A Rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to informwarfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding,”

Purpose: Summarize evidence regarding genetic testing in adults to inform warfarin dosing to reduce adverse drug events such as serious bleeding. Methods: Review published (and selected gray) literature using the Rapid-ACCE structure that addresses analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications. Results: Preliminary data suggest overall analytic sensitivity and specificity will be 98% or higher for CYP2C9 genotyping, but strength of evidence for analytic validity is low, especially for VKORC1 testing. Strength of evidence is high for the clinical validity of both genes in predicting stable warfarin dose, an intermediate outcome, but is low for the association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (95% CI 32-60%); specificity 69% (95% CI 62-75%) and absent for bleeding events associated with VKORC1 testing. No data are available to document clinical utility of genotyping before warfarin dosing. Conclusions: The most important gaps identified are: which variants should be included in a testing panel, lack of data from external proficiency testing, lack of validated dosing algorithm incorporating genetic and nongenetic factors, evidence of clinical utility, reliable economic analyses, and methods to address several ethical, legal, and social implications issues. Genet Med 2008:10(2):89 -98

National Survey of Providers Treating Patients with Metabolic Disorders Identified by Newborn Screening Demonstrates Challenges Faced by Clinical Care Systems

Objectives. To evaluate care processes for infants who are identified by newborn screening (NBS) and diagnosed with metabolic disorders during their first year of life. Methods. A survey instrument was used to assess the scope and intensity of services needed to provide quality health care for patients from birth to 1 year of age who have a metabolic disorder identified by NBS. Significance testing was not performed; descriptive analyses are reported. Results. Providers spend significant amounts of time on activities that are not direct patient care. The most challenging aspect of their work was the lack of reimbursement for care. Conclusion. Provision of genetics services for patients with a metabolic disorder is time and labor intensive, and insurance coverage and reimbursement for these services remain inadequate. Health care payment and/or system reform is necessary to provide optimal care to patients with metabolic disorders identified by NBS

Critical congenital heart disease newborn screening implementation: lessons learned

Introduction The purpose of this article is to present the collective experiences of six federally-funded critical congenital heart disease (CCHD) newborn screening implementation projects to assist federal and state policy makers and public health to implement CCHD screening. Methods A qualitative assessment and summary from six demonstration project grantees and other state representatives involved in the implementation of CCHD screening programs are presented in the following areas: legislation, provider and family education, screening algorithms and interpretation, data collection and quality improvement, telemedicine, home and rural births, and neonatal intensive care unit populations. Results The most common challenges to implementation include: lack of uniform legislative and statutory mandates for screening programs, lack of funding/resources, difficulty in screening algorithm interpretation, limited availability of pediatric echocardiography, and integrating data collection and reporting with existing newborn screening systems. Identified solutions include: programs should consider integrating third party insurers and other partners early in the legislative/statutory process; development of visual tools and language modification to assist in the interpretation of algorithms, training programs for adult sonographers to perform neonatal echocardiography, building upon existing newborn screening systems, and using automated data transfer mechanisms. Discussion Continued and expanded surveillance, research, prevention and education efforts are needed to inform screening programs, with an aim to reduce morbidity, mortality and other adverse consequences for individuals and families affected by CCHD

Diagnosis, testing, treatment, and outcomes among patients with advanced non‐small cell lung cancer in the United States

Abstract Introduction Characteristics of patients in clinical trials may differ from those of real‐world patients. Our objective was to describe biomarker testing and outcomes among patients with advanced non‐small cell lung cancer (aNSCLC) in a real‐world setting. Methods This retrospective cohort study included patients ≥18 years old, diagnosed with stage IIIB/C or IV NSCLC, and in the TEMPUS oncology dataset from January 1, 2012, to December 31, 2020. Patient characteristics associated with biomarker testing were evaluated in patients with positive biomarkers using univariate logistic regression models. Cox proportional hazard models were used to estimate median survival. Results Of 9540 patients included, 41.7% had biomarker testing, and 2158 had a positive biomarker result. Men (vs women; odds ratio [OR], 0.82; 95% CI: 0.74–0.91), Black patients (vs White; OR, 0.83; 95% CI: 0.72–0.97), patients with squamous (OR, 0.22; 95% CI: 0.19–0.25) or unknown histology (OR, 0.53; 95% CI: 0.45–0.61) (vs non‐squamous histology), and patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2+ (OR, 0.69; 95% CI: 0.57–0.84) or missing (OR, 0.56; 95% CI: 0.48–0.66) (vs ECOG PS of 0) were less likely to undergo biomarker testing. Patients with positive biomarkers who received NCCN‐recommended treatment options (55.7%) had significantly longer median overall survival (OS) (hazard ratio [HR], 0.84; 95% CI: 0.75–0.95) and real‐world progression‐free survival (rwPFS) (HR, 0.68; 95% CI: 0.62–0.75). Conclusion More than 50% of patients were untested for biomarkers. Patients who were less likely to be tested included men, Black patients, current smokers, patients with squamous aNSCLC, and patients with an ECOG PS of 2+. Patients with positive biomarkers who received NCCN‐recommended treatment options had significantly longer OS and PFS

Mutation detection in the ABCC6 gene and genotype–phenotype analysis in a large international case series affected by pseudoxanthoma elasticum

Background: Pseudoxanthoma elasticum ( PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 ( ATP binding cassette family C member 6) gene, which encodes MRP6 ( multidrug resistance- associated protein 6). Objective: To investigate the mutation spectrum of ABCC6 and possible genotype - phenotype correlations. Methods: Mutation data were collected on an international case series of 270 patients with PXE ( 239 probands, 31 affected family members). A denaturing high- performance liquid chromatography- based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype - phenotype correlations were assessed. Results: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23 29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. Conclusions: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored