The Invisible Hand in Clinical Research: The Study Coordinator's Critical Role in Human Subjects Protection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74962/1/j.1748-720X.2002.tb00410.x.pd

Newborn screening for cystic fibrosis: evaluation of benefits and risks and recommendations for state newborn screening programs

In November 2003, CDC and the Cystic Fibrosis Foundation cosponsored a workshop to review the benefits and risks associated with newborn screening for cystic fibrosis (CF). This report describes new research findings and outlines the recommendations of the workshop. The peer-reviewed evidence presented at the workshop supports the clinical utility of newborn screening for CF. Demonstrated long-term benefits from early nutritional treatment as a result of newborn screening for CF include improved growth and, in one study, cognitive development. Other benefits might include reduced hospitalizations and improved survival. Mixed evidence has been reported for pulmonary outcomes. Newborn screening in the United States is associated with diagnosis of CF a median of 1 year earlier than symptomatic detection, which might reduce the expense and anxiety associated with workup for failure to thrive or other symptoms. Certain psychosocial risks for carrier children and their families (e.g., anxiety and misunderstanding) are associated with newborn screening. Exposure of young children to infectious agents through person-to-person transmission in clinical settings, although not an inherent risk of newborn screening, is a potential cause of harm from early detection. Involving specialists in CF care and infection control, genetic counseling, and communication can minimize these potential harms. Although screening decisions depend on a state\u27s individual resources and priorities, on the basis of evidence of moderate benefits and low risk of harm, CDC believes that newborn screening for CF is justified. States should consider the magnitude of benefits and costs and the need to minimize risks through careful planning and implementation, including ongoing collection and evaluation of outcome data

Recommendations for ethical approaches to genotype-driven research recruitment

Recruiting research participants based on genetic information generated about them in a prior study is a potentially powerful way to study the functional significance of human genetic variation. However, it also presents significant ethical challenges that, to date, have received only minimal consideration. We convened a multi-disciplinary workshop to discuss key issues relevant to the conduct and oversight of genotype-driven recruitment and to translate those considerations into practical policy recommendations. Workshop participants were invited from around the U.S., and included genomic researchers and study coordinators, research participants, clinicians, bioethics scholars, experts in human research protections, and government representatives. Discussion was directed by experienced facilitators and informed by empirical data collected in a national survey of IRB chairs and in-depth interviews with research participants in studies where genotype-driven recontact occurred. A high degree of consensus was attained on the resulting 7 recommendations, which cover informed consent disclosures and choices, the process for how and by whom participants are recontacted, the disclosure of individual genetic research results, and the importance of tailoring approaches based on specific contextual factors. These recommendations are intended to represent a balanced approach—protecting research participants, yet avoiding overly restrictive policies that hinder advancement on important scientific questions

Is “incidental finding” the best term?: a study of patients’ preferences

There is debate within the genetics community about the optimal term to describe genetic variants unrelated to the test indication, but potentially important for health. Given the lack of consensus and the importance of adopting terminology that promotes effective clinical communication, we sought the opinion of clinical genetics patients

Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report

Newborn screening for cystic fibrosis offers the opportunity for early intervention and improved outcomes. This summary, resulting from a workshop sponsored by the Cystic Fibrosis Foundation to facilitate implementation of widespread high quality cystic fibrosis newborn screening, outlines the steps necessary for success based on the experience of existing programs. Planning should begin with a workgroup composed of those who will be responsible for the success of the local program, typically including the state newborn screening program director and cystic fibrosis care center directors. The workgroup must develop a screening algorithm based on program resources and goals including mechanisms available for sample collection, regional demographics, the spectrum of cystic fibrosis disease to be detected, and acceptable failure rates of the screen. The workgroup must also ensure that all necessary guidelines and resources for screening, diagnosis, and care be in place prior to cystic fibrosis newborn screening implementation. These include educational materials for parents and primary care providers; systems for screening and for providing diagnostic testing and counseling for screen-positive infants and their families; and protocols for care of this unique population. This summary explores the benefits and risks of various screening algorithms, including complex situations that can occur involving unclear diagnostic results, and provides guidelines and sample materials for state newborn screening programs to develop and implement high quality screening for cystic fibrosis

Patients' ratings of genetic conditions validate a taxonomy to simplify decisions about preconception carrier screening via genome sequencing

Advances in genome sequencing and gene discovery have created opportunities to efficiently assess more genetic conditions than ever before. Given the large number of conditions that can be screened, the implementation of expanded carrier screening using genome sequencing will require practical methods of simplifying decisions about the conditions for which patients want to be screened. One method to simplify decision making is to generate a taxonomy based on expert judgment. However, expert perceptions of condition attributes used to classify these conditions may differ from those used by patients. To understand whether expert and patient perceptions differ, we asked women who had received preconception genetic carrier screening in the last 3 years to fill out a survey to rate the attributes (predictability, controllability, visibility, and severity) of several autosomal recessive or X-linked genetic conditions. These conditions were classified into one of five taxonomy categories developed by subject experts (significantly shortened lifespan, serious medical problems, mild medical problems, unpredictable medical outcomes, and adult-onset conditions). A total of 193 women provided 739 usable ratings across 20 conditions. The mean ratings and correlations demonstrated that participants made distinctions across both attributes and categories. Aggregated mean attribute ratings across categories demonstrated logical consistency between the key features of each attribute and category, although participants perceived little difference between the mild and serious categories. This study provides empirical evidence for the validity of our proposed taxonomy, which will simplify patient decisions for results they would like to receive from preconception carrier screening via genome sequencing

Hyperhydration to Improve Kidney Outcomes in Children with Shiga Toxin-Producing E. coli Infection: A multinational embedded cluster crossover randomized trial (the HIKO STEC trial)

BACKGROUND: Shiga toxin-producing E. coli (STEC) infections affect children and adults worldwide, and treatment remain solely supportive. Up to 15-20% of children infected by high-risk STEC (i.e., E. coli that produce Shiga toxin 2) develop hemolytic anemia, thrombocytopenia, and kidney failure (i.e., hemolytic uremic syndrome (HUS)), over half of whom require acute dialysis and 3% die. Although no therapy is widely accepted as being able to prevent the development of HUS and its complications, several observational studies suggest that intravascular volume expansion (hyperhydration) may prevent end organ damage. A randomized trial is needed to confirm or refute this hypothesis. METHODS: We will conduct a pragmatic, embedded, cluster-randomized, crossover trial in 26 pediatric institutions to determine if hyperhydration, compared to conservative fluid management, improves outcomes in 1040 children with high-risk STEC infections. The primary outcome is major adverse kidney events within 30 days (MAKE30), a composite measure that includes death, initiation of new renal replacement therapy, or persistent kidney dysfunction. Secondary outcomes include life-threatening, extrarenal complications, and development of HUS. Pathway eligible children will be treated per institutional allocation to each pathway. In the hyperhydration pathway, all eligible children are hospitalized and administered 200% maintenance balanced crystalloid fluids up to targets of 10% weight gain and 20% reduction in hematocrit. Sites in the conservative fluid management pathway manage children as in- or outpatients, based on clinician preference, with the pathway focused on close laboratory monitoring, and maintenance of euvolemia. Based on historical data, we estimate that 10% of children in our conservative fluid management pathway will experience the primary outcome. With 26 clusters enrolling a mean of 40 patients each with an intraclass correlation coefficient of 0.11, we will have 90% power to detect a 5% absolute risk reduction. DISCUSSION: HUS is a devastating illness with no treatment options. This pragmatic study will determine if hyperhydration can reduce morbidity associated with HUS in children with high-risk STEC infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT05219110 . Registered on February 1, 2022