David E. Sandberg - US grants

Studies on the influence of in utero and lactational exposure to hormone-modulating pollutants have largely been restricted to studies of cognitive development. Outcome variables in these investigations were not selected to be sensitive to the potential sex hormone-modulating effects of these substances. The proposed epidemiologic study assesses the behavioral sequelae of early developmental exposure to environmental toxicants on human behaviors that exhibit gender-related variation. The study design utilizes an established cohort of subjects (New York State Angler Cohort Study) assembled to assess the association between consumption of contaminated sport fish on both short- and long-term health effects in adults and their offspring. Reproductive outcome data including detailed abstraction of hospital delivery records for mothers who had consumed varying quantities of contaminated fish are available for 3,365 offspring born between 1986-91. The majority of children are now approaching middle childhood, making them old enough to assess a broad spectrum of behavioral sequelae. The study is to be conducted as a postal questionnaire survey in which a parent/guardian serves as an informant of the child's behavior. The behavioral domains targeted for study are those which exhibit gender related variation under normal circumstances, including gender-role behavior of childhood, specific learning disabilities, handedness, and patterns of psychopathologic symptoms. Information on maternal exposure of contaminated fish, long- term and during pregnancy is available to assess dose-response effects. This proposed questionnaire survey represents the initial stage of a long-term research plan involving in-depth developmental investigations including neuropsychological assessments, structured clinical interviews, and more in-depth exposure characterization of the offspring. Such an in-depth follow-up investigation will incorporate research methods adequate to simultaneously evaluate both biological and social-environmental explanations of behavioral sequelae. The overall goal of this pilot project is to assess the relationship between toxicant exposures (pre-and postnatal) and behavioral outcomes selected because they are susceptible to perturbation of sex hormone physiology at sensitive periods of the sexual differentiation process and at concentrations that are not maternally toxic.

DESCRIPTION (provided by applicant): The birth of a child with a Disorder of Sex Development (DSD or "intersexuality") can create a crisis for the newborn's family and healthcare professionals. Decisions about gender assignment, genital surgeries, and strategies to minimize stigma often are made quickly and under pressure. Clinical management of patients with DSDs, based primarily on studies of biological influences on psychosexual development, has become controversial. Recent anecdotal reports of harm to patients and calls for immediate changes in the model of care appear to be influencing practice;however, there are no measurement tools to evaluate the effects of these changes on patients'(or families') quality of life. Health-related quality of life (HRQoL) measures are well-suited to address this problem because they address the effects of a condition and its treatment on subjectively-experienced physical, social, and emotional functioning of the individual and family. The objective of this study is to develop validated parent-proxy report (Quality of Life Disorders of Sex Development Questionnaire, QoL-DSDQ) and parent self-report (Quality of Life Disorders of Sex Development Questionnaire-Parent/Caregiver, QoL-DSDQ-P/C) HRQoL questionnaires that focus on issues specific to, and shared by young patients with DSDs and their families, which are not otherwise covered by generic HRQoL measures. This objective fits with the NIH Roadmap for Medical Research that calls for developing methods to improve clinical outcomes assessment through creating sensitive and well-validated HRQoL outcome measures. The goal of Study I is to develop a parent proxy-report of the child's (ages 2 to 6 years) HRQoL and a parent self-report measure of the impact of the child's (newborn to 6 years) condition on parent/caregiver quality of life. Provisional questionnaire items, developed in a pilot study, will be revised and refined through cognitive interviews with 75 parents of 45 affected children (newborn to 6 years with the full range of DSD) identified through four US medical centers. The goal of Study II is to establish the reliability and validity of the new instruments in a demographically and geographically diverse sample comprising 249 parents of 150 affected children (newborn to 6 years) recruited from 12 medical centers across the US. This study will yield the largest, most representative HRQoL dataset on children with DSDs and their parents. Future research will extend this methodology to older patients with DSDs. PUBLIC HEALTH RELEVANCE: Development of the Quality of Life-Disorders of Sex Development Questionnaire (QoL-DSDQ;parent/caregiver proxy and self-report versions) will enable clinicians to: (1) identify specific areas of patient and family need;(2) measure the effects of medical and surgical interventions on patient/family functioning;(3) provide empirical evidence to guide clinical management;and (4) address gaps in understanding of the psychosocial and psychosexual development in patients with disorders of sex development (DSD). Development of the QoL- DSDQ will also inform theories of typical and atypical gender development among those born physically typical or with a DSD by establishing a better balance between biological factors (genetic and hormonal) and social- environmental experiences in early development which, together, shape the development of sex differences in human behavior.

DESCRIPTION (provided by applicant): Disorders of sex development (DSD) are phenotypically heterogeneous, ranging from minor genital malformations (hypospadias, cryptorchidism, hypertrophy of the clitoris) to genital ambiguity. In the aggregate, DSD have an estimated incidence of about 1%. DSD can result in severe consequences for behavioral health, fertility, cancer risk and quality of life. For families, the birth of a child with a DSD, and the accompanying uncertainty about future psychological and sexual development, is believed to be extraordinarily stressful. Recently, the debate over clinical management of DSD, in particular gender assignment and genital surgery, has intensified; yet the scientific data on patient outcomes have remained very incomplete. Major obstacles to optimal clinical management of DSD include gaps in understanding of pathophysiology, impeding precise diagnostic categorization, along with the absence of prospective longitudinal studies of health and quality of life outcomes. This proposal delivers a platform for hypothesis-based research on the mechanisms of sex development and evidence-based care for patients and families affected by DSD. Aim 1 identifies novel genetic mechanisms of sex development and improves understanding of the pathophysiology and molecular diagnosis of DSD by a step-wise approach of specific DNA capture and sequencing, analysis of copy number variants, and identification of novel candidate genes for DSD. Aim 2 delivers standardized tools for reliable phenotypic descriptions across multiple study sites and investigators, including radiological, biochemical, histological evaluations and descriptions of genital phenotype and post- surgical appearance and function, facilitating interpretation of genetic, gender, and quality of life outcomes Aim 3 identifies short and medium-term outcomes by delivering a comprehensive psychosocial and health-related quality of life assessment battery using psychometrically robust measures suitable for use in routine clinical care, a necessary step leading to evidence-based psychosocial treatment protocols. Aim 4 builds a sustainable research infrastructure and ensures rapid translation of new evidence into ongoing clinical practice by integrating standardized DSD diagnostic and treatment protocols and fostering the transfer of best practices in healthcare delivery across network sites. This registry provides the analytic platform by which data are collected, analyzed, and shared among researchers and sites, while a collaborative network will supply the foundation for multidisciplinary basic, clinical, and translational research. This unique combination of genetic, phenotypic and psychosocial approaches will transform participating sites into self-sustaining DSD centers of excellence for clinical care along with the added value of a registry serving as a critical resource for hypothesis-driven research.

PROJECT SUMMARY Differences (or Disorders) of Sex Development (DSD) is a superordinate term encompassing congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. Adopting an inclusive definition, between 1 in 200 to 1,000 people are born with some degree of atypical sex development. Clinical management of DSD is in a state of flux with disagreements within and between professional, advocacy, and patient communities regarding optimal care. Advances in molecular diagnosis and surgical techniques, findings regarding psychological outcomes in affected persons, and patient advocacy group engagement, led to a consensus conference attended by international experts in the DSD field and patient advocacy. Consensus recommendations included changes to diagnostic and clinical management strategies and in nomenclature that eliminated terms considered confusing and stigmatizing; e.g., ?intersex,? ?hermaphroditism,? ?pseudohermaphroditism,? and ?sex reversal.? While scientific and medical communities rapidly adopted the new nomenclature, vocal patient community elements strongly opposed the word ?disorder? - experiencing it as unnecessary pathologization of atypical bodies that contributes to the perceived need for potentially harmful surgical ?normalization? procedures. Some affected adults now prefer the term ?intersex? - referring to an identity, rather than a medical condition. Further, little agreement exists across provider, advocacy, and patient communities regarding what constitutes optimal care for patients and families. Clinical management topics triggering contentious debate include decision- making over gender of rearing, genital surgery and its timing, gonad removal, and disclosing diagnostic details to patients. Evidence of these controversies exists in medical literature, social media, and courts of law, yet a remarkable lack of discussion, much less consensus, exists on how stakeholders value various outcomes. There has yet to be a study designed to systematically examine how patients, parents, healthcare providers, and other stakeholders differentially define and value optimal DSD health care delivery. The proposed study has the following aims: (1) Assess the importance ascribed by stakeholders to DSD clinical management options (i.e., identify what constitutes a ?successful outcome?), both immediately and in the future; (2) Identify differential trade-off preferences (e.g., trade-offs between genital appearance, preserving fertility, sexual function, privacy, patient autonomy) and choice processes made by different stakeholder groups; (3) Design and pilot evidence-based curricula for stakeholders that clarify priorities, and integrate these with evidence to facilitate informed and shared decision-making. The proposed approach to understanding differential valuation of clinical management elements and developing data-driven curricula is potentially generalizable to other congenital or chronic conditions involving multidisciplinary care in which treatments are elective and dependent on patient/family values and preferences.

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to develop a longitudinal study of patterns of care and health outcomes among individuals who were diagnosed with disorders of sex development (DSD). We propose a study of DSD patients from three large integrated health care systems (HCS): Kaiser Permanente Southern California (KPSC), Kaiser Permanente Georgia (KPGA), and Kaiser Permanente Mid-Atlantic States (KPMAS). These HCS share similarly structured electronic medical records (EMRs) and represent a geographically, socio- economically, and demographically diverse population of nearly 5 million members. Most methods of data collection described in the current application have been successfully implemented in our recently completed or ongoing studies of transgender people. Applying these methods to the 2006-2015 data at the participating sites, we identified 19,233 patients with ?likely DSD? based on diagnoses or keywords in the medical records. In addition, 47,107 individuals were identified as having ?possible DSDs? (e.g., non-specified uterine anomalies or hypospadias). The proposed project will address three areas of importance in DSD research: 1) patterns and guideline-concordance of care; 2) controversies in treatment; and 3) comorbidities and long-term health outcomes. We will use validated EMR data to estimate the percentages of confirmed DSD patients who underwent diagnostic workup and received care according to current recommendations. We will examine whether guideline concordant DSD management is associated with health outcomes, such as the need for additional care and behavioral health problems later in life. The often cited area of disagreement is the optimal timing of sex assignment surgery in cases of atypical or ambiguous genitalia with some advocating early procedures and others arguing for a deferral. Another controversial issue is the common practice of a prophylactic gonadectomy for DSD patients whose karyotype includes Y-chromosome material (+Y DSD). We will use relevant KPSC, KPGA, and KPMA diagnostic and procedure codes to identify genital surgery and gonadectomies. Using these data we will assess the association between timing of gender assignment procedures and surgical complications, gender dysphoria, or other health problems later in life. We will also review pathology reports to estimate the frequency and determinants of ?positive gonadectomy,? i.e., with evidence of malignant or premalignant lesions. We will then compare measures of health status of DSD patients to the corresponding measures among age- and membership matched non-DSD male and non-DSD female HCS enrollees (reference cohort). We will examine the incidence and prevalence of comorbidities and long-term health outcomes across age groups, categories of DSD conditions, and relative to the matched reference cohort. The proposed project will be carried out by a multidisciplinary team that includes experts in DSD research and care, EMR-based data collection, epidemiology, and evaluation of health services.

PROJECT SUMMARY Disorders/Differences of Sex Development (DSD) is an umbrella term covering congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. DSD are phenotypically heterogeneous, ranging from genital malformations (hypospadias, cryptorchidism, clitoral hypertrophy) to genital ambiguity. DSD have a collective incidence of about 1% and can result in serious consequences for fertility, cancer risk and quality of life across the lifespan. Debate over clinical management, in particular gender assignment and genital or gonadal surgery, has intensified; yet scientific data informing best practices remain limited. Clinical care in DSD is hampered by a fragmented research agenda and lack of standardization, leaving fundamental gaps in knowledge of DSD pathology and links between treatment options and desired outcomes. Major obstacles include gaps in understanding of pathophysiology (impeding precise diagnostic categorization), the absence of prospective longitudinal studies of psychosocial outcomes, and the potential moderating influence of biomedical, psychosocial and legal factors on medical decision making. This project is the first of its kind, globally, to prospectively study the variable pathways from DSD diagnosis and clinical management to psychosocial adaptation. This goal will be accomplished by exploiting the infrastructure and robust collaboration of the DSD?Translational Research Network (DSD-TRN). The Network comprises a consortium of 12 interdisciplinary healthcare teams across the nation in conjunction with patient stakeholder and bioethics representation. Our guiding principle is that evidence-based standardization of diagnostic and treatment protocols will be associated with higher rates of definitively diagnosed DSD, reduced variation in clinical practice, enhanced patient/family healthcare-related experiences, and improved psychosocial outcomes for patients and their families. The proposed project will deliver evidence needed to raise the quality of healthcare in DSD to levels observed for other rare diseases. Specific aims include: 1. Genetics. Improving and expanding the molecular diagnosis of DSD; 2. Psychosocial. Identifying diagnostic, clinical care, and family risk and resilience factors associated with variability in psychological outcomes of patients with DSD and their families; 3. Determinants of clinical management. Identifying biomedical, legal, and psychosocial determinants of clinical management decisions.