Donald B. Bailey - US grants

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. The typical male has an IQ of 50 to 55. Some are severely affected (low IQ, nonverbal), while others are mildly affected (mild intellectual disabiliy, can read, very sociable). Females are generally less affected than males but have an even broader range in function. A few females have severe intellectual and adaptive impairments, but most have a normal or borderline intellectual ability; about one-third have mild cognitive impairment. This wide range in cognitive ability almost certainly leads to variable ability to make choices and live independently. This application focuses on a particular form of choice making-decisional capacity-the ability to make a meaningful decision about whether to participate in research. Individuals with FXS have served as participants in research studies for more than 30 years. For the most part, this research has been relatively noninvasive, limited to parent surveys and neuropsychological or psycho-educational assessments. Some studies have drawn blood, collected saliva, measured heart rate, or used neuroimaging, but until recently there has been a paucity of treatment research. This scenario has changed dramatically in the last 3 years. Advances in understanding the molecular basis of FXS have led to a new generation of targeted treatment approaches, and clinical trials are underway using a variety of compounds. The possibility of side effects and the potential for significant changes in behavior and learning abilty elevate to a new level the importance of obtaining meaningful consent. Researchers and IRB members need data to help guide decisions about involving individuals with FXS in the consent process. Only a few studies have investigated decisional capacity of individuals with intellectual and developmental disabilities, and none have studied individuals with FXS. Virtually nothing is known about the extent to which individuals with FXS are involved in decisions about research participation, and no studies have investigated decisional capacity in FXS. This project will assess the range of decisional capacity in FXS, identify factors associated with variability in decisional capacity, and develop and evaluate a tablet-based decision aid to assist in obtaining informed consent. The study team includes experts in FXS, human research protection professionals, specialists in developing materials for informed decision making, a leading researcher in FXS clinical trials, and researchers who have developed and evaluated gold-standard measures for characterizing decisional capacity. The study will provide important information about the nature of decisional capacity in FXS and will provide guidance for researchers, IRB members, and pharmaceutical companies seeking to include individuals with FXS as study participants. PUBLIC HEALTH RELEVANCE: This project will be the first to study the ability of individuals with fragile X syndrome to provide informed consent to participate in research. Given the advent of clinical trials and treatment possibilities for these individuals, understanding their decisiona capacity will be important for researchers, clinicians, IRB members, and pharmaceutical companies. This project will assess the range of decisional capacity in FXS, identify factors associated with variability in decisional capacity, and develop and evaluate a tablet-based decision aid to assist in obtaining informed consent.

PROJECT SUMMARY/ABSTRACT Newborn screening (NBS) is designed for pre-symptomatic identification of serious conditions for which there are effective treatments that must begin early. Central to NBS policy is evidence that pre-symptomatic treatment is more effective than treatment after symptoms appear. Unfortunately, such evidence is difficult to amass because most nominated conditions are rare and the effort required to identify pre-symptomatic infants for clinical trials is substantial. Researchers and advocates find themselves in a classic ?Catch 22? situation?NBS cannot happen without sufficient evidence, but gathering this evidence necessarily requires large-scale population screening. This problem is such a formidable barrier to translational research that many disorders will never have the evidence needed to justify inclusion in NBS programs. We propose to develop and implement Early Check?a research program in which voluntary screening for a panel of conditions is offered on a statewide basis. Early Check would allow rapid screening for new candidate conditions, advance understanding of early disease, and facilitate registry and clinical trial recruitment. We will build and implement an experimental research program with an ongoing evaluation component in which we revise and improve the program as we learn from our implementation experiences and engagement with the general public and families directly affected by screening. Once we have finalized all aspects of the program, we will offer screening for a gradually expanding set of conditions to all 120,000 birthing families per year in North Carolina. Our first condition offered for screening will be spinal muscular atrophy, a life-threatening degenerative motor neuron disorder. We will determine participation rates; conduct screening; return results; provide counseling and clinical services; support families in caregiving decisions; inform families of ongoing clinical trials; provide support for families in deciding whether they want to participate in a clinical trial; and follow children and families over time to study benefits, harms, and psychosocial outcomes of screening. We will seek external funds to expand Early Check to other candidate disorders, such as fragile X syndrome. Implementation data will be used to refine the process, inform replication, and establish an infrastructure for testing other candidate conditions. To achieve long-term viability, we will develop a model of public-private partnerships based on collaborative engagement with federal agencies, foundations, patient advocacy groups, and industry.

PROJECT SUMMARY/ABSTRACT The extensive outbreak of Zika and its devastating impact on infants exposed in utero have left many vulnerable families facing the long-term implications of raising a child with potentially severe and limiting disabilities. Although there has been international focus on the Zika outbreak, an urgent need for longitudinal surveillance of affected infants and families remains. Through a partnership between researchers at RTI International and the Altino Ventura Foundation (FAV), we have an unprecedented opportunity to study the natural history of congenital Zika syndrome (CZS), long-term sequela, and factors associated with child and family outcomes. We will enroll 240 infants with CZS and their families in a comprehensive, longitudinal study of early childhood development, health, functional abilities, and family adaptation. This study has the potential to increase knowledge about the short- and long-term needs of these families; promote collaborative efforts to support families; and improve understanding of the prognosis, mediators/moderators, and treatment possibilities for individuals affected by CZS. Further, we will use the study as a platform to train investigators at FAV and build capacity for collaborative research beyond the initial funding period.