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 (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): 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): 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.

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 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 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.