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BACKGROUND: Tribal Nations experience substance misuse at high rates often attributed to historical and contemporary traumas. In response, several Tribal Nations are addressing these issues through efforts to promote recovery and prevention to substance misuse. OBJECTIVES: Partner with a Tribal Nation to develop a study to explore factors that contribute to the wellbeing of families to children with prenatal substance exposure and disseminate findings that can be translated back into the community. METHODS: We applied Community-based participatory research (CBPR), strengths-based, and community-driven approaches during this two-year study development phase. We experienced challenges and identified solutions to partnering with one Tribal Nation on an epidemiological mixed-methods study centered on families with children that have prenatal substance exposure. Key inputs were becoming familiarizing with the community setting, structural supports for CBPR research, incorporating Indigenous CBPR principles, and developing a Community Advisory Team. RESULTS: We successfully collaborated with the Confederated Salish Kootenai Tribes Early Childhood Services program to develop a robust study design and a dissemination plan to ensure translation of study findings to the community. The robust study design consisted of common themes specific to a highly stigmatized study population, substance-abusing pregnant women, to protect participant confidentiality. CONCLUSION: Research alignment with community goals, allotting meaningful time to develop a research partnership, and incorporating culturally sensitive and community-relevant measures contributed to the successful development of an effective and rigorous study to better serve the Tribal Nation on addressing substance misuse.

Mendelian randomization (MR) is often used to estimate effects of time-varying exposures on health outcomes using observational data. However, MR studies typically use a single measurement of exposure and apply conventional instrumental variable (IV) methods designed to handle time-fixed exposures. As such, MR effect estimates for time-varying exposures are often biased, and interpretations are unclear. We describe the instrumental conditions required for IV estimation with a time-varying exposure, and the additional conditions required to causally interpret MR estimates as a point effect, a period effect or a lifetime effect depending on whether researchers have measurements at a single or multiple time points. We propose methods to incorporate time-varying exposures in MR analyses based on g-estimation of structural mean models, and demonstrate its application by estimating the period effect of alcohol intake, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol on intermediate coronary heart disease (CHD) outcomes using data from the Framingham Heart Study. We use this data example to highlight the challenges of interpreting MR estimates as causal effects, and describe other extensions of structural mean models for more complex data scenarios.

Reverse causation occurs when the outcome variable at an earlier timepoint, or a proximal precursor of the outcome (such as pre-clinical disease), has a causal effect on the risk factor. This confounding by pre-clinical or prior outcome can lead to bias when trying to estimate an average causal effect of the risk factor on the outcome. By proposing genetic variants as instrumental variables, Mendelian randomization can make inferences about the effect of shifting the trajectory of a risk factor on a later-measured outcome. As genetic variants are fixed at conception, it has been stated that Mendelian randomization investigations are not affected by reverse causation. While Mendelian randomization analyses have some protection against bias due to reverse causation, the claim of complete immunity is a misconception. We provide three plausible scenarios and accompanying examples of how reverse causation can influence Mendelian randomization estimates: 1) the effect of the genetic variant on the risk factor is mediated (at least in part) by the outcome, 2) the genetic association with the outcome is distorted by a feedback mechanism whereby the risk factor and outcome variable both influence each other over time, and 3) the genetic association with the outcome is distorted by an effect of the outcome in the parental generation on the outcome in the offspring generation. In these scenarios, we show that all causal effects typically estimated in Mendelian randomization analyses will be biased, though hypothesis testing can still be valid in Scenario 2 and 3 for a sharp causal null hypothesis. This underscores the general recommendation to view Mendelian randomization as primarily testing a causal null hypothesis rather than estimating a causal effect.

We aimed to study the effects of hypothetical interventions on systolic blood pressure (SBP) and smoking on risk of stroke and dementia using data from 15 years of follow-up in the Rotterdam Study. We used data from 4930 individuals, aged 55–80 years, with no prior history of stroke, dementia or cognitive impairment, followed for 15 years within the Rotterdam Study, a population-based cohort. We defined the following sustained interventions on SBP: (1) maintaining SBP below 120 mmHg, (2) maintaining SBP below 140 mmHg, (3) reducing SBP by 10% if above 140 mmHg, (4) reducing SBP by 20% if above 140 mmHg, and a combined intervention of quitting smoking with each of these SBP-lowering strategies. We considered incident stroke and incident dementia diagnoses as outcomes. We applied the parametric g-formula to adjust for baseline and time-varying confounding. The observed 15-year risk for stroke was 10.7%. Compared to no specified intervention (i.e., the “natural course”), all interventions that involved reducing SBP were associated with a stroke risk reduction of about 10% (e.g., reducing SBP by 20% if above 140 mmHg risk ratio: 0.89; 95% CI 0.76, 1). Jointly intervening on SBP and smoking status further decreased the risk of stroke (e.g., risk ratio: 0.83; 95% CI 0.71, 0.94). None of the specified interventions were associated with a substantive change in dementia risk. Our study suggests that a joint intervention on SBP and smoking cessation during later life may reduce stroke risk, while the potential for reducing dementia risk were not observed. Electronic supplementary material The online version of this article (10.1007/s10654-020-00694-5) contains supplementary material, which is available to authorized users. A Spanish version of the manuscript is provided as supplementary material.

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.

Background Strong and consistent associations between access to firearms and suicide have been found in ecologic and individual-level observational studies. For adolescents, a seminal case–control study estimated that living in a home with (vs without) a firearm was associated with a fourfold increase in the risk of death by suicide. Methods We use data from a nationally representative study of 10 123 US adolescents aged 13–18 years to (1) measure how much adolescents who live in a home with a firearm differ from those who do not in ways related to their risk of suicide, and (2) incorporate these differences into an updated effect estimate of the risk of adolescent suicide attributable to living in a home with firearms. Results Almost one-third (30.7%) of adolescents reported living in a home with firearms. Relative to those who did not, adolescents reporting living in a home with a firearm were slightly more likely to be male, older and reside in the South and rural areas, but few differences were identified for mental health characteristics. The effect size found by Brent and colleagues appeared robust to sources of possible residual confounding: updated relative risks remained above 4.0 across most sensitivity analyses and at least 3.1 in even the most conservative estimates. Conclusions Although unmeasured confounding and other biases may nonetheless remain, our updated estimates reinforce the suggestion that adolescents’ risk of suicide was increased threefold to fourfold if they had lived in homes with a firearm compared with if they had not.

In this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for clinical trials, we propose a `predictimand' framework of different questions that may be of interest when predicting risk in relation to treatment started after baseline. We provide a formal definition of the estimands matching these questions, give examples of settings in which each is useful and discuss appropriate estimators including their assumptions. We illustrate the impact of the predictimand choice in a dataset of patients with end-stage kidney disease. We argue that clearly defining the estimand is equally important in prediction research as in causal inference., Comment: under review

BackgroundPrevious studies using Mendelian randomization have found that fetal alcohol exposure may be associated with lower IQ and test scores in childhood.ObjectivesWe aim to replicate and extend these findings in Generation R Study, a birth cohort based in Rotterdam, the Netherlands.MethodsWe used data from Generation R which recruited pregnant women between 2002 and 2006. Alcohol use was assessed via questionnaire during each trimester. IQ was measured in the children between ages 5 and 8 using the Snijders-Oomen Non-Verbal Intelligence Test. Scores from a national standardized test administered around age 12 were used as a measure of cognition. We estimated the associations between ten genetic variants in the mothers previously found to be related to alcohol consumption and metabolism and each of the outcomes. In the children, we also estimated the association between the same genetic variants as well as two polygenic scores for alcohol consumption and the outcomes.ResultsMaternal genetic variants were not found to be related to either outcome but wide confidence intervals did not preclude important effects. A few genetic variants in the children were suggestive of a decrease in IQ. Likewise, one genetic variant and the genetic score had estimates and confidence intervals consistent with increases in standardized test scores.ConclusionsOur results provide slight support for associations between genetic variants in children related to maternal prenatal alcohol consumption and IQ and cognition outcomes. These findings are in line with two previous studies on this topic.

The participants in randomized trials and other studies used for causal inference are often not representative of the populations seen by clinical decision-makers. To account for differences between populations, researchers may consider standardizing results to a target population. We discuss several different types of homogeneity conditions that are relevant for standardization: Homogeneity of effect measures, homogeneity of counterfactual outcome state transition parameters, and homogeneity of counterfactual distributions. Each of these conditions can be used to show that a particular standardization procedure will result in unbiased estimates of the effect in the target population, given assumptions about the relevant scientific context. We compare and contrast the homogeneity conditions, in particular their implications for selection of covariates for standardization and their implications for how to compute the standardized causal effect in the target population. While some of the recently developed counterfactual approaches to generalizability rely upon homogeneity conditions that avoid many of the problems associated with traditional approaches, they often require adjustment for a large (and possibly unfeasible) set of covariates., Final author manuscript. To appear in European Journal of Epidemiology

Several of the hypothesized or studied exposures that may affect dementia risk are known to increase the risk of death. This may explain counterintuitive results, where exposures that are known to be harmful for mortality risk sometimes seem protective for the risk of dementia. Authors have attempted to explain these counterintuitive results as biased, but the bias associated with a particular analytic method cannot be defined or assessed if the causal question is not explicitly specified. Indeed, we can consider several causal questions when competing events like death, which cannot be prevented by design, are present. Current dementia research guidelines have not explicitly considered what constitutes a meaningful causal question in this setting or, more generally, how this choice justifies and should drive particular analytic decisions. To contextualize current practices, we first perform a systematic review of the conduct and interpretation of longitudinal studies focused on dementia outcomes where death is a competing event. We then describe and demonstrate how to address different causal questions (referred here as “the total effect” and “the controlled direct effect”) with traditional analytic approaches under explicit assumptions. Our application focuses on smoking cessation in late-midlife. To illustrate core concepts, we discuss this example both in terms of a hypothetical randomized trial and with an emulation of such a trial using observational data from the Rotterdam Study.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2: P=1.6×10−6, IFNAR2: P=9.8×10−11, and IL-10RB: P=1.9×10−14) using cis-eQTL genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared eQTL signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Purpose To quantify eating disorder (ED) stability and diagnostic transition among a community-based sample of adolescents and young adult females in the United States. Methods Using 11 prospective assessments from 9,031 U.S. females ages 9–15 years at baseline of the Growing Up Today Study, we classified cases of the following EDs involving bingeing and purging: bulimia nervosa (BN), binge ED, purging disorder (PD), and subthreshold variants defined by less frequent (monthly vs. weekly) bingeing and purging behaviors. We measured number of years symptomatic and probability of maintaining symptoms, crossing to another diagnosis, or resolving symptoms across consecutive surveys. Results Study lifetime disorder prevalence was 2.1% for BN and roughly 6% each for binge ED and PD. Most cases reported symptoms during only one survey year. Twenty-six percent of cases crossed between diagnoses during follow-up. Among participants meeting full threshold diagnostic criteria, transition from BN was most prevalent, crossing most frequently from BN to PD (12.9% of BN cases). Within each disorder phenotype, 20%–40% of cases moved between subthreshold and full threshold criteria across consecutive surveys. Conclusions Diagnostic crossover is not rare among adolescent and young adult females with an ED. Transition patterns from BN to PD add support for considering these classifications in the same diagnostic category of disorders that involve purging. The prevalence of crossover between monthly and weekly symptom frequency suggests that a continuum or staging approach may increase utility of ED classification for prognostic and therapeutic intervention.

Sometimes instrumental variable methods are used to test whether a causal effect is null rather than to estimate the magnitude of a causal effect. However, when instrumental variable methods are applied to time-varying exposures, as in many Mendelian randomization studies, it is unclear what causal null hypothesis is tested. Here, we consider different versions of causal null hypotheses for time-varying exposures, show that the instrumental variable conditions alone are insufficient to test some of them, and describe additional assumptions that can be made to test a wider range of causal null hypotheses, including both sharp and average causal null hypotheses. Implications for interpretation and reporting of instrumental variable results are discussed. Electronic supplementary material The online version of this article (10.1007/s10654-018-0396-6) contains supplementary material, which is available to authorized users.

Contains fulltext : 200463.pdf (Publisher’s version ) (Open Access) A potential mechanism by which smoking affects ischemic stroke is through wider venules, but this mediating role of wider venules has never been quantified. Here, we aimed to estimate to what extent the effect of smoking on ischemic stroke is possibly mediated by the venules via the recently developed four-way effect decomposition. This study was part of a population-based study including 9109 stroke-free persons participated in the study in 1990, 2004, or 2006 (mean age: 63.7 years; 58% women). Smoking behavior (smoking versus non-smoking) was identified by interview. Retinal venular calibers were measured semi-automatically on retinal photographs. Incident strokes were assessed until January 2016. A regression-based approach was used with venular calibers as mediator to decompose the total effect of smoking compared to non-smoking into four components: controlled direct effect (neither mediation nor interaction), pure indirect effect (mediation only), reference interaction effect (interaction only) and mediated interaction effect (both mediation and interaction). During a mean follow-up of 12.5 years, 665 persons suffered an ischemic stroke. Smoking increased the risk of developing ischemic stroke compared to non-smoking with an excess risk of 0.41 (95% confidence interval 0.10; 0.67). With retinal venules as a potential mediator, the excess relative risk could be decomposed into 77% controlled direct effect, 4% mediation only, 4% interaction only, and 15% mediated interaction. To conclude, in the pathophysiology of ischemic stroke, the effect of smoking on ischemic stroke may partly explained by changes in the venules, where there is both pure mediation and mediated interaction.

Purpose of review When leveraging observational data to estimate treatment effects, it is useful to explicitly specify the “target trial” the investigators aspire to emulate. One concern is whether a proposed analysis plan can address the realities of the differences between the available non-randomized observational study and the target trial. When large or unknown sources of unmeasured confounding are suspected, investigators might consider turning to instrumental variable (IV) methods. Of course, the interpretation and appropriateness of IV analyses need to be considered carefully. The purpose of this review is to summarize recent methodologic advancements in how epidemiologists weigh the validity of an IV analysis and to place these methodologic advancements in the context of the feasible target trial’s protocol components. Recent findings There have been increased development and application of tools for sensitivity analyses, falsification strategies, and the identification of previously overlooked problems with IV analyses as applied in pharmacoepidemiology. Many of these recent insights can be seen as articulating restrictions on or tradeoffs between the types of target trials that can be validly emulated when using a classical IV analysis. Summary Putting classical IV methods in the context of target trials underscores the importance of recent methodologic developments and, more generally, when and how an IV analysis would be appropriate. We see that some tradeoffs in defining the target trials are unavoidable, that some tradeoffs may be offset or explored via sensitivity analyses, and that this serves as a framework for scientific discourse regarding IV and non-IV results emulating potentially different trials with different tradeoffs.

Objective Extensive evidence suggests that children and adolescents often inaccurately perceive their body size. However, the extent of this misperception is unclear. This paper describes the agreement between children's actual weight and the perception of body size (self-reported and maternally reported) and the association of actual weight with self-reported body satisfaction. Methods In a population-based cohort study of 3,408 children aged 9 to 10 years, we assessed the children's self-perception and ideal perception of their body size with the Children's Body Image Scale. Maternal perception of offspring body size was assessed with the question “How would you describe your child at the moment?” Children's height and weight were measured. Results Children tended to rate themselves toward average proportions; e.g., 83.0% of 499 children with overweight/obesity perceived themselves as less heavy then they were. Of those who underestimated their body size, most (79.2%) had a desire to be thinner; all of the children who correctly recognized their overweight/obesity had such a desire. Conclusions Despite the misperception of body size, the majority of children with overweight/obesity indicated dissatisfaction with their body size, suggesting more self-awareness than would be assumed based on the self-perception assessment of body size alone.

Objective The majority of persons with eating disorders (EDs) do not seek ED treatment, yet little is known about treatment-seeking barriers or facilitators. The aim of the study is to describe the characteristics associated with seeking ED treatment among U.S. adolescents with EDs. Method Data from a nationally representative cross-sectional study of U.S. adolescents ages 13–18 years were used for these analyses. Specifically, adolescents who met criteria for lifetime EDs (N = 281) were included. Sociodemographic information, characteristics of EDs, psychiatric comorbidities, and other mental health service use were assessed via interview. Results Only 20% of adolescents sought ED treatment. Females were 2.2 (95% CI 0.8, 6.4) times more likely to seek treatment than males (19.9% vs. 8.9%). Adolescents who met criteria for anorexia nervosa or bulimia nervosa were 2.4 (95% CI 0.9, 6.3) and 1.9 (95% CI 1.0, 3.8) times more likely to seek treatment than adolescents who met criteria for binge-eating disorder (27.5% and 22.3% vs. 11.6%). Specific ED behaviors (restriction and purging), ED-related impairment, and any mental health service use were also associated with adolescent treatment seeking. Discussion Adolescent treatment seeking was infrequent overall, with individuals with counter-stereotypic ED presentations least likely to have sought treatment. Adolescent treatment seeking could be promoted through increasing awareness among the public and healthcare professionals that EDs affect a heterogeneous group of people. More generally, research involving both treatment-seeking and non-treatment-seeking individuals holds great potential to refine the field's knowledge of ED etiology, prevalence, treatment, and prevention.

ObjectiveObservational data can be used to attempt to emulate a target trial of statin use and estimate analogues of intention-to-treat and per protocol effects on dementia risk.MethodsUsing data from a prospective cohort study in the Netherlands, we conceptualized a sequence of “trials” in which eligible individuals ages 55–80 years were classified as statin initiators or noninitiators for every consecutive month between 1993 and 2007 and were followed until diagnosis of dementia, death, loss to follow-up, or the end of follow-up. We estimated 2 types of effects of statin use on dementia and a combined endpoint of dementia or death: the effect of initiation vs no initiation and the effect of sustained use vs no use. We estimated risk by statin treatment strategy over time via pooled logistic regression. We used inverse-probability weighting to account for treatment-confounder feedback in estimation of per-protocol effects.ResultsOf 233,526 eligible person-trials (6,373 individuals), there were 622 initiators and 232,904 noninitiators. Comparing statin initiation with no initiation, the 10-year risk differences (95% confidence interval) were −0.1% (−2.3% to 1.8%) for dementia and 0.3% (−2.7% to 3.3%) for dementia or death. Comparing sustained statin use vs no use, the 10-year risk differences were −2.2% (−5.2% to 1.6%) for dementia and −5.1% (−10.5% to −1.1%) for dementia or death.ConclusionsIndividuals with sustained statin use, but not statin initiation alone, had reduced 10-year risks of dementia and dementia or death. Our results should be interpreted with caution due to the small number of initiators and events and potential for residual confounding.

While the number of studies using Mendelian randomization (MR) methods has grown exponentially in the last decade, the quality of reporting of these studies often has been poor. Similar to other reporting guidelines such as CONSORT (Consolidated Standards of Reporting Trials) for randomised trials and STROBE (STrenghtening the Reporting of Observational studies in Epidemiology) for observational studies in epidemiology, the STROBE-MR working group aims to provide guidance to authors on how to improve reporting of MR studies and help readers, reviewers, and journal editors to evaluate the quality of the presented evidence. Empirical evidence indicates that many reports of MR studies do not clearly state or examine the various assumptions of MR methods and report insufficient details on the data sources, which makes it hard to evaluate the quality and reliability of the results. The STROBE-MR guidance covers both one sample and two sample MR studies. At present, the draft checklist consists of 20 items, organized into the title and abstract, introduction, methods, results and discussion sections of articles. As these guidelines aim to reach the entire MR community, we would like to give everyone the opportunity to contribute their comments. The following draft of the STROBE-MR checklist is open for public discussion and all feedback will be taken into account during its next revision. For feedback, please use the comment section below this post on PeerJ Preprints. We hope the final guidelines will serve the entire community and contribute to improving the reporting of MR studies in the future.

Hypertension is a major modifiable risk factor for stroke. Associations of blood pressure with incident stroke are mostly based on single or average blood pressure levels. However, this approach does not take into account long-term trajectories of blood pressure, which can vary considerably in the elderly. Within the population-based Rotterdam Study, we examined trajectories of systolic blood pressure in 6745 participants (60.0% women) over an age-range from 55 to 106 years and jointly modeled their risk of stroke and competing causes of death using joint latent class mixed modeling. Four trajectories were identified. Class 1 was characterized by blood pressure increasing gradually from on average 120 to 160 mm Hg over 5 decades (n=4938). Compared with this class, class 2, characterized by a similar midlife blood pressure, but a steep increase (n=822, increasing from 120 to 200 mm Hg), and class 4, characterized by a high midlife blood pressure (n=115; average 160 mm Hg) and had a higher risk of stroke and death. Class 3, characterized by a moderate midlife blood pressure (n=870; average 140 mm Hg), had a similar risk of death as class 1, but the highest risk of stroke. Assessing trajectories of blood pressure provides a more nuanced understanding of the associations between blood pressure, stroke, and mortality. In particular, high blood pressure and rapidly increasing blood pressure patterns are associated with a high risk of stroke and death, whereas moderately high blood pressure is only related to an increased risk of stroke. Future studies should explore the potential pathogenic significance of these patterns.

Background Many patients with major depressive disorder (MDD) who begin antidepressant treatment discontinue use before for six months, the recommended minimum treatment length. This study sought to identify predictors of six-month antidepressant persistence including predictors utilizing patients' electronic prescription records. Methods Commercially insured children (3–17 years) and adults (18–64 years) with MDD who initiated antidepressant treatment, 1/1/2003–2/28/2010, were assessed for six-month persistence (based on prescriptions' days supply, allowing a 30-day grace period). Antidepressant persistence prediction models were developed separately for children and adults. Two additional measures, days without medication between the first and second antidepressant fill (children and adults) and prior persistence on other medications (adults only), were added to the models, concordance (c) statistics were compared and risk reclassification evaluated. Results Among children (n=8837 children) and adults (n=47,495) with MDD, six-month antidepressant persistence was low and varied by age (37%, 18–24 years to 52%, 3–12 and 50–64 years). Independent baseline predictors of persistence were identified, with model c-statistics: children=0.582, adults=0.584. Patients with more days without medication between fills were less likely to be persistent (10–30 vs. 0 days, children: RR=0.72, adults: RR=0.74), as were adults not previously persistent to other medications (RR=0.73). Limitations The definition of six-month persistence is dependent on correct days supply values and the grace period utilized; potential predictors were limited to measures available in claims data. Conclusions Six-month antidepressant persistence was low and overall prediction of persistence was poor; however, days without medication between fills and prior persistence on other medications marginally improved the ability to predict antidepressant persistence.

Observational analyses for causal inference often rely on real world data collected for purposes other than research. A frequent goal of these observational analyses is to use the data to emulate a hypothetical randomized experiment, i.e., the target trial, that mimics the design features of a true experiment, including a clear definition of time zero with synchronization of treatment assignment and determination of eligibility. We review a recent observational analysis that explicitly emulated a target trial of screening colonoscopy using insurance claims from U.S. Medicare. We then compare this explicit emulation with alternative, simpler observational analyses that do not synchronize treatment assignment and eligibility determination at time zero and/or do not allow for repeated eligibility. This empirical comparison suggests that lack of an explicit emulation of the target trial leads to biased estimates, and shows that allowing for repeated eligibility increases the statistical efficiency of the estimates.

___Purpose:___ Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used during pregnancy. Findings that prenatal NSAID exposure may affect offspring neurodevelopment have been inconsistent. We investigated the effect of prenatal NSAID exposure on childhood neurodevelopment and explored the susceptibility of our effect estimates to forms of bias via negative exposure, negative outcome, and multi-informant analyses. ___Methods:___ In a cohort of pregnant women (n = 6876), perinatal NSAID use was assessed by prescriptions and self-report. Primary neurodevelopmental outcomes included attention problems using maternal reports at 1½, 3, and 5 years. To explore potential systematic biases, we compared estimates from maternally reported attention problems to a teacher's report and a measure of nonverbal intelligence assessed at a clinic visit at age 6 years; we also used NSAID use before pregnancy and somatic problems as a “negative” exposure and outcome, respectively. ___Results:___ Maternal reports suggested that prenatal exposure to NSAIDs was associated with more attention problems at younger ages (eg, at age 3: mean difference in attention problems score: 0.30; 95% CI 0.12, 0.48). However, no strong association with attention problems was found in the teacher report, and a similarly strong association between prenatal NSAID exposure and somatic complaints suggests residual confounding by indication likely remains. Moreover, prenatal exposure to NSAIDs was not associated with an observed measure of IQ (mean difference in IQ score: −0.32; 95% CI: −1.82, 1.19). ___Conclusions:___ Jointly, our results suggest that the observed associations between prenatal exposure to NSAIDs and child attention problems reflect systematic biases of a null or small effect.

Summary Background Late-life depressive symptoms have been extensively studied for their relationship with incident dementia, but have been typically assessed at a single timepoint. Such an approach neglects the course of depression, which, given its remitting and relapsing nature, might provide further insights into the complex association of depression with dementia. We therefore repeatedly measured depressive symptoms in a population of adults over a decade to study the subsequent risk of dementia. Methods Our study was embedded in the Rotterdam Study, a population-based study of adults aged 55 years or older in Rotterdam (Netherlands), ongoing since 1990. The cohort is monitored continuously for major events by data linkage between the study database and general practitioners. We examined a cohort of participants who were free from dementia, but had data for depressive symptoms from at least one examination round in 1993–95, 1997–99, or 2002–04. We assessed depressive symptoms with the validated Dutch version of the Center for Epidemiology Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale-Depression. We used these data to identify 11-year trajectories of depressive symptoms by latent class trajectory modelling. We screened participants for dementia at each examination round and followed up participants for 10 years for incident dementia by latent trajectory from the third examination round to 2014. We calculated hazard ratios (HR) for dementia by assigned trajectory using two Cox proportional hazards models (model 1 adjusted for age and sex only, and model 2 adjusted additionally for APOE ɛ4 carrier status, educational level, body-mass index, smoking, alcohol consumption, cognitive score, use of antidepressants, and prevalent disease status at baseline). We repeated the analyses censoring for incident stroke, restricting to Alzheimer's disease as an outcome, and accounting for mortality as a competing risk for dementia. Findings From 1993–2004, we obtained data for depressive symptoms from at least one examination round for 3325 participants (median age: 74·88 years [IQR 70·62–80·06], 1995 [60%] women). We identified five trajectories of depressive symptoms in these 3325 individuals, characterised by maintained low CES-D scores (low; 2441 [73%]); moderately high starting scores but then remitting (decreasing; 369 [11%]); low starting scores, increasing, then remitting (remitting; 170 [5%]); low starting scores that steadily increased (increasing; 255 [8%]); and maintained high scores (high; 90 [3%]). During 26 330 person-years, 434 participants developed incident dementia. Only the trajectory with increasing depressive symptoms was associated with a higher risk of dementia compared with the low depressive symptom trajectory, using model 2 (HR 1·42, 95% CI 1·05–1·94; p=0·024). Additionally, only the increasing trajectory was associated with a higher risk of dementia compared with the low trajectory after censoring for incident stroke (1·58, 1·15–2·16; p=0·0041), restricting to Alzheimer's disease as an outcome (1·44, 1·03–2·02; p=0·034), and accounting for mortality as a competing risk (1·45, 1·06–1·97; p=0·019). Interpretation Risk of dementia differed with different courses of depression, which could not be captured by a single assessment of depressive symptoms. The higher risk of dementia only in the increasing trajectory suggests depression might be a prodrome of dementia. Funding Erasmus Medical Center; ZonMw; the Netherlands Ministry of Education Culture and Science; and the Netherlands Ministry for Health, Welfare and Sports.

Prior research evaluated various effects of the 2004 black-box warning by the U.S. Food and Drug Administration (FDA) on the risk of suicidality among children associated with use of antidepressants, but the warning's effect on dosing of antidepressants has not been evaluated. This study estimated whether the initial antidepressant dose prescribed decreased and the proportion of patients who augmented the dose on the second fill increased following the 2004 warning and its 2007 expansion to young adults.The study utilized the LifeLink Health Plan Claims Database. The study cohort consisted of commercially insured children (ages 5-17), young adults (18-24), and adults (25-64) who initiated a selective serotonin reuptake inhibitor (SSRI) (citalopram, fluoxetine, paroxetine, or sertraline) from January 1, 2000, to December 31, 2009. Dose per day was determined by days' supply, strength, and quantity dispensed. Initiation with a low dose and augmentation of1 mg/day on the second prescription before and after the 2004 warning were considered.Of 51,948 children who initiated an SSRI, 15% initiated with a low dose before the 2004 warning compared with 31% after the warning; there was a smaller change among young adults (6 percentage points) and adults (3 percentage points). The overall increase in dose augmentations among children and young adults was driven by the increase in patients initiating with a low dose.The proportion of commercially insured children initiating an SSRI with a low dose was higher after the 2004 FDA warning on the risk of suicidality among children, suggesting improved prescribing practices surrounding SSRI dosing among children.

Purpose The decision whether to continue antidepressant use for depression during pregnancy requires weighing maternal and child risks and benefits. Little is known about the effectiveness of antidepressant therapy during pregnancy. The goal of this study is to evaluate whether standard administrative claims data can be used to evaluate the effectiveness of antidepressants. Methods Using prescription and healthcare visit Medicaid claims (2000–2007), we identified 28 493 women with a depression diagnosis and antidepressant fill in the 90 days before their last menstrual period. Antidepressant continuation was defined based on prescription fills during the first trimester. Depression hospitalizations and deliberate self-harm served as measures of the effectiveness of treatment continuation during pregnancy. Propensity score and instrumental variable analyses were used to attempt to account for confounding. Results Relative to women who discontinued antidepressant therapy, women who continued were more likely to have a depression inpatient stay (odds ratio [OR] = 2.2, 95% confidence interval [95%CI]: 2.0–2.4) and deliberate self-harm code (OR = 1.4, 95%CI: 0.7–2.7). Accounting for measured covariates in the propensity score analysis, including age, race, comorbidities, comedications, features of the depression diagnosis, and antidepressant class, led to slightly attenuated estimates (OR = 2.0, 95%CI: 1.8–2.2; OR = 1.1, 95%CI: 0.5–2.4). Similar associations were estimated in subgroups with different levels of baseline depression severity. Proposed preference-time, calendar-time-based, and geography-based instruments were unlikely to meet the required conditions for a valid analysis. Conclusions Our findings suggest that either antidepressant medications do not reduce the risk of depression relapse in pregnant women, or that administrative data alone could not be used to validly estimate the effectiveness of psychotropic medications during pregnancy. Copyright © 2015 John Wiley & Sons, Ltd.

Comparative effectiveness research frequently uses instrumental variable methods to estimate causal effects.1–3 Such methods require investigators to propose a variable (the “instrument”) that meets the three instrumental conditions: it is associated with treatment, it causes the outcome only through treatment, and its effect on the outcome is not confounded. Commonly proposed instruments are based on facility or physician prescribing preferences,1,2 e.g., a physician’s preference for Treatment A over Treatment B. Even if preference met the instrumental conditions, an additional condition is necessary to identify a causal effect. Most instrumental variable applications assume the additional condition of monotonicity.3,4 The monotonicity assumption implies there are no “defiers”, i.e., no patients who would be prescribed Treatment A when seen by a physician who usually prefers B and would be prescribed Treatment B when seen by a physician who usually prefers A (a rigorous and more general definition is provided below). Under this assumption, instrumental variable methods can be used to identify the average causal effect in the subset of patients who would be prescribed the treatment preferred by any treating physician, i.e., the “compliers”. Monotonicity generally cannot be verified because we cannot observe what would have happened had the same patient been treated by another physician. Monotonicity might be reasonably assumed if patient characteristics naturally collapsed into a single dimension related to treatment decisions (e.g., a propensity score), and clinicians had different cut points along this continuum for deciding when to prescribe which treatment. However, given the complexity of information physicians integrate into their prescribing decisions, preferences are unlikely to be so cleanly ordered. As a simplified example, consider a physician who generally prefers Treatment A, but prescribes Treatment B for more physically active patients (e.g., because Treatment A is associated with risk of motor-skill impairment), and another physician who generally prefers Treatment B, but makes exceptions for patients with a family history of diabetes (e.g., because a new study suggests such patients might respond better to Treatment A). Any physically active patient with a family history of diabetes who could potentially have seen either of these providers would “defy” both preferences and thus violate the monotonicity assumption, even conditional on covariates other than physical activity and family history. Despite many opportunities for monotonicity violations, the possible bias introduced from such violations in instrumental variable analyses has not been previously explored. Moreover, the meaning of monotonicity itself is unclear in realistic applications of instrumental variable analyses with preference-based instruments, something rarely discussed in the literature. Here we (1) define monotonicity and the interpretation of instrumental variable estimates in the context of preference-based instruments and a dichotomous prescribing decision (e.g., Treatment A vs. B), (2) describe a novel study design to assess deviations from monotonicity empirically by surveying physicians about their prescribing preferences and the treatment decisions they would make for a set of hypothetical patients, and (3) implement a pilot study to demonstrate the feasibility of our design to detect monotonicity violations when studying the effects of atypical versus conventional antipsychotic medication on risk of death in the elderly.

Objectives Pragmatic randomized trials are important tools for shared decision-making, but no guidance exists on patients' preferences for types of causal information. We aimed to assess preferences of patients and investigators toward causal effects in pragmatic randomized trials. Study Design and Setting We (a) held three focus groups with patients ( n = 23) in Boston, MA; (b) surveyed ( n = 12) and interviewed ( n = 5) investigators with experience conducting pragmatic trials; and (c) conducted a systematic literature review of pragmatic trials ( n = 63). Results Patients were distrustful of new-to-market medications unless substantially more effective than existing choices, preferred stratified absolute risks, and valued adherence-adjusted analyses when they expected to adhere. Investigators wanted both intention-to-treat and per-protocol effects but felt methods for estimating per-protocol effects were lacking. When estimating per-protocol effects, many pragmatic trials used inappropriate methods to adjust for adherence and loss to follow-up. Conclusion We made four recommendations for pragmatic trials to improve patient centeredness: (1) focus on superiority in effectiveness or safety, rather than noninferiority; (2) involve patients in specifying a priori subgroups; (3) report absolute measures of risk; and (4) complement intention-to-treat effect estimates with valid per-protocol effect estimates.

Antidepressants may increase the risk of fractures by disrupting sensory-motor function, thereby increasing the risk of falls, and by decreasing bone mineral density and consequently increasing the fall- or impact-related risk of fracture. Selective serotonin reuptake inhibitor (SSRI) antidepressants appear to increase fracture risk relative to no treatment, while less is known about the effect of serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants, despite SNRIs being prescribed with increasing frequency. No prior study has directly examined how fracture risk differs among patients initiating SNRIs versus those initiating SSRIs. The objective of this study was to assess the effect of SNRI versus SSRI initiation on fracture rates. Data were derived from a PharMetrics claims database, 1998–2010, which is comprised of commercial health plan information obtained from managed care plans throughout the US. We constructed a cohort of patients aged 50 years or older initiating either of the two drug classes (SSRI, N = 335,146; SNRI, N = 61,612). Standardized mortality weighting and Cox proportional hazards regression were used to estimate hazard ratios (HRs) for fractures by antidepressant class. In weighted analyses, the fracture rates were approximately equal in SNRI and SSRI initiators: HRs for the first 1- and 5-year periods following initiation were 1.11 [95 % confidence interval (CI) 0.92–1.36] and 1.06 (95 % CI 0.90–1.26), respectively. For the subgroup of patients with depression who initiated on either SNRIs or SSRIs, those initiating SNRIs had a modestly, but not significantly, elevated fracture risk compared with those who initiated on SSRIs [HR 1.31 (95 % CI 0.95–1.79)]. We found no evidence that initiating SNRIs rather than SSRIs materially influenced fracture risk among a cohort of middle-aged and older adults.

Background Recent evidence suggests increased risk for mortality in bulimia nervosa (BN). However, little is yet known about suicidal behavior in BN. Aims To examine frequency and correlates of suicidal ideation and attempts in adolescents and adults with BN in two population-based samples. Method A total of 10,123 adolescents and 2980 adults in two nationally representative surveys of mental disorder were queried regarding eating disorder symptoms and suicidal ideation and attempts. Results Less than 1 percent (0.9%) of adolescents and 1.0% of adults met the criteria for BN. Suicidal ideation was more common among adolescents with BN (53.0%) compared with those with binge eating disorder (BED) (34.4%), other psychopathology (21.3%) or no psychopathology (3.8%). Similar trends emerged for the association between BN and self-reported suicidal plans or attempts. Among adults, suicidality was more common in BN than in the no psychopathology group, but not significantly different from the anorexia nervosa (AN), BED, or other psychopathology subgroups. Conclusion There is a high risk of suicidal ideation and behavior among those with BN. These results underscore the importance of addressing suicide risk in adolescents and adults with eating disorder symptoms.

Valid case definitions are necessary to understand etiology and assess effectiveness of treatment and prevention strategies. However, achieving such validity is complicated for diseases and disorders that lack a definitive biological test or rely on symptom manifestations, such as eating and other psychiatric disorders1. To address this, investigators propose classification systems of variable utility with an understanding that there is no clear “gold standard” approach. For example, although case definitions based on DSM diagnoses may imperfectly model disordered eating, they can be invaluable to researchers and practitioners who hope to predict and understand the course of illness or response to treatment1,2. However, it may be developmentally inappropriate to extrapolate classification approaches based on adult studies to understanding presentations in youth. For example, among adults there is one body mass index cut-off for obesity, but among children one must take into account age and gender to interpret whether a child’s body mass index is sufficiently elevated to be considered obese3. With eating disorders, it is possible that eating and weight concerns present differently and/or at subthreshold levels more frequently in preadolescence, adolescence, and young adulthood; if so, applying a classification system without acknowledgment of these differences could misrepresent the prevalence and public health impact, and may miss opportunities to identify causes, consequences, or correlates of the disorders. This could be particularly disconcerting in adolescence, which is when eating disorders often onset and perhaps an ideal time to intervene4,5. One technique for empirical classification is latent class (LC) analysis, which clusters subjects based upon their observed response patterns into mutually-exclusive classes6. A compelling feature of the LC modeling approach is that, relative to other categorical and dimensional empirical classification approaches, LC analyses make relatively fewer and weaker assumptions. Specifically, LC analyses require that, while observed covariates may be highly correlated unconditionally, the observed covariates are uncorrelated within a class7. Although a strong assumption, clinical homogeneity within classes is an attractive feature. In contrast, dimensional approaches to classification, although often parsimonious and in certain circumstances more biologically plausible, require many additional assumptions about the distributions of and relationships between the observed covariates and unobserved dimensions. For example, dimensional approaches, such as exploratory factor analysis, require the assumption that the errors for factors are independent, have a mean of zero, have equal variance across factors, are multivariate normally distributed, and for orthogonal models, the factors are independent. LC analysis has been a popular tool in addressing eating disorder classifications (see review by Crow et al 20117), but has been primarily employed in clinical samples of adult patients. As only a small minority of individuals who report disordered eating symptomatology in nationally- representative studies seek treatment for their eating/weight problems 4, it may often be preferable to draw inferences from community-based rather than treatment-seeking samples. Few LC studies have analyzed younger populations and most only included treatment-seeking cases. LC analysis has only been used in one community-based sample of youth, but the 12–23 year old females were analyzed together8. In order to identify possibly prodromal, subclinical, or additional presentations that may arise during the age periods of high incidence4,5, it is essential to evaluate possible classifications in more finely-grained age strata. Several questions remain unanswered. Is it possible to develop an empirically based classification structure for female preadolscents, adolescents, and young adults? If so, would the classification structure vary across developmental stages, or could a similar set of classes be found throughout youth and young adulthood? Would these classes resemble those seen in empirically-based classification structures for adults? Would these classes be clinically relevant, i.e., would they be predictive of course or adverse outcomes? Answering these questions is essential for future research to understand the natural history of eating disorders and for improvements in early detection, prevention, and treatment. With all these questions in mind, the primary goal of the current study is to empirically derive an eating disorder classification structure for females across developmental stages using LC models, potentially allowing classification to vary through youth and young adulthood. To evaluate the predictive validity of this classification structure, we assessed the association between class membership and the co- occurrence and incidence of drug use, binge drinking, and high depressive symptoms.

Objectives We aimed to describe and report the initial validity of a newly developed structured interview for sleep disorders (Diagnostic Interview for Sleep Patterns and Disorders [DISP]) administered by trained lay interviewers. Methods A total of 225 patients with various sleep disorders were recruited from two nationally recognized sleep centers in the United States. The International Classification of Sleep Disorders , second edition (ICSD-2) criteria, were used to classify sleep disorders (e.g., delayed sleep phase disorder, hypersomnia, narcolepsy with cataplexy [NC], restless legs syndrome [RLS], periodic limb movement disorder [PLMD], insomnia, rapid eye movement sleep behavior disorder [RBD], and obstructive sleep apnea [OSA]). Interview diagnoses were compared with final diagnoses by sleep specialists (reference diagnosis based on clinical history, examination, and polysomnography [PSG] when indicated). Results DISP diagnoses had fair to substantial concordance with clinician diagnoses for various sleep disorders, with area under the receiver operator characteristic curves (AUC) ranging from 0.65 to 0.84. Participants classified by the clinician as having a sleep disorder were moderately well-detected (sensitivity ranging from 0.50 for RBD disorder to 0.87 for insomnia). Substantial specificity (>0.8) also was seen for five of the eight sleep disorders (i.e., delayed sleep phase, hypersomnia, NC, PLMD, and RBD). Interviews were more likely than clinicians to detect disorders secondary to the primary sleep problem. Conclusions The DISP provides an important tool for the detection of a wide range of sleep disorders in clinical settings and is particularly valuable in the detection of secondary disorders that were not the primary referral diagnosis.

Background: Clinical anecdote suggests that rates of eating disorders (ED) vary between schools. Given their high prevalence and mortality, understanding risk factors is important. We hypothesised that rates of ED would vary between schools, and that school proportion of female students and proportion of parents with post-high school education would be associated with ED, after accounting for individual characteristics. Method: Multilevel analysis of register-based, record-linkage data on 55 059 females born in Stockholm County, Sweden, from 1983, finishing high school in 2002-10. Outcome was clinical diagnosis of an ED, or attendance at a specialist ED clinic, aged 16-20 years. Results: The 5-year cumulative incidence of ED diagnosis aged 16-20 years was 2.4%. Accounting for individual risk factors, with each 10% increase in the proportion of girls at a school, the odds ratio for ED was 1.07 (1.01 to 1.13), P = 0.018. With each 10% increase in the proportion of children with at least one parent with post-high school education, the odds ratio for ED was 1.14 (1.09 to 1.19), P < 0.0001. Predicted probability of an average girl developing an ED was 1.3% at a school with 25% girls where 25% of parents have post-high school education, and 3.3% at a school with 75% girls where 75% of parents have post-high school education. Conclusions: Rates of ED vary between schools; this is not explained by individual characteristics. Girls at schools with high proportions of female students, and students with highly educated parents, have higher odds of ED regardless of individual risk factors.

Assessments using multiple informants have been increasingly incorporated into studies of childhood psychiatric disorders, with many epidemiologic studies including interviews or questionnaires completed by the child, a parent, and even a teacher1-3. These methods have been used in studies of many different psychiatric disorders, including major depressive, bipolar, generalized anxiety, attention deficit/hyperactivity, and conduct disorders2, 4. For disorders that involve symptom denial or non-normative behavioral manifestations in particular, incorporating an adult informant is often integral to measuring a valid diagnosis5. Prior epidemiologic studies of eating disorders during adolescence have relied solely on information provided by the adolescent. Clinical studies, however, highlight the importance of a parental perspective and parental involvement6, 7. Indeed, best practice for obtaining a clinical diagnosis of an adolescent's eating disorder should include information from the parents8. Clinical studies have shown relatively low concordance between parent and adolescent symptom reports, with prior investigators postulating this may be due to minimization of symptoms and hiding of behaviors9-11. More specifically, anorexia nervosa is defined in part by a denial of the illness, so parents may be particularly helpful in accurately identifying and describing these symptoms; alternatively, bulimic behaviors frequently involve secrecy and shame, which may imply parent report is indicative of severity and treatment-seeking. For studies that gather information from multiple sources, four general analytic approaches have been implemented: (1) using data only from one informant (even if data from another informant is collected); (2) using data from each informant separately; (3) pooling information into a single construct (e.g., “OR rules”); or (4) jointly modeling the information. Although the first three approaches are most commonly employed, these methods have notable limitations, including inefficiency (Approach 1), limited interpretability (Approach 2), missing data issues (Approaches 2, 3), and inability to directly assess the relevance of source of information (Approaches 1, 2, 3). Alternatively, models developed by Fitzmaurice and colleagues (Approach 4) overcome many of these limitations12, 13. Specifically, this approach allows information from multiple informants to contribute jointly to the same model, which allows for efficient use of all available data, and provides an opportunity to directly assess whether the source of information changes the relationship between the construct of interest (e.g., eating disorder symptoms) and both risk factors (e.g., sex) and outcomes (e.g., health outcomes). In the Avon Longitudinal Study of Parents and their Children (ALSPAC), a population-based cohort study following children from birth through adulthood, parents and adolescents were asked about the adolescent's eating disorder symptoms at two assessments in adolescence14. We used this information to: (1) estimate the prevalence of eating disorder symptoms according to different methods for utilizing the available information; (2) model the prevalence of eating disorder symptoms within levels of covariates; and (3) assess the predictive validity of parent and adolescent report of eating disorder symptoms in models predicting subsequent measurements of body mass and composition.

Chewing and spitting (CS) out food is a relatively understudied eating disorder behavior. The aim of this study was to examine lifetime and current frequencies of CS across eating disorder diagnostic groups and to compare the severity of eating disorder symptomatology between participants who did and did not endorse CS. A total of 972 individuals presenting for outpatient eating disorder treatment between 1985 and 1996 completed a questionnaire that included items regarding current and lifetime eating disorder behaviors, including CS. Results indicated that both lifetime and current prevalence estimates of CS varied cross-diagnostically, with CS being more common among those with anorexia nervosa and bulimia nervosa compared to those with eating disorder not otherwise specified. CS was significantly associated with several eating disorder symptoms, including compensatory behaviors, meal restriction, and lower BMI. Those who reported CS were also younger in age compared to those who did not report CS. These findings indicate that CS is associated with more severe eating and weight pathology and is not equally prevalent across eating disorder diagnoses. These results also support the relatively high occurrence of CS and the importance of targeting this behavior in eating disorder treatment. Future research should clarify the correlates, mechanisms, and function of CS in eating disorders.

Many research diagnostic interviews employ skip rules, such that some questions are only asked based on answers to prior questions. In the context of large-scale epidemiological studies, skip rules are important to study feasibility by reducing the time, money, and participant burden required for assessment. However, less is understood about information lost when questions are skipped. This study examines the relative prevalence, clinical significance, and additional time required to assess eating disorder symptom patterns skipped in the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to understand the costs and benefits of following skip rules. Data come from the second stage of a two-stage cohort sample (N = 400) in which the SCID-I eating disorders module was administered without following skip rules. Results were weighted to correct for the sampling framework. Over a third of subjects endorsed symptoms that would have been missed had skip rules been followed. Uncaptured symptom patterns were associated with increased psychosocial impairment, and the additional time required to assess all symptoms averaged 1.8 minutes per participant. Clinically significant symptom patterns are missed by the SCID-I and similar diagnostic tools, suggesting that epidemiologic studies using such instruments under-estimate the prevalence and public health impact of mental disorders.

Objective To investigate differences in fertilization, clinical pregnancy, and miscarriage rates between men with a markedly high sperm DNA fragmentation index (DFI) (>50%) and those with low DFI (≤15%) in couples matched by female partner age and ovarian reserve as determined by antimullerian hormone (AMH) level. Design Retrospective cohort study. Setting University-affiliated fertility center. Patient(s) Men undergoing intracytoplasmic sperm injection (ICSI) cycles who had low (n = 114) or markedly high (n = 36) DNA damage. Intervention(s) None. Main Outcome Measure(s) Sperm DNA damage evaluated by acridine orange flow cytometry and expressed as the DFI, with the potential confounders of ovarian reserve and age controlled for by multivariable logistic regression analysis. Result(s) The fertilization and clinical pregnancy rates were not different between the two groups. We observed a trend toward a higher miscarriage rate with the high DFI group, but it did not reach statistical significance. Conclusion(s) Intracytoplasmic sperm injection in men with a high DFI with sperm selected by movement and morphology characteristics resulted in a similar pregnancy rate compared with the controls with a normal DFI. However, the trend observed of an increase in miscarriages suggests that any potential negative impact may appear later in development. Future studies involving a larger cohort may determine if the miscarriage trend reaches statistical significance.

OBJECTIVE: Adolescents who self-injure often engage in bingeing/purging (BP). Ecological momentary assessment (EMA) has potential to offer insight into the relationship between self-injury and BP. The aims of this study were to examine the frequency and context of BP using EMA in a sample of nonsuicidal self-injurious (NSSI) adolescents. METHOD: Thirty adolescents with a history of NSSI responded to questions regarding self-destructive thoughts/behaviors using a palm-pilot device. Descriptive analyses compared thought/behavior contexts during reports of BP and NSSI thoughts/behaviors (occurring together vs. individually). RESULTS: BP thoughts were present in 22 (73%) participants, occurring on 32% of the person-days recorded; 59% of these participants actually engaged in BP behavior. Seventy-nine percent of BP thoughts co-occurred with other self-destructive thoughts. Adolescents were more often with friends/peers than alone or with family when having BP thoughts. Worry and pressure precipitated both BP and NSSI thoughts, but perceived criticism and feelings of rejection/hurt were associated more often with BP thoughts than with NSSI thoughts. DISCUSSION: BP thoughts and behaviors were common in this sample, often occurring with other self-destructive thoughts. Future EMA research is needed to address the function of BP symptoms, the contextual variables that increase risk for BP thoughts, and the factors that predict the transition of thoughts into behaviors in adolescents with and without self-injury. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013). Language: en

Background: Ecological studies support the hypothesis that suicide may be “contagious” (i.e., exposure to suicide may increase the risk of suicide and related outcomes). However, this association has not been adequately assessed in prospective studies. We sought to determine the association between exposure to suicide and suicidality outcomes in Canadian youth. Methods: We used baseline information from the Canadian National Longitudinal Survey of Children and Youth between 1998/99 and 2006/07 with follow-up assessments 2 years later. We included all respondents aged 12–17 years in cycles 3–7 with reported measures of exposure to suicide. Results: We included 8766 youth aged 12–13 years, 7802 aged 14–15 years and 5496 aged 16–17 years. Exposure to a schoolmate’s suicide was associated with ideation at baseline among respondents aged 12–13 years (odds ratio [OR] 5.06, 95% confidence interval [CI] 3.04–8.40), 14–15 years (OR 2.93, 95% CI 2.02–4.24) and 16–17 years (OR 2.23, 95% CI 1.43–3.48). Such exposure was associated with attempts among respondents aged 12–13 years (OR 4.57, 95% CI 2.39–8.71), 14–15 years (OR 3.99, 95% CI 2.46–6.45) and 16–17 years (OR 3.22, 95% CI 1.62–6.41). Personally knowing someone who died by suicide was associated with suicidality outcomes for all age groups. We also assessed 2-year outcomes among respondents aged 12–15 years: a schoolmate’s suicide predicted suicide attempts among participants aged 12–13 years (OR 3.07, 95% CI 1.05–8.96) and 14–15 years (OR 2.72, 95% CI 1.47–5.04). Among those who reported a schoolmate’s suicide, personally knowing the decedent did not alter the risk of suicidality. Interpretation: We found that exposure to suicide predicts suicide ideation and attempts. Our results support school-wide interventions over current targeted interventions, particularly over strategies that target interventions toward children closest to the decedent.

Diagnostic criteria for eating disorders (ED) remain largely based on clinical presentations, but do not capture the full range of behaviours in the population. We aimed to derive an empirically based ED behaviour classification using behavioural and body mass index (BMI) indicators at three time-points in adolescence, and to validate classes investigating prospective associations with adverse outcomes. Adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) provided data on ED at age 14 (n = 6615), 16 (n = 5888), and 18 years (n = 5100), and had weight and height measured. Psychological and behavioural outcomes were assessed at 15.5/16 and 17.5/18 years. We fit gender- and age-stratified latent class models, and employed logistic regression to investigate associations between classes and later outcomes. One asymptomatic and two symptomatic (largely representing higher and lower frequency ED behaviours) classes were observed at each time-point, although their relative prevalence varied by age and gender. The majority of girls in symptomatic classes remained symptomatic at subsequent assessments. Girls in symptomatic classes had higher odds of subsequent anxiety and depressive disorders, binge drinking, drug use, and deliberate self-harm. Data analyses were underpowered amongst boys. The presence of two symptomatic classes (characterised by different ED behaviour frequency) and their prospective association with adverse outcomes suggest a need to refine diagnostic thresholds based on empirical data. Despite some instability of classes, particularly in mid-adolescence, evidence that half of girls in symptomatic classes remained symptomatic suggests persistence of ED behaviours in adolescence, and highlights a need for early identification to reduce chronicity.

RNAs from other cell types have minimal impact on male fecundity–associated sperm RNA elements.

The study assessed the prevalence of suicidal ideation, suicide plans, and suicide attempts as well as patterns of mental health service use among adolescents.Data came from the National Comorbidity Survey–Adolescent Supplement, a nationally representative sample of 10,123 adolescents aged 13 to 18 years who participated in computer-assisted, face-to-face interviews between February 2001 and January 2004. Prevalences of suicidal thoughts and behaviors in the past year were determined. Past-year use of any mental health treatment and receipt of four or more visits from one provider among youths with suicidal ideation, plans, or attempts were also assessed. Associations were evaluated by using logistic regression.During the course of 12 months, 3.6% of adolescents reported suicidal ideation without a plan or attempt, .6% reported a suicide plan without an attempt, and 1.9% made a suicide attempt. Overall, two-thirds of adolescents with suicidal ideation (67.3%) and half of those with a plan (54.4%) or attempt (56.9%) did not have any contact with a mental health specialist in the past year. Different predictors of use of care were identified for each group.Adolescent suicidality often is untreated in the United States. Increased outreach efforts to improve treatment access for youths with suicidal ideation and attempts are needed.

The purpose of this study was to examine the 2-year longitudinal stability of objective bulimic (binge eating) episodes (OBEs) and subjective bulimic (binge eating) episodes (SBEs) in a multisite eating disorders sample.Participants included 288 females with eating disorder symptoms who were assessed every 6 months using the Eating Disorder Examination.Markov modeling revealed considerable longitudinal variability between types of binge eating over 6-month time intervals with relatively higher probability estimates for consistency between OBEs and SBEs than specific transitions between types for the overall sample as well as for eating disorder diagnostic groups. Transition patterns examining all five time points indicated notable variability in binge-eating patterns among participants.These findings suggest that although longitudinal patterns of binge types are variable among individuals with eating disorders, consistency in OBEs and SBEs was the most common pattern observed.

Eating disorders represent a significant public health concern because they are associated with serious medical and psychiatric morbidity, role impairment, and often go under-treated.1,2 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)3 currently includes three eating disorders: (i) anorexia nervosa (AN), restricting and binge/purge subtypes; (ii) bulimia nervosa (BN), purge and non-purge subtypes; and (iii) eating disorder not otherwise specified (EDNOS). The DSM is first and foremost a clinical tool and designed to guide clinical practice. However, the prevalence and heterogeneity of EDNOS in clinical settings are problematic and may limit the usefulness of the DSM-IV eating disorder criteria. Preparation for the fifth edition of the DSM has led to the re-evaluation of the significance of the current classification system with specific consideration being afforded to the category of EDNOS.4 The “not otherwise specified” (NOS) category in DSM-IV typically refers to a group of individuals that falls outside the main diagnostic categories. Consequently, EDNOS has received less empirical attention,5 which has lead to limited knowledge about the prevalence and clinical characteristics of EDNOS. Several recent studies of clinical samples of adolescents6 and adults,7–13 as well as a meta-analyses of the relationship between EDNOS and the official eating disorder diagnoses,14 indicate that the majority (well over 50% across studies) of adolescents and adults presenting for eating disorder treatment are diagnosed with EDNOS. On the other hand, a recent study of college students showed that proposed DSM-5 diagnostic criteria significantly reduce reliability on EDNOS.15 Nonetheless, the heterogeneity of an EDNOS diagnosis is problematic and limits the information conveyed with this classification. Relatively precise sets of diagnostic criteria are mapped out for AN and BN, and DSM-IV defines the preliminary research criteria for one type of EDNOS (binge eating disorder [BED]), yet no other criteria for EDNOS are specified.16 Thus, EDNOS is a combination of individuals who narrowly fall short of meeting full criteria for AN and BN, those with BED, as well as a variety of other poorly defined presentations. Taken together, and as we have argued before,6 the diagnosis of EDNOS is unwieldy for at least three reasons: first, the majority of patients presenting for eating disorder treatment are assigned a diagnosis that was intended to be a residual category, second, little specific information about eating disorder pathology is conveyed in this diagnosis, and third, this diagnosis fails to convey much information about appropriate treatment strategies. Systematic research that improves the description of EDNOS or investigates efficacious treatments for individuals with EDNOS remains sparse. Several have been proposed, however, there is limited agreement regarding potential resolutions to this diagnostic conundrum. For instance, some have argued for the relaxation of the strict diagnostic criteria for AN or BN, which would allow for the reclassification of individuals with EDNOS based upon specific clinical features such as weight loss or binge eating and/or purging.12,16–18 The remainder of EDNOS could then be subdivided into specific types or potentially distinct disorders (e.g., individuals who purge without binge eating).19 Another, and perhaps more radical proposal, is to highlight the similarities rather than differences between individuals with eating disorders, also referred to as a ‘transdiagnostic’ solution to the problems of nosology16 based on the lack of differences between subthreshold AN and BN and their full-syndrome counterparts.12 However, the latter approach may overlook meaningful differences between EDNOS subgroups.19 A recent study of EDNOS in adolescents further complicates this depiction by highlighting similarities between AN and BN on the one hand that in turn differ from the EDNOS subgroups on the other.6 The present study was designed to add to the growing body of literature on EDNOS in order to provide information that may inform the validity of the classification system of eating disorders. Prior studies have focused on clinical samples with little information available about the presentation of EDNOS in the population at-large. Therefore, the first goal of our study was to describe the relative distribution of AN, BN, and EDNOS in two large population-based surveys, the National Comorbidity Survey Replication Adolescent Supplement (NCS-A) sample of adolescents, and the National Comorbidity Survey Replication (NCS-R) sample of adults. NCS-A was a population-based sample of adolescents aged 13–18 years and NCS-R was a separate survey for adults over 18 years of age. The prevalence rates of eating disorders and subtypes thereof in adults1 and adolescents2 were presented in earlier publications. Our second goal was to examine comparisons between AN, BN and EDNOS on a variety of clinically meaningful indicators and to describe the range of EDNOS presentations on these indicators. These comparisons allowed us to specifically examine the prevalence, clinical severity, and heterogeneity of EDNOS in these large population-based surveys of adolescents and adults. Third, data from this examination may suggest revisions to the DSM, which could have significant implications for clinical research and practice, as well as for public policy.

Exposure to Western popular culture is hypothesized to increase risk for eating disorders. This study tests this hypothesis with respect to the proposed diagnosis of binge eating disorder (BED) in an epidemiological sample of people of Mexican origin in Mexico and the U.S. Data come from the Mexico National Comorbidity Survey, National Comorbidity Survey Replication, and National Latino and Asian American Survey (N = 2268). Diagnoses were assessed with the WMH-CIDI. Six groups were compared: Mexicans with no migrant family members, Mexicans with at least one migrant family member, Mexican return-migrants, Mexican-born migrants in the U.S., and two successive generations of Mexican-Americans in the U.S. The lifetime prevalence of BED was 1.6% in Mexico and 2.2% among Mexican-Americans. Compared with Mexicans in families with migrants, risk for BED was higher in US-born Mexican-Americans with two U.S.-born parents (aHR = 2.58, 95% CI 1.12-5.93). This effect was attenuated by 24% (aHR = 1.97, 95% CI 0.84-4.62) with adjustment for prior-onset depressive or anxiety disorder. Adjustment for prior-onset conduct disorder increased the magnitude of association (aHR = 2.75, 95% CI 1.22-6.20). A similar pattern was observed for binge eating. Among respondents reporting binge eating, onset in the U.S. (vs. Mexico) was not associated with prevalence of further eating disorder symptoms. Migration from Mexico to the U.S. is associated with an increased risk for BED that may be partially attributable to non-specific influences on internalizing disorders. Among respondents reporting binge eating in either country, similar levels of further symptoms were endorsed, suggesting some cross-cultural generalizability of criteria.

OBJECTIVE The purpose of this investigation was to derive an empirical classification of eating disorder symptoms in a heterogeneous eating disorder sample using latent class analysis (LCA) and to examine the longitudinal stability of these latent classes (LCs) and the stability of DSM-IV eating disorder (ED) diagnoses. METHOD A total of 429 females with ED symptoms were assessed using the Eating Disorder Examination every 6 months for 2 years. LCA was used to derive empirical classification at baseline. Latent transition analysis (LTA) was used to examine the longitudinal stability of LCs, and Markov modeling procedures were used to examine DSM-IV ED diagnoses over all the time points. RESULTS LCA yielded a 3-class solution: binge eating and purging, binge eating only, and low body mass index. LTA indicated that these LCs showed greater stability over 2 years than DSM-IV diagnoses with the probability of remaining in the same class ranging from 0.69 to 0.91 for LCs and from 0.40 to 0.75 for DSM-IV diagnoses. Transition patterns also revealed more stability for LCs with only 21% changing classes compared with 63% of the DSM-IV diagnostic categories. CONCLUSION Empirically derived classes of ED symptoms showed greater longitudinal stability than DSM-IV diagnoses over a 2-year time period, suggesting that modifying the criteria to be consistent with empirically based classification (e.g., reducing frequency requirements of binge eating and purging) may reduce ED diagnostic crossover in DSM-5.

Objective—This study examined group differences in ratings of amounts of food at the threshold of what is considered “unusually large” to develop empirically derived definitions of binge eating criteria for bulimia nervosa and binge eating disorder. Method—Groups included undergraduate students, community members, and participants from an eating disorder (ED) longitudinal study. Data were collected via self-report questionnaires. Results—Ordinal logistic regression indicated that males reported a higher threshold for amounts of food compared to females. Overweight participants from the student and ED samples, but not from the community sample, reported higher thresholds. The presence of binge eating and fear of weight gain were also associated with higher thresholds. Discussion—These findings provide evidence that gender, social context, BMI, and eating disorder status are important considerations in determining what is an unusually large amount of food. Future diagnostic guidelines should consider the importance of these factors when defining binge eating.

Background: Several studies have demonstrated an association between headache and disturbed sleep. None have examined this association across the headache spectrum. Our goal was to determine whether migraine and migraine with aura differ from nonmigraine headache in terms of associated insomnia complaints or severity of sleep problems. Methods: A probability sample of US adults was used. A structured interview administered by trained interviewers was used. Diagnostic criteria for migraine and migraine with aura were based on the International Headache Society classification. The presence or absence of four forms of sleep disturbance associated with an insomnia diagnosis was ascertained. Results: There was a significant association between frequent severe headache, including migraine with and without aura, and disordered sleep. Adults with headache reported more frequently difficulty initiating sleep (odds ratio [confidence interval] = 2.0 [1.6–2.5]), difficulty staying asleep (2.5 [2.1–3]), early morning awakening (2.0 [1.7–2.5]) and daytime fatigue (2.6 [2.2–3.2]) and also were more than twice as likely to report three or more of these symptoms(2.5 [2–3.1]) compared to the individuals without headache. Discussion: Adults with severe headache are at significantly higher risk of also suffering from sleep problems, when compared with the general population, regardless of specific headache type. Optimal treatment of headache must include investigation for sleep disorders and vice versa.