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

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel

Group recommended a panel of mutations and variants that should be tested to determine carrier status within the CFTR gene as a part of population screening programs.1,2 This was initially done in response to the recommendations of an NIH CF Consensus Conference that CF carrier screening be consid-ered by all couples for use before conception or prenatally.3 At that time, the Working Group recognized limitations in our understanding of the population frequencies of several CF al-leles and proposed to review mutation distribution data after the first two years of the program. In 2002, as part of an ongo-ing effort to ensure that the cystic fibrosis carrier screening programs are current with respect to the scientific literature and other available data and practices, we initiated a second review of data on the distribution of mutations in different ethnic groups and we began to assess whether providers wer

TSH and FT4 reference interval recommendations and prevalence of gestational thyroid dysfunction: quantification of current diagnostic approaches

Context Guidelines recommend use of population- and trimester-specific TSH and FT4 reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. Methods We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using non-pregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. Results The study population comprised 52,496 participants from 18 cohorts. Compared to the use of trimester-specific reference intervals, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction and non-pregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. Conclusion Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable over- and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy