Biomedical subjects

Rita McWilliams

Publications and source records attributed to Rita McWilliams.

4 recordsLinked to original sources

PubMed2006

Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis.

BACKGROUND & AIMS: Neonatal intestinal obstruction (meconium ileus [MI]) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and nongenetic modifiers to the development of this major complication of CF. METHODS: A total of 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage. RESULTS: Specific mutations in the CF transmembrane conductance regulator (CFTR), the gene responsible for CF, correlated with MI, indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (P = 1 x 10(-5)), showing that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (P = 8 x 10(-4)). Unlike MI, concordance analysis indicated that the risk for development of distal intestinal obstruction syndrome in CF patients is caused primarily by nongenetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene on chromosome 19 in a region previously linked to MI. CONCLUSIONS: The CFTR gene along with 2 or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, whereas intestinal obstruction in older CF patients is caused primarily by nongenetic factors.

Chromosomes, Human, Pair 11↗

PubMed2005

Increased prevalence of chronic rhinosinusitis in carriers of a cystic fibrosis mutation.

OBJECTIVE: To explore whether there is an increased prevalence of chronic rhinosinusitis (CRS) in known cystic fibrosis (CF) carriers. Self-reported CRS affects 13% to 14% of the US population and clusters in families, which suggests that genetic factors may play an etiologic role. Cystic fibrosis is an inherited recessive disorder that invariably affects the sinuses. The frequency of CF mutations has been reported to be higher in patients with CRS than in unaffected controls. PATIENTS: Obligate CF carriers (parents of patients with CF) were recruited from the Johns Hopkins CF clinic. The presence of signs and symptoms of CRS was assessed by a sinus disease questionnaire. A subgroup of participants was evaluated by a physician experienced in the diagnosis of CRS. RESULTS: Fifty-three (36%) of 147 obligate CF carriers who returned a completed questionnaire had self-reported CRS. Twenty-three CF carriers (14 with and 9 without CRS based on self-reporting in the questionnaire) were clinically evaluated. Seven were diagnosed as having CRS (all 7 with self-reported CRS), while another 6 had allergic rhinitis or recurrent acute rhinosinusitis (all 6 with self-reported CRS), and 10 had no evidence of active sinus disease (1 with self-reported CRS). The sensitivity (100%) and specificity (56%) of the questionnaire for physician-diagnosed CRS was similar to that of other survey instruments used to estimate the prevalence of self-reported CRS in the general population. CONCLUSION: Carriers of a single CF mutation have a higher prevalence of CRS than the general population.

Case-Control Studies↗

PubMed2003

Problematic variation in local institutional review of a multicenter genetic epidemiology study.

CONTEXT: Sequencing of the human genome provides an immense resource for studies correlating DNA variation and epidemiology. However, appropriately powered genetic epidemiology studies often require recruitment from multiple sites. OBJECTIVES: To document the burden imposed by review of multicenter studies and to determine the variability among local institutional review boards (IRBs) in the approval of a multicenter genetic epidemiology study. DESIGN: A PubMed search was performed to determine the frequency of citations of multicenter studies by 5-year intervals from 1974 through 2002. A 7-question survey was sent to all participating study centers to obtain information on frequency of IRB meetings, dates for submission and approval, use/nonuse of a specific consent form, type of review performed, types of consent forms required, preparation time, and number of changes requested by the IRB at each center. Centers also provided a copy of all consent forms they generated and IRB correspondence regarding the study. SETTING AND PARTICIPANTS: Thirty-one of 42 cystic fibrosis care centers in this single US multicenter genetic epidemiology study of cystic fibrosis replied, yielding a 74% response rate. MAIN OUTCOME MEASURES: Frequency of published research studies and consistency among IRBs. RESULTS: The number of all published single-center studies has increased 1.3-fold since 1985, while the number of published epidemiology and genetic epidemiology multicenter studies increased by 8- and 9-fold, respectively, during this same period. Evaluation of the risk of the same genetic epidemiology study by 31 IRBs ranged from minimal to high, resulting in 7 expedited reviews (23%) and 24 full reviews (77%). The number of consents required by the IRBs ranged from 1 to 4; 15 IRBs (48%) required 2 or more consents, while 10 (32%) did not require assent for children. The most common concern (52%) of IRBs pertained to the genetic aspects of the study. CONCLUSIONS: Review of a protocol for a multicenter genetic epidemiology study by local IRBs was highly variable. Lack of uniformity in the review process creates uneven human subjects protection and incurs considerable inefficiency. The need for reform, such as the proposed centralized review, is underscored by the ever increasing rate of genetic discoveries facilitated by the Human Genome Project and the unprecedented opportunity to assess the relevance of genetic variation to public health.

Cystic Fibrosis↗

PubMedDate not supplied

Concept paper: a virtual centralized IRB system.

CONTEXT: As the volume and complexity of research have increased, the amount of time spent on Institutional Review Board (IRB) review has decreased. The complexity of research has expanded, requiring increasingly specialized knowledge to review it. Dilemma: Under the current system, increasing numbers of research studies requiring expertise in ethics, new technologies or diverse study designs place a substantial burden upon local IRBs and often result in substantial variability among their reviews. This lack of uniformity in the review process creates uneven human subjects' protection thus undermining the intent of the Common Rule. OBJECTIVES: To outline a scenario for expert centralized IRB review via implementation of a national virtual IRB review system overseen by the Office for Human Research Protections (OHRP). CONCLUSIONS: The complicated ethical issues and science involved in much of current research warrant an expert review panel. Centralized review would enable expert review specific to the research at hand, ensure consistency in human subjects protection, reduce the burden on local IRBs, and may reduce time spent obtaining approval. A centralized virtual system would allow IRB members to remain at their institutions while providing unprecedented expert review through currently available technology, and make information regarding monitoring and adverse event reporting available online in real-time.

Clinical Trials as Topic↗