conclusions about the presence of meaningful G × E interactions, which take into account the nature of the observed interactions and whether they map onto sensible genotypic models.