Cynthia M. Bulik, Ph.D. - US grants

DESCRIPTION (Applicant's Abstract): This K01 Mentored Research Scientist Development Award for Dr. Bulik, sponsored by Dr. Kenneth Kendler, Describes a rigorous three year training program in genetic epidemiology with a focus on eating disorders. Eating disorders represent a significant public health problem for women in the United States and other Westernized countries, yet fairly little is known about their etiology. Completion of the program will allow Dr. Bulik to combine her extensive clinical research experience in eating disorders with newly acquired skills in genetics and epidemiology in order to conduct independent research that will address etiological questions in the filed. To achieve this aim, Dr. Bulik will receive training in the areas of epidemiology, biometrical and Mendelian genetics, advanced statistical techniques for the analysis genetically-informative data, and molecular genetics. She will apply this new knowledge to a series of studies examining the epidemiology, genetics, and genetic epidemiology of eating disorders. Specific research objectives include: i) examining the reliability of the diagnosis of bulimia nervosa; ii) evaluating predictors of diagnostic reliability; iii) evaluating the current diagnostic nosology for the classification of eating disorders; iv) examining the extent to which major depression and bulimia nervosa share common genetic and environmental risk factors; v) examining the extent to which substance dependence and bulimia nervosa share common genetic and environmental risk factors; vi) developing an integrated epigenetic model of eating disorders; vii) exploring the extent to which specified familial risk-factors contribute to the transmission of bulimia nervosa; viii) exploring environmental contributions to the etiology of bulimia nervosa using a co-twin control design; ix) examining the patterns and prevalence of disordered eating in a population-based sample of female African-American twins; and x) collecting additional detailed information on eating behaviors and attitudes from a birth-registry sample of female twins. Dr. Bulik will also receive extensive training and experience in working with a variety of genetic epidemiologic research designs. By completing this program, Dr. Bulik and her sponsors envision making substantial scientific contributions that will advance the understanding of eating disorders in ways that are only achievable using genetically-informative data. At the end of the three year period, Dr. Bulik will have received sufficient high-quality training and experience to be a highly productive independent research scientist in genetic epidemiology.

DESCRIPTION: Although eating and weight-related disorders are treatable, most afflicted individuals never receive proper treatment. Despite the existence of excellent prototype cognitive-behavioral programs for the treatment of binge-eating disorder (BED) and other eating disorders, we face a crisis of dissemination. The goal of this project is to join cognitive-behavioral therapy (CBT) with novel information technology to develop an interactive CBT program that will allow individuals to experience the basics of CBT in the privacy of their own homes. This Exploratory/Development Grant for Mental Health Intervention (R21) proposes a four stage project to develop a CD-ROM-based program for the effective delivery of cognitive-behavioral therapy (CBT) to obese individuals with binge-eating disorder (OBED) and other unhealthy eating behaviors. In Phase 1 of the project, we will continue development of a CD-ROM program that we began in 1998. The program will be a rich, vivid, and interactive approach to CBT that provides helpful psychoeducation on unhealthy eating and weight-related practices; clearly introduces the basic concepts and techniques of CBT; provides rich and vivid examples of techniques; provides individualized and interactive exercises for practicing CBT principles; and enables users to contact the central web site and staff with questions. This program will be applicable to a broad range of adult women and men of all races and backgrounds. In Phase 2, we will implement a rigorous four-stage beta-testing procedure that includes: group testing sessions followed by individual and focus group debriefing for feedback; peer review by experts in the field of CBT for eating disorders; and in-home beta testing prior to final production. Phase III of the project will be a small feasibility and pilot study comparing the efficacy of the CD-ROM-based delivery of CBT to traditional manual-based group therapy for individuals with OBED and a wait list control. Data from this pilot study will be used to support Phase IV, which will develop a proposal for a large-scale clinical trial comparing CD-ROM-based intervention with traditional group therapy. We anticipate that a CD-ROM-based program will be an efficacious and cost-effective intervention. For some, this program may suffice for treating their eating and weight-related problems. For others, it may be a useful adjunct to traditional psychotherapy or an introductory step to treatment which will familiarize them with the principles and techniques of CBT and increase their comfort and motivation to seek additional professional care.

[unreadable] DESCRIPTION (provided by applicant): Two related and growing bodies of research suggest that women with eating disorders (EDs) experience pregnancy complications more frequently than healthy women, and individuals with EDs are more likely than healthy individuals to have a history of birth complications themselves. More specifically, women with EDs have a higher rate of perinatal complications, cesarean deliveries, and post-partum depression. Moreover, their offspring tend to weigh less than offspring of women without EDs and experience more problems with growth and development. In terms of the second point above, prospective epidemiological research suggests that individuals with anorexia nervosa (AN) are more likely to have been born prematurely, have been small for gestational age (SGA), and have suffered from cephalohematoma. Both bodies of research suggest that perinatal events may be critical to the etiology of EDs and that the perinatal period may be of particular relevance in further elucidating etiological factors in EDs. Although the mechanism of actions is not yet clear, individuals with threshold or subthreshold ED symptoms may increase their risk of adverse pregnancy outcomes by restricting food intake around the time of conception. Indeed, recent animal studies have shown that moderate maternal undernutrition around the time of conception can increase the risk of preterm birth. Together, these studies suggest a cycle of risk, that could be influenced by both genetic and environmental factors, that may flow through generations to perpetuate risk for EDs in families. No study has yet been able to study this cycle of risk in a single population-based sample. We propose to explore the impact of EDs, related behaviors and nutrition during the perinatal period on pregnancy outcome in a sample of 100,000 births in Norway. The Norwegian Mother and Child Cohort Study (Mor & barn undersokelsen) is a prospective population-based study of 100,000 births to 100,000 mothers and 80,000 fathers in Norway. Assessments are extensive including blood for DNA, psychosocial factors, infections, medication use, nutrition, life styles, occupational exposure, use of health services, substance abuse, socioeconomic factors, and chemical and physical factors in the environment. Health variables include fetal ultrasound, maternal and paternal history, and health outcomes for the mother and child detected during and after pregnancy. EDs and related behaviors are assessed at 17 weeks pregnancy and 18 months post partum. This study will provide prospective data on the risk to pregnancy outcome and child development associated with EDs in the mother independent of the effects of depression, anxiety and nutrition. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Cognitive-behavioral therapy (CBT) is a partially effective treatment for bulimia nervosa. CBT helps reduce rates of binging and purging and between 40-60% of individuals treated with CBT recover. Increasingly, internet-based approaches to health care are gaining popularity and showing efficacy in the treatment of a variety of psychiatric disorders as well as obesity. We propose to develop an rich, vivid, and interactive electronic form of CBT (available on web and CD-ROM) that enables self-monitoring, provides helpful psychoeducation on the facts about bulimia nervosa; clearly introduces the basic concepts and techniques of CBT; provides rich and vivid examples of techniques; and provides individualized and interactive exercises for practicing CBT principles. This project is one facet of a programmatic strategy to enhance the available repertoire of information-technology enhanced treatment approaches for individuals with eating disorders. We have already produced and herein present preliminary results of a CD-ROM-based CBT program for binge eating disorder and obesity (POWER: Preventing Overweight With Exercise and Reasoning) and a second family-based program for childhood overweight. Once completed and tested, this internet-based program for bulimia nervosa will have multiple uses. It could be used as a first step in a program of stepped care in which individuals can experience the basics of CBT at the privacy of their own computer. For some, this program may suffice for treating their bulimia nervosa. For others, the true value of this program will be as an adjunct to traditional CBT or as a source for booster sessions after traditional therapy ends. This program will be appropriate for late adolescent and adult women (with special user selected modules for men) of all races and backgrounds. We will implement a rigorous beta-testing procedure by health care providers knowledgeable about the treatment of bulimia nervosa and by patients with current bulimia nervosa. At the end of the R21 we will have a high-quality product that will be ready for testing in clinical trials.

[unreadable] DESCRIPTION (provided by applicant): The Department of Psychiatry at the University of North Carolina at Chapel Hill requests a new 5 year post- doctoral research training grant in eating disorders to address the critical shortage identified by NIH for skilled researchers in the eating disorders field. Our program will attract five qualified postdoctoral applicants per year from fields including medicine, psychology, nutrition, and related disciplines to provide rigorous advanced training in aspects of eating disorders research ranging from bench to society. The program will develop productive investigators on the path towards independence who will contribute to the advance of knowledge in the etiology, prevention, and treatment of eating disorders. Our training program includes 14 senior research faculty, 5 junior research faculty, and 5 clinical advisors from psychiatry, psychology, nutrition, sociology, genetics, epidemiology, and pediatrics. The six core aims of this proposal are for trainees: 1) to achieve a high level of research competency in a specialist area within eating disorders while becoming well versed in the broader context of the eating disorders field; 2) to achieve competency in research design, methodology, and biostatistics; 3) to appreciate and respect ethical issues related to research with human participants in general and eating disorders participants in specific; 4) to maintain awareness of key clinical issues with eating disorders patients; 5) to complete a research project of a magnitude commensurate with their prior research training under the supervision of a member of the training faculty; and, 6) to prepare for a career as an independent investigator. The UNC Eating Disorders Program and Department of Psychiatry have built substantial bridges across departments and schools at UNC. In close collaboration with our Interdisciplinary Obesity Center (P20 RR020649: Popkin), we are extremely well- poised to attract and develop a strong research workforce of interdisciplinary eating disorders researchers enriched with female and minority trainees. A systematic series of internal and external program evaluations with clear semiannual benchmarks will facilitate ongoing development and optimization of the program, with the ultimate goal of introducing highly trained, methodologically rigorous, clinically competent researchers to the field of eating disorders. Our trainees will ultimately generate high quality proposals for submission for funding to the NIH in order to move the field of eating disorders to the next level of scientific sophistication. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This R01 is submitted in response to RFA-MH-07-090 Innovative Trials for the Treatment of Anorexia Nervosa in Late Adolescence and Adulthood. With a specific focus on adult anorexia nervosa (AN), we propose to unite the expertise of a team skilled in the treatment of AN with world leaders in the development of couple-based interventions to develop an innovative intervention for couples in which one member is suffering from AN. The intervention "UCAN: Uniting Couples (in the treatment of) Anorexia Nervosa" acknowledges that AN occurs in an interpersonal context, both being affected by the person's social environment and impacting important interpersonal relationships. Moreover, the demonstrated success of family therapy for younger individuals with AN underscores the importance of leveraging family support in the treatment of AN. UCAN tailors cognitive-behavioral couple-based interventions that have been employed successfully for the treatment of depression, anxiety disorders, smoking cessation, and cancer to address the core psychopathology of AN, while also addressing the unique and challenging stresses that AN places on intimate relationships. Our initial conceptualization of the intervention focuses first on addressing AN within the context of the relationship with foci such as altering interactions around eating and weight, normalizing activity and health behaviors, body image, physical affection, and sexuality and second on addressing the broader relationship to maintain treatment gains, prevent relapse, and foster relationship satisfaction. The specific aims are: 1) to develop and standardize a manualized intervention for couples in which one member suffers from AN; 2) to determine feasibility and acceptability of a beta- version of UCAN in an open trial as an augmentation to treatment as usual (TAU) and to refine UCAN based on feedback from the preliminary trial; 3) to test UCAN+TAU versus TAU in a randomized controlled trial of 24 couples in which one member has AN; and 4) to adapt an observational couples assessment measure with the eventual goal of incorporating biological measures of affiliation and stress. Our primary patient outcomes will be BMI and global improvement, and our secondary patient outcomes will be depression, anxiety, and relationship adjustment and communication. Partner outcomes will also include caregiving measures. This trial will be designed explicitly to gather preliminary outcome data to inform sample size and power calculations for a subsequent larger randomized controlled trial. Findings from this investigation have the potential to result in the creation of an effective, acceptable, developmentally tailored intervention that will improve both core AN pathology as well as couple functioning. Future extensions of the intervention will include couple-based interventions for eating disorders such as bulimia nervosa and binge eating disorder. We propose to develop a couple-based intervention for adults with anorexia nervosa entitled "UCAN: Uniting Couples (in the treatment of) Anorexia Nervosa." We will create an effective, acceptable, developmentally tailored intervention that leverages the support of partners to improve both core anorexia nervosa pathology as well as couple functioning. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Although eating disorders, particularly anorexia nervosa, can affect fertility, many women with eating disorders and eating disorder histories are becoming mothers. Many of these women have difficulty achieving adequate nutrition during pregnancy, initiating and maintaining breastfeeding, adequately nourishing their children, modulating expectations regarding eating in their children, and judging what is normative and what is pathological in their children. These mothers are highly motivated to seek guidance to help reduce their children's risk of eating disorders. This proposed Exploratory Research Grant (R34) aims to develop a parenting intervention for mothers with current or past eating disorders called NURTURE (Networking, Uniting, and Reaching out To Upgrade Relationships and Eating). Our intervention is based on preliminary information from focus groups with mothers with eating disorders and extant research. We will systematically develop a manualized intervention for mothers with histories of threshold and subthreshold eating disorders who have children between the ages of 0-2. The specific aims of this R34 are: 1) to develop and standardize a modular manualized intervention for mothers with eating disorders to facilitate therapist training and treatment dissemination;2) to implement NURTURE in a small, randomized, delayed entry controlled trial to determine feasibility and acceptability;2) to evaluate whether immediate treatment with NURTURE is superior to a delayed entry control for improving targeted outcomes, and 4) to identify potential moderators and mediators of treatment. Our primary outcome will be observer ratings of videotaped maternal-child mealtime interactions and secondary outcomes will include measures of general parenting self-efficacy and maternal behaviors that enhance the social and emotional growth of their children. This trial will be designed explicitly to gather preliminary outcome data to inform sample size and power calculations for a subsequent larger randomized controlled trial. Results of this investigation have the potential to develop an effective and acceptable intervention that will improve both feeding-related and general parenting efficacy in mothers with eating disorders. Extensions of the intervention will include developmentally appropriate modules for mothers of children of various ages as well as web-based variants to optimize dissemination of the intervention.

DESCRIPTION (provided by applicant): Bulimia nervosa (BN) is a serious mental illness marked by substantial medical and psychiatric morbidity. Although cognitive-behavioral therapy (CBT) is the treatment of choice for BN, dissemination of this evidence-based approach has been suboptimal, with the majority of individuals requiring care never receiving treatment. Moreover, up to one-third of individuals relapse after CBT, indicating the need for maintenance interventions. Thus the evaluation of new strategies for dissemination of CBT and the development of novel interventions to maximize maintenance of treatment benefits are critical to improve our ability to treat BN. Optimizing technology is a logical next step to move the field forward and enhance public health reach. Thus in this application, in response to PA-07-295: Information Technologies and the Internet in Health Services and Intervention Delivery (R01), we seek to determine whether CBT delivered via the internet with moderated chat-group support is as effective as is face-to-face group CBT. We propose to randomize 180 patients to either standard face to face group CBT (the gold standard) or CBT via the internet (CBT.net) in a two-site, 20 week acute treatment trial. Treatments will be compared on measures of attrition, adherence, acceptability, binge and purge frequency, abstinence, and cost effectiveness. Specifically, we hypothesize that CBT.net will not be inferior to group CBT on primary outcome measures and that it will be more cost-effective. All participants will be followed up at three, six, and twelve months following completion of the acute treatment. This trial will utilize an internet based program for BN developed by Dr. Bulik (R21MH070781 "Web-based Cognitive Therapy for Bulimia Nervosa"). Successful completion of this project will provide critical information about the provision of treatment via the internet for patients who do not have access to evidence-based care. If CBT delivered via the internet is similarly efficacious to that delivered in the standard face to face group format, results of the proposed would have the potential to yield a cost- effective strategy to disseminate evidence-based treatments for BN. The purpose of this study is to compare an internet-delivered cognitive-behavioral treatment (CBT) program for bulimia nervosa with standard group CBT. If effective, CBT via the internet could be a cost-effective strategy to disseminate evidence-based treatments for BN.

DESCRIPTION (provided by applicant): Relapse and readmission rates after hospital-based treatment of anorexia nervosa (AN) are unacceptably high, placing a major financial, psychological, and social burden on patients and family members. We propose the application of a Health Information Technology (HIT) service to bridge the transition between higher levels of care (i.e., inpatient, partial hospitalization, residential) and outpatient care with the goal of reducing relapse and readmission. This proposal in response to RFA-PA-09-164 "NIH Exploratory/Developmental Research Grant Program (Parent R21)", describes the development and feasibility testing of an iPhone-based HIT service, iEAT: Information Technology to Enhance Anorexia Treatment, that will serve as a self-monitoring and communication tool for patients with AN and their providers. The transition to outpatient care is marked by a dramatic decrease in provider contact and increased exposure to potentially triggering environmental factors. By providing this self-monitoring and communication bridge, we aim to ease the transition between levels of care. iEAT will augment weekly outpatient treatment by allowing patients and providers to monitor and manage AN-related symptoms and behaviors thereby increasing and improving patient self-care and communication with their providers. We will develop IEAT in 3 stages involving stakeholders (patients and providers) at each step. In Stage 1, we will conduct in-depth interviews with patients and providers to fully understand needs and develop iEAT. In Stage 2, we will beta-test the program with 4 patients and their providers. Feedback will inform the final version of the application which will then be tested in Stage 3 in an uncontrolled trial of 10 patients and their providers. Patients will be trained in the use of the iEAT enabled iPhones prior to hospital discharge and providers will participate via iPhone or web interface. Patients will input daily entries of dietary exchanges, thoughts, mood, and urges to restrict and purge, as well as other variables that emerge from Stage 1 and 2 testing. Patients will receive automated feedback messages based on their entries, prompts when entries are missed, scheduled individualized feedback from their provider, and weekly treatment team feedback regarding progress towards treatment goals. iEAT will allow patients and providers to view summaries of their daily entries as well as clinical data collected during weekly outpatient visits (e.g., weight, self-report measures). At four months post-discharge, iEAT will be evaluated based on validity of entries, adherence, frequency and quality of the data entries over time, as well as patient and provider reports on its utility and acceptability. iEAT will then be tested formally in a subsequent larger randomized controlled trial to determine whether it enhances post-discharge maintenance of treatment goals and decreases readmission. iEAT has the potential to ease the transition between levels of care and provide a cost-effective and user- friendly approach to increase patient-provider contact, enhance self-monitoring of symptoms, and decrease hospital readmission for individuals with AN. PUBLIC HEALTH RELEVANCE: Treatment for anorexia nervosa (AN) is expensive and is marked by frequent relapse and re-hospitalization. iEAT has the potential to ease the transition between levels of care and provide a cost-effective and user- friendly approach to increase patient-provider contact, enhance self-monitoring of symptoms, and decrease hospital readmission for individuals with AN. The technology developed here will be made available through other mobile phone platforms and readily modifiable for management of other psychiatric and medical conditions.

DESCRIPTION (provided by applicant): No single, conventional treatment has been shown to significantly benefit adults with anorexia nervosa (AN), which ranks among the leading causes of disability and premature death in young women. We propose to test the hypothesis that a novel, couple-based intervention developed for adult AN (UCAN [Uniting Couples (in the treatment of) Anorexia Nervosa]) developed under RFA-MH-07-090 significantly enhances treatment outcome and reduces risk of relapse compared with treatment conducted entirely on an individual basis, the standard mode of treatment delivery in the community. This application, submitted in response to PA-10-067 Research Project Grant (Parent R01) will further establish the efficacy of UCAN. UCAN mutually engages patients and partners in reducing the psychopathology of AN and its impact on relationship functioning. Encouraging results from our pilot - significant weight gain and unprecedentedly low treatment drop out - support this application. In order to determine whether UCAN is superior to individual treatment alone, we propose a randomized controlled trial comparing: 1) UCAN plus individual cognitive-behavioral therapy (UCAN+CBT) to 2) Individual CBT. All patients receive the same core of interventions used in conventional AN treatment, specifically: 1) medical management, 2) nutrition counseling, and 3) individual CBT. Further, participants will be randomly assigned either to: 1) UCAN or 2) a higher dose of individual CBT. The design addresses a question of clinical, developmental, and conceptual importance heretofore unexplored: Is treatment of adult AN optimized when it includes active participation of the patient's partner, compared with the community standard of individual therapy only. The primary aims are to compare the efficacy of UCAN+CBT with Individual CBT in: 1) increasing BMI and improving global clinical improvement, and 2) increasing retention in and satisfaction with treatment. Exploratory aims will address whether: 1) evidence exists to suggest that improvement in primary outcome variables may be partially mediated by improvements in relationship functioning and patient readiness to change; and 2) illness duration, subtype (restricting vs. binge/purge), and baseline level of emotion dysregulation should be considered as candidate moderators of treatment outcome in subsequent trials. We will collect data to guide the design of a more comprehensive cost-effectiveness analysis if a subsequent multi-site trial is warranted. The primary outcomes are change in BMI, global improvement, retention, and treatment satisfaction. We will recruit 50 couples (40 completers) over 3.75 years and follow all patients for one year. The Data Monitoring Group (DMG) will monitor recruitment, treatment fidelity, assessments, and human subject protections. Results from this trial will guide future, more definitive trials and inform therapeutic perspectives guiding the treatment of adults with AN. The development of innovative, efficacious treatments for adult AN is essential to reducing the chronic morbidity, high risk of mortality, and substantial personal, familial, and public health burdens incurred by this debilitating and recalcitrant illness.

The proposed project seeks to determine the manner in which genetically mediated psychological and metabolic factors influence risk for anorexia nervosa (AN) using a prospective longitudinal design. AN is a disorder of considerable public health importance due to high chronicity, low recovery rates, high mortality, and significant individual and family costs. Despite years of research, we still understand little about the pathophysiology of AN, hampering the development of pharmacological interventions and early intervention strategies. Recent findings from our investigative team suggest that body mass, metabolic factors, and growth patterns might not only prospectively predict AN onset, but also might reflect underlying genetic contributions of these parameters to illness risk. Extending these findings, the overarching aims of our proposed research are: first, to test if high genetic risk for AN and low genetic risk for obesity (using polygenic risk scores) are associated with a broad and narrow AN phenotypes; second, to examine associations between these polygenic risk scores and metabolic, growth, and body composition patterns prior to AN onset; and third, to determine whether high genetic risk for AN and low genetic risk for obesity are associated with severity and persistence of AN. We will leverage the considerable wealth of existing data in the Avon Longitudinal Study of Parents and Children (ALSPAC), a longitudinal population-based cohort that includes existing genome-wide, metabolic, growth, body composition data, as well as data on AN behaviours and AN diagnoses with measurements from before birth to age 25 on ~7,000 individuals. Our findings will clarify the developmental pathophysiology of AN, contribute to deepening the understanding of the biology and genetics of the illness, and potentially inform the development of effective approaches to treatment of this too often lethal illness.

Project Summary/Abstract Psychosocial treatments for binge-eating disorder (BED) and bulimia nervosa (BN) have demonstrated efficacy in specialty settings, yet, most treatment for BED/BN occurs in outpatient settings with more limited resources. In response to RFA-MH-16-410, we propose to test the preliminary effectiveness of a couple-based intervention for BED/BN (UNiting couples In the Treatment of Eating disorders [UNITE]) relative to an established evidence-based individual treatment (cognitive-behavioral therapy-enhanced; CBT-E) in a community clinic setting. One strategy to bolster effectiveness is to activate resources in the patient?s environment (e.g., include partners in treatment). Unless partners understand BED/BN and how to be of assistance, relationships can be a stressor. Indeed, relationship stressors are common binge/purge triggers and adverse interpersonal environments contribute to illness maintenance. Individuals with BED/BN report high levels of relationship distress, negative interactions, and poor communication skills. Including a partner in treatment can transform the relationship from a stressor into an agent of positive change. We propose to augment effectiveness of BED/BN treatment by addressing interpersonal factors directly by including partners in treatment. We will test the preliminary effectiveness of UNITE in a small randomized controlled trial (RCT) of 28 adult patients and their partners (24 completing couples) in a community clinic. We hypothesize that results will yield evidence supporting enhanced outcomes in UNITE compared with CBT-E on the primary outcome of binge abstinence (and purge abstinence in BN) and other measures of psychopathology and general functioning, and significantly greater treatment satisfaction. Moreover, we propose that treatment gains will be achieved and maintained by engaging eating disorder-related relationship targets, including improved (T1) communication around BED/BN, (T2) problem-solving/behavioral change skills specific to BED/BN, and (T3) partner-assisted emotion regulation. Assessment will include observational and speech prosody measures during couples? clinic interactions and self-reports reflecting functioning outside of the clinic. The Data Monitoring Group will oversee recruitment, assessments, and human subject protections. If we demonstrate preliminary effectiveness and target engagement in a community clinic setting, we will plan a larger RCT isolating our relationship targets and, if effective, progress towards implementation science. Our ultimate is to expand the community clinician?s armamentarium for treating BED and BN and increase the available treatment options for individuals with these illnesses.

Project Summary We propose the Eating Disorders Genetics Initiative (EDGI) to rapidly and efficiently advance genomic discovery across the three major eating disorders (EDs) [AN (anorexia nervosa), BN (bulimia nervosa), and BED (binge-eating disorder)]. We propose a testable conceptualization of EDs as arising from a shared genetic vulnerability to a core trait (e.g., dysregulated appetite) that is further differentiated across clinical presentations of AN, BN, and/or BED by differing genetic predispositions to dimensional ED behaviors (e.g., binge eating, vomiting, excessive exercise), BMI, personality, comorbid psychopathology, physical activity, and metabolic traits. We propose that this palette of genetic risk is further influenced by environmental factors that affect emergence, course, and outcome of the ED. EDGI will empirically test and refine this model. Importantly, we will ascertain ancestrally diverse cases reflecting known epidemiological distributions of EDs. Using an efficient online ascertainment approach, EDGI will: (Aim 1) obtain deep phenotyping on course of illness, comorbid psychiatric conditions, treatment response, healthcare utilization, and quality of life on ~4000 participants in the Anorexia Nervosa Genetics Initiative (ANGI) from the US, Australia (AUS), and New Zealand (NZ); (Aim 2) ascertain, phenotype, and genotype 4500 new AN cases [(US, AUS, NZ, and Denmark (DK; identified in national records an genotypes from PKU cards from birth)]; ~5950 BN cases (US, AUS, NZ, DK); ~4050 BED cases (US, AUS, NZ) and 1500 controls; (Aim 3) conduct pre-planned genome-wide association studies (GWAS) for AN, BN, BED, any ED, and component behaviors, with external replications with Swedish and Icelandic data, plus a specific set of post-GWAS analyses; (Aim 4) apply advanced analytic strategies to test and refine our etiological model of EDs to explicate within-ED heterogeneity, explore the genetic relation between EDs and a broad array of psychiatric, metabolic, anthropometric, physical activity, educational phenotypes and the forces that shape those relationships, and preliminarily explore polygenic risk (PRS) x environmental interactions. EDGI represents the next logical step in ED genomics. Our scientific team recently completed ANGI, yielding compelling genetic findings for AN including the identification of 8 significant loci and intriguing genetic correlations with both psychiatric and metabolic traits strongly suggesting that AN is a metabo-psychiatric disorder. EDGI will expand to include BN and BED. Deliverables include: (a) rich phenotypic and genotypic data on large AN, BN, and BED samples; (b) clarification of the nature of genetic relationship among EDs and between EDs and other target traits; (c) an empirical model of ED risk and differentiation; (d) preliminary insight into how genes and environment interact in EDs; (e) sample and data deposit per current legal and regulatory standards and publicly available summary statistics. Our ultimate goal aligns with the Psychiatric Genomics Consortium (PGC) by delivering ?actionable? findings that will be transformable into biologically, clinically, and therapeutically meaningful insights on EDs.

PROJECT SUMMARY/ABSTRACT Bulimia nervosa (BN) and binge eating disorder (BED) are life-interrupting and associated with significant impairment. Via a unique opportunity that allowed us to adapt the widely used cognitive-behavioral based app Recovery Record for use on 1000 Apple Watches, we propose to optimize two domains of data being collected over a 30-day period in 1000 individuals with bulimia nervosa (BN) or binge-eating disorder (BED). This proposal augments a parent study [Binge Eating Genetics INitiative (BEGIN)], supported by NIMH (saliva kits for DNA at no cost). We will collect longitudinal passive sensor data via native applications in the Apple Watch and active data on binge-eating, purging, nutrition, mood, and cognitions using Recovery Record adapted for the Apple Watch. We will combine sensor-based measurements of autonomic nervous system (ANS) activity, actigraphy, and geolocation with active Recovery Record measures to characterize real world conditions under which individuals are more/less likely to binge and/or purge in their daily lives. Applying dynamical systems analytic approaches, both across and within individuals, we will identify stable, low-risk, and high-risk patterns that will enable the prediction of transition to high risk epochs that signal impending binge or purge episodes. Our work will provide an empirical foundation for transcending current cognitive- behavioral therapy approaches that are dependent on self-report (often retrospective) of high risk states, will enhance the understanding of eating disorders in terms of regulation, and will yield a personalized precision medicine approach to eating disorders treatment. Efficient and reliable quantitative characterization is the essential first step in the development of real-time interventions driven by automated recognition of individualized transitions into high-risk periods for disordered eating behaviors. Our aims are: 1) To predict the occurrence of binge eating and purging episodes in individuals with BN or BED with passive sensor data; 2) To test theoretically-derived regulatory models of binge eating and purging as reflected in differences in temporal patterns; and 3) To refine our capacity to predict high risk states by augmenting passive data with contextual factors collected by Recovery Record. This proposal optimizes the richness and longitudinal structure of the deep phenotypic data collected in BEGIN to lay the foundation for the next translational step in which we will develop personalized just-in-time interventions that can disrupt eating disorders behaviors in real time before they occur.

Project Summary Now in its 13th year, the Psychiatric Genomics Consortium is perhaps the most innovative and productive experiment in the history of psychiatry. The PGC unified the field and attracted a cadre of outstanding scientists (802 investigators from 157 institutions in 41 countries). PGC work has led to identification of ~500 genetic loci in the 11 psychiatric disorders we study. Our work has led to 320 papers, many in high-profile journals (Nature 3, Cell 5, Science 2, Nat Genet 27, Nat Neurosci 9, Mol Psych 37, Biol Psych 25). As summary statistics are freely available, psychiatric disorders often feature prominently in papers by non-PGC investigators. To advance discovery and impact, we propose to continue the work of the PGC across 11 disorder groups. Considerable new data are coming in the next five years. We thus can rapidly and efficiently increase our knowledge of the fundamental basis of major psychiatric disorders. Aim 1: we will continue to advance genetic discovery for severe psychiatric disorders in all working groups, systematically interface with large biobank studies to ensure maximal comparability, and aggressively promote new studies of individuals with psychiatric disorders from diverse ancestries to increase discovery and improve fine-mapping. Aim 2: most studies analyze common variation (Aim 1), rare CNV (Aim 2), and rare exome/genome resequencing results (via collaboration) in isolation: we will apply an integrative framework to rigorously evaluate the contributions of all measured types of genetic variation on risk for psychiatric disorders. Aim 3: we will move beyond classical case-control definitions to a more biologically-based and nuanced understanding by enabling large trans-diagnostic studies, convene trans-disciplinary teams to use genetics to address unresolved questions about the nature of psychiatric disorders, and to promote large studies of the severest cases seen in psychiatric practice (leveraging the global reach of PGC investigators). Aim 4: we will work to maximize the impact of our work via translational efforts: close collaborations with neuroscience consortia to understand the biological implications of our findings; work to identify modifiable causal risk factors; and work to robustly predict clinical outcomes and identify patient subsets. Aim 5: we will increase impact of our work by extending and formalizing outreach to different communities (including pharma and biotech), via digital media (Twitter, Facebook, Wikipedia), and by developing, distributing, and updating resources/educational material for patients, families, and medical professionals. We will convene a Scientific Advisory Board to ensure we respond positively to those invested in our results Successful completion of this body of work will greatly advance knowledge of the genetic basis of psychiatric disorders with potentially major nosological and treatment implications. These goals are consistent with a core mission of the NIMH, and the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights.