Computerized Adaptive Tests Detect Change Following Orthopaedic Surgery in Youth with Cerebral Palsy.

BACKGROUND: The Cerebral Palsy Computerized Adaptive Test (CP-CAT) is a parent-reported outcomes instrument for measuring lower and upper-extremity function, activity, and global health across impairment levels and a broad age range of children with cerebral palsy (CP). This study was performed to examine whether the Lower Extremity/Mobility (LE) CP-CAT detects change in mobility following orthopaedic surgery in children with CP. METHODS: This multicenter, longitudinal study involved administration of the LE CP-CAT, the Pediatric Outcomes Data Collection Instrument (PODCI) Transfer/Mobility and Sports/Physical Functioning domains, and the Timed Up & Go test (TUG) before and after elective orthopaedic surgery in a convenience sample of 255 children, four to twenty years of age, who had CP and a Gross Motor Function Classification System (GMFCS) level of I, II, or III. Standardized response means (SRMs) and 95% confidence intervals (CIs) were calculated for all measures at six, twelve, and twenty-four months following surgery. RESULTS: SRM estimates for the LE CP-CAT were significantly greater than the SRM estimates for the PODCI Transfer/Mobility domain at twelve months, the PODCI Sports/Physical Functioning domain at twelve months, and the TUG at twelve and twenty-four months. When the results for the children at GMFCS levels I, II, and III were grouped together, the improvements in function detected by the LE CP-CAT at twelve and twenty-four months were found to be greater than the changes detected by the PODCI Transfer/Mobility and Sports/Physical Functioning scales. The LE CP-CAT outperformed the PODCI scales for GMFCS levels I and III at both of these follow-up intervals; none of the scales performed well for patients with GMFCS level II. CONCLUSIONS: The results of this study showed that the LE CP-CAT displayed superior sensitivity to change than the PODCI and TUG scales after musculoskeletal surgery in children with CP

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Purpose We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks forBRCA1andBRCA2pathogenic variant carriers. Methods Retrospective cohort data on 18,935BRCA1and 12,339BRCA2female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results The ER-negative PRS showed the strongest association with BC risk forBRCA1carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33],P = 3x10(-72)). ForBRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36],P = 7x10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk forBRCA1(HR = 1.32 [95% CI 1.25-1.40],P = 3x10(-22)) andBRCA2(HR = 1.44 [95% CI 1.30-1.60],P = 4x10(-12)) carriers. The associations in the prospective cohort were similar. Conclusion Population-based PRS are strongly associated with BC and EOC risks forBRCA1/2carriers and predict substantial absolute risk differences for women at PRS distribution extremes.Peer reviewe

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Peer reviewe

Diagnosis and management of Cornelia de Lange syndrome:first international consensus statement

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning

Detecting functional change in response to exercise in knee osteoarthritis: a comparison of two computerized adaptive tests

Abstract Background The intent of this study was to examine and compare the ability to detect change of two patient reported outcome (PRO) instruments that use a computerized adaptive test (CAT) approach to measurement. The Patient Reported Outcomes Measurement Information System (PROMIS®) Physical Function scale is a generic PRO, while the Osteoarthritis Computerized Adaptive Test (OA-CAT) is an osteoarthritis-specific PRO. Methods This descriptive, longitudinal study was conducted in a community setting, involving individuals from the greater Boston area. Inclusion criteria: age > 50, self-reported doctor-diagnosed knee osteoarthritis (OA) and knee pain. The PROMIS® Physical Function CAT and OA-CAT Functional Difficulty scale were administered at baseline and at the conclusion of a 6-week exercise program. Effect sizes (ES) were calculated for both measures, and bootstrap methods were used to construct confidence intervals and to test for significant ES differences between the measures. Results The OA-CAT Functional Difficulty scale achieved an ES of 0.62 (0.43, 0.87) compared to the PROMIS® Physical Function CAT ES of 0.42 (0.24, 0.63). ES estimates for the two CAT measures were not statistically different. Conclusions The condition-specific OA-CAT and generic PROMIS® Physical Function CAT both demonstrated the ability to detect change in function. While the OA-CAT scale showed larger effect size, no statistically significant difference was found in the effect size estimates for the generic and condition-specific CATs. Both CATs have potential for use in arthritis research. Trial registration This trial is registered with ClinicalTrials.gov on 6/21/11 (Identifier NCT01394874