Use of the instrumental inequalities in simulated mendelian randomization analyses with coarsened exposures.

Mendelian randomization (MR) requires strong unverifiable assumptions to estimate causal effects. However, for categorical exposures, the MR assumptions can be falsified using a method known as the instrumental inequalities. To apply the instrumental inequalities to a continuous exposure, investigators must coarsen the exposure, a process which can itself violate the MR conditions. Violations of the instrumental inequalities for an MR model with a coarsened exposure might therefore reflect the effect of coarsening rather than other sources of bias. We aim to evaluate how exposure coarsening affects the ability of the instrumental inequalities to detect bias in MR models with multiple proposed instruments under various causal structures. To do so, we simulated data mirroring existing studies of the effect of alcohol consumption on cardiovascular disease under a variety of exposure-outcome effects in which the MR assumptions were met for a continuous exposure. We categorized the exposure based on subject matter knowledge or the observed data distribution and applied the instrumental inequalities to MR models for the effects of the coarsened exposure. In simulations of multiple binary instruments, the instrumental inequalities did not detect bias under any magnitude of exposure outcome effect when the exposure was coarsened into more than 2 categories. However, in simulations of both single and multiple proposed instruments, the instrumental inequalities were violated in some scenarios when the exposure was dichotomized. The results of these simulations suggest that the instrumental inequalities are largely insensitive to bias due to exposure coarsening with greater than 2 categories, and could be used with coarsened exposures to evaluate the required assumptions in applied MR studies, even when the underlying exposure is truly continuous.

Partial Identification of the Effects of Sustained Treatment Strategies.

Although many epidemiologic studies focus on point identification, it is also possible to partially identify causal effects under consistency and the data alone. However, the literature on the so-called "assumption-free" bounds has focused on settings with time-fixed exposures. We describe assumption-free bounds for the effects of both static and dynamic sustained interventions. To provide intuition for the width of the bounds, we also discuss a mathematical connection between assumption-free bounds and clone-censor-weight approaches to causal effect estimation. The bounds, which are often wide in practice, can provide important information about the degree to which causal analyses depend on unverifiable assumptions made by investigators.

Falsification of the instrumental variable conditions in Mendelian randomization studies in the UK Biobank.

Mendelian randomization (MR) is an increasingly popular approach to estimating causal effects. Although the assumptions underlying MR cannot be verified, they imply certain constraints, the instrumental inequalities, which can be used to falsify the MR conditions. However, the instrumental inequalities are rarely applied in MR. We aimed to explore whether the instrumental inequalities could detect violations of the MR conditions in case studies analyzing the effect of commonly studied exposures on coronary artery disease risk.Using 1077 single nucleotide polymorphisms (SNPs), we applied the instrumental inequalities to MR models for the effects of vitamin D concentration, alcohol consumption, C-reactive protein (CRP), triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol on coronary artery disease in the UK Biobank. For their relevant exposure, we applied the instrumental inequalities to MR models proposing each SNP as an instrument individually, and to MR models proposing unweighted allele scores as an instrument. We did not identify any violations of the MR assumptions when proposing each SNP as an instrument individually. When proposing allele scores as instruments, we detected violations of the MR assumptions for 5 of 6 exposures.Within our setting, this suggests the instrumental inequalities can be useful for identifying violations of the MR conditions when proposing multiple SNPs as instruments, but may be less useful in determining which SNPs are not instruments. This work demonstrates how incorporating the instrumental inequalities into MR analyses can help researchers to identify and mitigate potential bias.

Bounding the average causal effect in Mendelian randomisation studies with multiple proposed instruments: An application to prenatal alcohol exposure and attention deficit hyperactivity disorder.

BACKGROUND: As large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR. OBJECTIVES: We aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected. METHODS: Using data from the Norwegian Mother, Father and Child Cohort Study (n = 2056) and Avon Longitudinal Study of Parents and Children (n = 6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified. RESULTS: The MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied. CONCLUSIONS: Our results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumptions for their specific setting.

Partial Identification of the Average Causal Effect in Multiple Study Populations: The Challenge of Combining Mendelian Randomization Studies.

BACKGROUND: Researchers often use random-effects or fixed-effects meta-analysis to combine findings from multiple study populations. However, the causal interpretation of these models is not always clear, and they do not easily translate to settings where bounds, rather than point estimates, are computed. METHODS: If bounds on an average causal effect of interest in a well-defined population are computed in multiple study populations under specified identifiability assumptions, then under those assumptions the average causal effect would lie within all study-specific bounds and thus the intersection of the study-specific bounds. We demonstrate this by pooling bounds on the average causal effect of prenatal alcohol exposure on attention deficit-hyperactivity disorder symptoms, computed in two European cohorts and under multiple sets of assumptions in Mendelian randomization (MR) analyses. RESULTS: For all assumption sets considered, pooled bounds were wide and did not identify the direction of effect. The narrowest pooled bound computed implied the risk difference was between -4 and 34 percentage points. CONCLUSIONS: All pooled bounds computed in our application covered the null, illustrating how strongly point estimates from prior MR studies of this effect rely on within-study homogeneity assumptions. We discuss how the interpretation of both pooled bounds and point estimation in MR is complicated by possible heterogeneity of effects across populations.

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms.

OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Shared Genetic Factors Contributing to the Overlap between Attention-Deficit/Hyperactivity Disorder Symptoms and Overweight/Obesity in Swedish Adolescent Girls and Boys.

Attention-deficit/hyperactivity disorder (ADHD) and obesity are positively associated, with increasing evidence that they share genetic risk factors. Our aim was to examine whether these findings apply to both types of ADHD symptoms for female and male adolescents. We used data from 791 girl and 735 boy twins ages 16-17 years to examine sex-specific phenotypic correlations between the presence of ADHD symptoms and overweight/obese status. For correlations exceeding .20, we then fit bivariate twin models to estimate the genetic and environmental correlations between the presence of ADHD symptoms and overweight/obese status. ADHD symptoms and height/weight were parent- and self-reported, respectively. Phenotypic correlations were .30 (girls) and .08 (boys) for inattention and overweight/obese status and .23 (girls) and .14 (boys) for hyperactivity/impulsivity and overweight/obese status. In girls, both types of ADHD symptoms and overweight/obese status were highly heritable, with unique environmental effects comprising the remaining variance. Furthermore, shared genetic effects explained most of the phenotypic correlations in girls. Results suggest that the positive association of both types of ADHD symptoms with obesity may be stronger in girls than boys. Further, in girls, these associations may stem primarily from shared genetic factors.

Diemer and Swanson Reply to "Considerations Before Using Pandemic as Instrument".

Dimitris and Platt (Am J Epidemiol. 2021;190(11):2275-2279) take on the challenging topic of using "shocks" such as the severe acute respiratory system coronavirus 2 (SARS-CoV-2) pandemic as instrumental variables to study the effect of some exposure on some outcome. Evoking our recent lived experiences, they conclude that the assumptions necessary for an instrumental variable analysis will often be violated and therefore strongly caution against such analyses. Here, we build upon this warranted caution while acknowledging that such analyses will still be pursued and conducted. We discuss strategies for evaluating or reasoning about when such an analysis is clearly inappropriate for a given research question, as well as strategies for interpreting study findings with special attention to incorporating plausible sources of bias in any conclusions drawn from a given finding.

Mendelian randomisation approaches to the study of prenatal exposures: A systematic review.

BACKGROUND: Mendelian randomisation (MR) designs apply instrumental variable techniques using genetic variants to study causal effects. MR is increasingly used to evaluate the role of maternal exposures during pregnancy on offspring health. OBJECTIVES: We review the application of MR to prenatal exposures and describe reporting of methodologic challenges in this area. DATA SOURCES: We searched PubMed, EMBASE, Medline Ovid, Cochrane Central, Web of Science, and Google Scholar. STUDY SELECTION AND DATA EXTRACTION: Eligible studies met the following criteria: (a) a maternal pregnancy exposure; (b) an outcome assessed in offspring of the pregnancy; and (c) a genetic variant or score proposed as an instrument or proxy for an exposure. SYNTHESIS: We quantified the frequency of reporting of MR conditions stated, techniques used to examine assumption plausibility, and reported limitations. RESULTS: Forty-three eligible studies were identified. When discussing challenges or limitations, the most common issues described were known potential biases in the broader MR literature, including population stratification (n = 29), weak instrument bias (n = 18), and certain types of pleiotropy (n = 30). Of 22 studies presenting point estimates for the effect of exposure, four defined their causal estimand. Twenty-four studies discussed issues unique to prenatal MR, including selection on pregnancy (n = 1) and pleiotropy via postnatal exposure (n = 10) or offspring genotype (n = 20). CONCLUSIONS: Prenatal MR studies frequently discuss issues that affect all MR studies, but rarely discuss problems specific to the prenatal context, including selection on pregnancy and effects of postnatal exposure. Future prenatal MR studies should report and attempt to falsify their assumptions, with particular attention to issues specific to prenatal MR. Further research is needed to evaluate the impacts of biases unique to prenatal MR in practice.

Application of the Instrumental Inequalities to a Mendelian Randomization Study With Multiple Proposed Instruments.

BACKGROUND: Investigators often support the validity of Mendelian randomization (MR) studies, an instrumental variable approach proposing genetic variants as instruments, via. subject matter knowledge. However, the instrumental variable model implies certain inequalities, offering an empirical method of falsifying (but not verifying) the underlying assumptions. Although these inequalities are said to detect only extreme assumption violations in practice, to our knowledge they have not been used in settings with multiple proposed instruments. METHODS: We applied the instrumental inequalities to an MR analysis of the effect of maternal pregnancy vitamin D on offspring psychiatric outcomes, proposing four independent maternal genetic variants as instruments. We assessed whether the proposed instruments satisfied the instrumental inequalities separately and jointly and explored the instrumental inequalities' properties via simulations. RESULTS: The instrumental inequalities were satisfied (i.e., we did not falsify the MR model) when considering each variant separately. However, the inequalities were violated when considering four variants jointly and for some combinations of two or three variants (two of 36 two-variant combinations and 18 of 24 three-variant combinations). In simulations, the inequalities detected structural biases more often when assessing proposed instruments jointly, although falsification in the absence of structural bias remained rare. CONCLUSIONS: The instrumental inequalities detected violations of the MR assumptions for genetic variants jointly proposed as instruments in our study, although the instrumental inequalities were satisfied when considering each proposed instrument separately. We discuss how investigators can assess instrumental inequalities to eliminate clearly invalid analyses in settings with many proposed instruments and provide appropriate code.

Prenatal and perinatal risk factors for eating disorders in women: A population cohort study.

OBJECTIVE: The fetal programming model hypothesizes that developmental programming in utero and in early life induces adaptations that predetermine the adult phenotype. This study investigated whether prenatal/perinatal complications are associated with lifetime eating disorders in women. METHOD: Participants included 46,373 adult women enrolled in the Norwegian Mother and Child Cohort Study (den norske Mor & barn-undersøkelsen [MoBa]). MoBa mothers and their mothers (MoBa grandmothers) were the focus of the current study. MoBa mothers with lifetime eating disorders were compared to a referent group. RESULTS: MoBa mothers who weighed more at birth (birth weight, adjusted odds ratio [OR] = 1.14; 95% confidence interval [CI]: 1.10-1.19) or were born large-for-gestational-age (adjusted OR = 1.39; 95% CI: 1.27-1.52) were more likely to develop binge-eating disorder in later life. MoBa mothers who weighed less at birth were more likely to develop anorexia nervosa (birth weight, adjusted OR = 0.88; 95% CI: 0.81-0.95). Bulimia nervosa and purging disorder (PD) were not significantly predicted by the prenatal and perinatal factors examined. DISCUSSION: Results of this study, which include the first known investigation of prenatal and perinatal factors in binge-eating disorder and PD, suggest that fetal programming may be relevant to the development of anorexia nervosa and binge-eating disorder. Future genetically informative research is needed to help disentangle whether these associations are a function of genetic influences or a true environmental fetal programming effect.

Beyond the Binary: Differences in Eating Disorder Prevalence by Gender Identity in a Transgender Sample.

Purpose: To investigate whether the prevalence of eating disorders (EDs) differs across diverse gender identity groups in a transgender sample. Methods: Secondary analysis of data from Project VOICE, a cross-sectional study of stress and health among 452 transgender adults (ages 18-75 years) residing in Massachusetts. Age-adjusted logistic regression models were fit to compare the prevalence of self-reported lifetime EDs in female-to-male (FTM), male-to-female (MTF), and gender-nonconforming participants assigned male at birth (MBGNC) to gender-nonconforming participants assigned female at birth (FBGNC; referent). Results: The age-adjusted odds of self-reported ED in MTF participants were 0.14 times the odds of self-reported ED in FBGNC participants (p=0.022). In FTM participants, the age-adjusted odds of self-reported ED were 0.46 times the odds of self-reported ED in FBGNC participants, a marginally significant finding (p=0.068). No statistically significant differences in ED prevalence were found for MBGNC individuals. Conclusions: Gender nonconforming individuals assigned a female sex at birth appear to have heightened lifetime risk of EDs relative to MTF participants. Further research into specific biologic and psychosocial ED risk factors and gender-responsive intervention strategies are urgently needed. Training clinical providers and ensuring competency of treatment services beyond the gender binary will be vital to addressing this disparity.

Maternal eating disorders and perinatal outcomes: A three-generation study in the Norwegian Mother and Child Cohort Study.

Previous studies of the relationship between maternal eating disorders and adverse perinatal outcomes have failed to control for familial transmission of perinatal phenotypes, which may confound the reported association. In a unique design afforded by the Norwegian Mother and Child Cohort Study and Medical Birth Registry of Norway, we linked three generations through birth register records and maternal-reported survey data to investigate whether maternal eating disorders increase risk after parsing out the contribution of familial transmission of perinatal phenotypes. The samples were 70,881 pregnancies in grandmother-mother-child triads for analyses concerning eating disorder exposure during pregnancy and 52,348 for analyses concerning lifetime maternal eating disorder exposure. As hypothesized, eating disorders predicted a higher incidence of perinatal complications even after adjusting for grandmaternal perinatal phenotypes. For example, anorexia nervosa immediately prior to pregnancy was associated with smaller birth length (relative risk = 1.62; 95% CI [1.20, 2.14]), bulimia nervosa with induced labor (relative risk = 1.21; 95% CI [1.07, 1.36]), and binge-eating disorder with several delivery complications, larger birth length (relative risk = 1.25; 95% CI [1.17, 1.34]), and large-for-gestational-age (relative risk = 1.04; 95% CI [1.01, 1.06]). Maternal pregravid body mass index and gestational weight mediated most associations. Our results support that exposure to eating disorders increases the risk for negative health outcomes in pregnant women and their babies. (PsycINFO Database Record

Gender Identity, Sexual Orientation, and Eating-Related Pathology in a National Sample of College Students.

PURPOSE: This study examined associations of gender identity and sexual orientation with self-reported eating disorder (SR-ED) diagnosis and compensatory behaviors in transgender and cisgender college students. METHODS: Data came from 289,024 students from 223 U.S. universities participating in the American College Health Association-National College Health Assessment II (median age, 20 years). Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were compared among transgender students (n = 479) and cisgender sexual minority (SM) male (n = 5,977) and female (n = 9,445), unsure male (n = 1,662) and female (n = 3,395), and heterosexual male (n = 91,599) and female (n = 176,467) students using chi-square tests. Logistic regression models were used to estimate the odds of eating-related pathology outcomes after adjusting for covariates. RESULTS: Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were highest among transgender students and lowest among cisgender heterosexual men. Compared to cisgender heterosexual women, transgender students had greater odds of past-year SR-ED diagnosis (odds ratio [OR], 4.62; 95% confidence interval [CI], 3.41-6.26) and past-month use of diet pills (OR, 2.05; 95% CI, 1.48-2.83) and vomiting or laxatives (OR, 2.46; 95% CI, 1.83-3.30). Although cisgender SM men and unsure men and women also had elevated rates of SR-ED diagnosis than heterosexual women, the magnitudes of these associations were lower than those for transgender individuals (ORs; 1.40-1.54). CONCLUSIONS: Transgender and cisgender SM young adults have elevated rates of compensatory behavior and SR-ED diagnosis. Appropriate interventions for these populations are urgently needed.

Associations between body mass index, post-traumatic stress disorder, and child maltreatment in young women.

The objective of this study was to examine interrelationships between child maltreatment, post-traumatic stress disorder (PTSD) and body mass index (BMI) in young women. We used multinomial logistic regression models to explore the possibility that PTSD statistically mediates or moderates the association between BMI category and self-reported childhood sexual abuse (CSA), physical abuse (CPA), or neglect among 3,699 young women participating in a population-based twin study. Obese women had the highest prevalence of CSA, CPA, neglect, and PTSD (p<.001 for all). Although all three forms of child maltreatment were significantly, positively associated with overweight and obesity in unadjusted models, only CSA was significantly associated with obesity after adjusting for other forms of maltreatment and covariates (OR=2.21, 95% CI: 1.63, 3.00). CSA and neglect, but not CPA, were associated with underweight in unadjusted models; however, after adjusting for other forms of maltreatment and covariates, the associations were no longer statistically significant (OR=1.43, 95% CI: 0.90-2.28 and OR=2.16, 95% CI: 0.90-5.16 for CSA and neglect, respectively). Further adjustment for PTSD generally resulted in modest attenuation of effects across associations of child maltreatment forms with BMI categories, suggesting that PTSD may, at most, be only a weak partial mediator of these associations. Future longitudinal studies are needed to elucidate the mechanisms linking CSA and obesity and to further evaluate the role of PTSD in associations between child maltreatment and obesity.