Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics.

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, although down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci; the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses were found robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who generate and share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

What Brings You in Today? Sex, Race, Substance Type, and Other Sociodemographic and Health-Related Characteristics Predict if Substance Use is the Main Reason for a Clinical Encounter.

Background: Substance-related diagnoses (SRDs) are a common healthcare presentation. This study identified sociodemographic and health-related characteristics associated with having an SRD as the primary reason for a clinical encounter compared to those with an SRD who are treated for other reasons. Methods: Electronic health record (EHR) data on patients with an SRD (n=12,358, ages 18-90) were used to assess if an SRD was the primary reason for a clinical encounter from January 1, 2012-January 1, 2018. Patients were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios, and 95% confidence intervals were calculated. Results: In the matched cohort of 8,630, most reported male sex (65.8%), White race (70.0%), and single marital status (62.7%) with a mean age of 47.2 (SD=14.6). Patient reported female sex, Black race, age 70+, married status, and low-income (<$50,000) were associated with a lower likelihood of presenting to care for an SRD as the primary reason for a clinical encounter. A nicotine-, alcohol-, opioid-, or stimulant-related diagnosis was associated with a higher likelihood of presenting to care for an SRD as the primary reason for the clinical visit. Conclusion: This is the first study to investigate whether sociodemographic and health-related characteristics were associated with having an SRD as the primary reason for a clinical encounter. Using rigorous methods, we investigated a unique clinical question adding new knowledge to predictors of patients seeking clinical care. Understanding these predictors can help us better align service provision with population needs and inform new approaches to tailoring care.

Development and validation of a postnatal risk score that identifies children with prenatal alcohol exposure.

BACKGROUND: This study aimed to develop an efficient and easily calculable risk score that can be used to identify an individual's risk of having been exposed to alcohol prenatally. METHODS: Data for this study were collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, Phases 2 and 3. Two cohorts (ages 5 to 17 years) completed a comprehensive neurobehavioral battery and a standard dysmorphology exam: a development cohort (DC; n = 325) and a comparative cohort (CC; n = 523). Both cohorts included two groups: those with histories of heavy prenatal alcohol exposure (AE-DC, n = 121; AE-CC, n = 177) and a control group that included subjects with minimal or no prenatal alcohol exposure (CON-DC, n = 204; CON-CC, n = 346). Behavioral assessments and physical exam data were combined using regression techniques to derive a risk score indicating the likelihood of prenatal alcohol exposure. Subjects were then divided into two subgroups: (1) low risk and (2) high risk. Chi-square (χ2 ) determined classification accuracy and ROC curves were produced to assess the predictive accuracy. Correlations between risk scores and intelligence quotient and executive function scores were calculated. RESULTS: Subjects were accurately classified in the DC (χ2  = 78.61, p < 0.001) and CC (χ2  = 86.63, p < 0.001). The classification model also performed well in the DC (ROC = 0.835 [SE = 0.024, p < 0.001]) and CC (ROC = 0.786 [SE = 0.021, p < 0.001]). In the AE-CC and CON-CC, there were modest but significant associations between the risk score and executive function (AE-CC: r = -0.20, p = 0.034; CON-CC: r = -0.28, p < 0.001) and intelligence quotient (AE-CC: r = -0.20, p = 0.034; CON-CC: r = -0.28, p < 0.001). CONCLUSION(S): The risk score significantly distinguished alcohol-exposed from control subjects and correlated with important cognitive outcomes. It has significant clinical potential and could be easily deployed in clinical settings.

Adaptive, Externalizing, and Internalizing Behavior of Children with Prenatal Alcohol Exposure: A Comparison of Three Parent-Report Questionnaires.

This study compared the Behavior Assessment System for Children-Third Edition (BASC-3) to the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales-Third Edition (VABS-3) in children with and without histories of prenatal alcohol exposure. Data were collected from Collaborative Initiative on Fetal Alcohol Spectrum Disorders Phase 4 sites. Caregivers rated their child's behavior using three questionnaires: BASC-3, CBCL, and VABS-3. BASC-3 Adaptive Skills, Externalizing Problems, and Internalizing Problems scores were correlated with comparable scores from the CBCL (Externalizing and Internalizing Problems) and VABS-3 (Adaptive Skills) both within and across groups. Sensitivity, specificity, and positive and negative predictive values were calculated for the BASC-3. BASC-3 sensitivity rates were 78.1%, 80.5%, and 47.0% and specificity rates were 79.4%, 80.4%, and 81.5% for Adaptive Skills, Externalizing Problems, and Internalizing Problems, respectively. Positive predictive values were 87.1%, 88.0%, and 81.9% and negative predictive values were 67.0%, 69.8%, and 46.3% for Adaptive Skills, Externalizing Problems, and Internalizing Problems, respectively. Results replicated previous reports of behavioral and adaptive difficulties in children with prenatal alcohol exposure. These findings provide support for using the BASC-3 in this population.

Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations.

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N = 130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across hundreds of biomarkers, health, and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from the UK Biobank (UKB; N = 334,659). We observed consistent positive genetic correlations with substance use and obesity in both cohorts. Other genetic correlations were discrepant, including positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in the UKB, and genetic correlations with cognition that were negative in 23andMe but positive in the UKB. Phenome-wide association study using polygenic scores of coffee intake derived from 23andMe or UKB summary statistics also revealed consistent associations with increased odds of obesity- and red blood cell-related traits, but all other associations were cohort-specific. Our study shows that the genetics of coffee intake associate with substance use and obesity across cohorts, but also that GWAS performed in different populations could capture cultural differences in the relationship between behavior and genetics.

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Craving among patients seeking treatment for substance use disorder.

BACKGROUND: Craving has been implicated as a central feature of addiction and a predictor of relapse. However, a complete understanding of how craving varies across patient populations is lacking. This study aimed to better inform the effective and accurate use of craving as a clinical prognostic tool for patients with substance use disorders (SUD). METHODS: This cross-sectional study utilized information gathered on patients (n = 112) entering specialty treatment for a SUD. Craving in the prior 30 days was assessed with a single item with other intake questionnaires. RESULTS: Patients who reported substance use in the last 30 days were more likely to report craving compared to patients who did not report substance use in the last 30 days (AOR = 6.86 [95% CI 2.17-21.7], p-value = 0.001). Patients who reported Hispanic/Latinx ethnicity were less likely to report craving compared to patients who did not report Hispanic/Latinx ethnicity (AOR = 0.28 [95% CI 0.08-0.95], p-value = 0.04). There was no association between craving and Adverse Childhood Events (OR = 1.03 [95% CI 0.84-1.25], p-value = 0.81). CONCLUSION: The association between recent substance use and craving supports previous findings. The observed variation in craving among patients who report Hispanic/Latinx ethnicity is novel and suggests socio-cultural influences and possibly genetic factors influencing reported craving amongst patients. Additional research is needed to further understand the underlying factors leading to this finding, in order for better utilization of craving as a clinical indicator across patient populations.

Validation of the FASD-Tree as a screening tool for fetal alcohol spectrum disorders.

BACKGROUND: As many as 80% of individuals with fetal alcohol spectrum disorders (FASD) are misdiagnosed or not diagnosed. This study tests the accuracy and validity of a web-based screening tool (the FASD-Tree) for identifying children and adolescents with FASD. METHODS: Children with histories of prenatal alcohol exposure (PAE) and controls (N = 302, including 224 with PAE and 78 controls) were examined for physical signs of fetal alcohol syndrome (FAS), and parents completed behavioral questionnaires. Data were entered into the FASD-Tree, a web-based decision tree application. The FASD-Tree provided two outcomes: a dichotomous indicator (yes/no) and a numeric risk score (0 to 5), which have been shown separately to identify children with PAE and neurobehavioral impairment and to correlate with neurobehavioral outcomes. Overall accuracy (ACC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the decision tree, risk score, and their combination. Misclassified cases were examined for systematic bias. RESULTS: The FASD-Tree was successful in accurately identifying youth with histories of PAE and the subgroup of individuals with FASD, indicating its validity as an FASD screening tool. Overall accuracy rates for FASD-Tree components ranged from 75.0% to 84.1%, and both the decision tree outcome and risk score, and their combination, resulted in fair to good discrimination (area under the curve = 0.722 to 0.862) of youth with histories of PAE or FASD. While most participants were correctly classified, those who were misclassified differed in IQ and attention. Race, ethnicity, and sex did not affect the results. CONCLUSION: The FASD-Tree is not a biomarker of PAE and does not provide definitive evidence of prenatal alcohol exposure. Rather it is an accurate and valid screening tool for FASD and can be used by clinicians who suspect that a patient has a history of PAE, even if the exposure is unknown.

Substance-related diagnosis type predicts the likelihood and co-occurrence of preterm and cesarean delivery.

This article aimed to evaluate whether a substance-related diagnosis (SRD; i.e., alcohol, opioids, cannabis, stimulants, nicotine) predicts the likelihood and co-occurrence of preterm (20-37 weeks' gestation) and cesarean delivery.This study reviewed electronic health record data on women (aged 18-44 years) who delivered a single live or stillbirth at ≥ 20 weeks of gestation from 2012 to 2019. Women with and without an SRD were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios and 95% confidence intervals were calculated.Of the 19,346 deliveries, a matched cohort of 2,158 deliveries was identified. Of these, 1,079 (50%) had an SRD, 280 (13%) had a preterm delivery, 833 (39%) had a cesarean delivery, and 166 (8%) had a co-occurring preterm and cesarean delivery. An SRD was significantly associated with preterm and cesarean delivery (AOR = 1.84 [95% CI, 1.41-2.39], p-value= <0.0001; AOR = 1.51 [95% CI, 1.23-1.85], p-value= <0.0001). An alcohol-related diagnosis (AOR = 1.82 [95% CI, 1.01-3.28], p-value= 0.0471), opioid-related diagnosis (AOR = 1.94 [95% CI, 1.26-2.98], p-value= 0.0027), stimulant-related diagnosis (AOR = 1.65 [95% CI, 1.11-2.45], p-value= 0.0142), and nicotine-related diagnosis (AOR = 1.54 [95% CI, 1.05-2.26], p-value= 0.0278) were associated with co-occurring preterm and cesarean delivery.Pregnant women with an SRD experienced disproportionally higher odds of preterm and cesarean delivery compared to pregnant women without an SRD. Substance-type predicts the type of delivery outcome. An SRD in pregnant women should be identified early to reduce potential harm through intervention and treatment.

Results of a screening tool for fetal alcohol spectrum disorders are associated with neuropsychological and behavioral measures.

PURPOSE: This study assessed whether the outcome of a screening tool for fetal alcohol spectrum disorders (FASD), the FASD-Tree, was associated with neuropsychological and behavioral outcomes. METHODS: Data for this study were collected as part of the fourth phase of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD-4). Participants (N = 175, 5 to 16 years) with or without histories of prenatal alcohol exposure were recruited from San Diego and Minneapolis. Each participant was screened using the FASD-Tree and administered a neuropsychological test battery; parents or guardians completed behavioral questionnaires. The FASD-Tree incorporates physical and behavioral measures and provides an outcome regarding the presence of FASD (FASD-Positive or FASD-Negative). Logistic regression was used to test whether the FASD-Tree outcome was associated with general cognitive ability, executive function, academic achievement, and behavior. Associations were tested in two groups: the whole sample and only correctly classified participants. RESULTS: Results of the FASD-Tree were associated with neuropsychological and behavioral measures. Participants classified as FASD-Positive were more likely than those classified as FASD-Negative to have a lower IQ score and exhibit poorer performance on measures of executive and academic functions. Behaviorally, participants classified as FASD-Positive were rated as having more behavior problems and adaptive difficulties. Similar relationships were found for all measures when including only participants correctly classified by the FASD-Tree screening tool. CONCLUSION: Results from the FASD-Tree screening tool were associated with neuropsychological and behavioral measures. Participants classified as FASD-Positive were more likely to have impairment in all domains tested. The results support the effectiveness of the FASD-Tree as a screening tool for use in clinical settings, providing an efficient and accurate way to identify patients in need of additional evaluation.

Genome-Wide Association Studies of Coffee Intake in UK/US Participants of European Ancestry Uncover Gene-Cohort Influences.

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N=130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across thousands of biomarkers and health and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from UK Biobank (UKB; N=334,659). The results of these two GWAS were highly discrepant. We observed positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in UKB. Genetic correlations with cognition were negative in 23andMe but positive in UKB. The only consistent observations were positive genetic correlations with substance use and obesity. Our study shows that GWAS in different cohorts could capture cultural differences in the relationship between behavior and genetics.

Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics.

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci, while the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses are robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

Do polygenic indices capture "direct" effects on child externalizing behavior? Within-family analyses in two longitudinal birth cohorts.

Behaviors and disorders characterized by difficulties with self-regulation, such as problematic substance use, antisocial behavior, and symptoms of attention-deficit/hyperactivity disorder (ADHD), incur high costs for individuals, families, and communities. These externalizing behaviors often appear early in the life course and can have far-reaching consequences. Researchers have long been interested in direct measurements of genetic risk for externalizing behaviors, which can be incorporated alongside other known risk factors to improve efforts at early identification and intervention. In a preregistered analysis drawing on data from the Environmental Risk (E-Risk) Longitudinal Twin Study (N=862 twins) and the Millennium Cohort Study (MCS; N=2,824 parent-child trios), two longitudinal cohorts from the UK, we leveraged molecular genetic data and within-family designs to test for genetic effects on externalizing behavior that are unbiased by the common sources of environmental confounding. Results are consistent with the conclusion that an externalizing polygenic index (PGI) captures causal effects of genetic variants on externalizing problems in children and adolescents, with an effect size that is comparable to those observed for other established risk factors in the research literature on externalizing behavior. Additionally, we find that polygenic associations vary across development (peaking from age 5-10 years), that parental genetics (assortment and parent-specific effects) and family-level covariates affect prediction little, and that sex differences in polygenic prediction are present but only detectable using within-family comparisons. Based on these findings, we believe that the PGI for externalizing behavior is a promising means for studying the development of disruptive behaviors across child development.

Differences in outpatient, emergency, and inpatient use among pregnant women with a substance-related diagnosis.

BACKGROUND: As a vulnerable population, pregnant women with a substance-related diagnosis (ie, substance use, misuse, or dependence) may use healthcare disproportionately. OBJECTIVE: The primary goal of this study was to evaluate the differences in the use of outpatient clinical visits, emergency department visits, and inpatient days in the hospital among women with and without a substance-related diagnosis during the antepartum period. STUDY DESIGN: This retrospective study retrieved electronic health record data on women (age, 18-44 years) who delivered a single live birth or stillbirth at ≥20 weeks of gestation from April 1, 2012, to September 30, 2019. Imbalance in measured maternal sociodemographic and obstetrical characteristics between women with and without a substance-related diagnosis was attenuated using propensity score matching on key demographic characteristics (eg, age), yielding a matched 1:1 sample. Unadjusted and adjusted logistic regressions models were used to determine the association between a substance-related diagnosis and outpatient visits, emergency visits, and inpatient days. RESULTS: From the total sample (n=16,770), the matched cohort consisted of 1986 deliveries. Of these, most were White (51.0%), or mixed or of some other race (31.1%). The mean age was 29.8 (standard deviation, 5.6). A substance-related diagnosis was identified in 993 women (50%) because of matching. Women with a substance-related diagnosis were more likely to have ≤10 outpatient visits than women without a substance-related diagnosis (adjusted odds ratio, 1.81 [95% confidence interval, 1.44-2.28]; P<.0001). Alcohol-, opioid-, and stimulant-related diagnoses were independently associated with ≤10 outpatient visits (adjusted odds ratio, 3.16 [95% confidence interval, 1.67-6.04]; P=.0005; adjusted odds ratio, 3.02 [95% confidence interval, 1.79-5.09]; P<.0001; adjusted odds ratio, 2.18 [95% confidence interval, 1.39-3.41]; P=.0007, respectively). Women with a substance-related diagnosis were more likely to have ≥1 emergency visit than women without a substance-related diagnosis (adjusted odds ratio, 1.36 [95% confidence interval, 1.00-1.85]; P<.0001). Opioid-, stimulant-, and nicotine-related diagnoses were independently associated with ≥1 emergency visit (adjusted odds ratio, 2.28 [95% confidence interval, 1.09-4.77]; P=.0287; adjusted odds ratio, 2.01 [95% confidence interval, 1.07-3.78]; P=.0301; adjusted odds ratio, 3.38 [95% confidence interval, 1.90-6.02]; P<.0001, respectively). Women with a substance-related diagnosis were more likely to have ≥3 inpatient days than women without a substance-related diagnosis (adjusted odds ratio, 1.69 [95% confidence interval, 1.07-2.67]; P=.0256). Opioid-, stimulant-, and nicotine-related diagnosis were independently associated with ≥3 inpatient days (adjusted odds ratio, 3.52 [95% confidence interval, 1.42-8.75]; P=.0067; adjusted odds ratio, 3.51 [95% confidence interval, 1.31-9.34]; P=.0123; adjusted odds ratio, 2.74 [95% confidence interval, 1.11-6.73]; P=.0285, respectively). CONCLUSION: Women with a substance-related diagnosis during the antepartum period who delivered a single live birth or stillbirth at ≥20 weeks of gestation were experiencing fewer outpatient visits, more emergency department visits, and more inpatient days than women without a substance-related diagnosis. The type of substance-related diagnosis (eg, alcohol, opioids, stimulants, or nicotine) was associated with different patterns of healthcare use. The results from this study have reinforced the need to identify substance-related diagnoses in pregnant women early to minimize disproportionate healthcare service utilization through intervention and treatment.