EXECUTIVE SUMMARYAn original evidence review examined screening and diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the subsequent outcomes in a population of newly diagnosed cases of colorectal cancer (CRC). This supplementary evidence review focuses on five issues of further interest to the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG), as summarized below. Clarifying how to define the clinical disorder-Lynchsyndrome. In this supplementary review, Lynch syndrome refers to individuals with a predisposition to CRC and certain other malignancies as a result of a germline mismatch repair (MMR) gene mutation-including those with an existing cancer and those who have not yet developed cancer. This definition allows planned analyses of clinical validity and utility to be more straightforward. Several recent editorials and publications recommend that the ambiguous term HNPCC be abandoned and that this clarified definition of Lynch syndrome should be used instead. Removing family history from consideration as a preliminary test.A previous evidence review showed that screening performance of both the Amsterdam and the Bethesda criteria to identify individuals with Lynch syndrome were highly heterogeneous, possibly due to differences among the populations tested. In a general population, Amsterdam criteria are associated with relatively low sensitivity (28 -45%), but high specificity (99%), whereas Bethesda criteria are associated with higher sensitivity (73-91%), but at the cost of lower specificity (82-77%). Neither provides the necessary high sensitivity/specificity in a reliable and consistent manner. There are also gaps in knowledge relating to the time required to collect family history, the consistency with which it is collected, and the accuracy of the information. Inadequate evidence was available to determine the distribution of mutations in the MMR genes, but the limited data suggest 32% will be in MLH1, 38% in MSH2, 14% in MSH6, and 15% in PMS2. Adequate evidence was available to estimate sensitivity (69%) and specificity (point estimate of 100%) for identifying Lynch syndrome using a specific mutation in the BRAF gene among those with absent IHC staining for MLH1. An alternative to BRAF mutation testing might be direct testing of MLH1 methylation status, but this was not evaluated. Benefits and harms to probands and relatives with Lynchsyndrome. Between 2 and 12 first-degree relatives of probands (newly diagnosed CRC cases with Lynch syndrome, or index cases) can be contacted, based on resources and methodology. There was adequate evidence to document uptake of counseling among these firstdegree relatives who were contacted (52%) and subsequently targeted for MMR gene mutation testing (95% however, may be subject to family history bias. The U.S. Multisociety Task Force on Colorectal Cancer recommends colonoscopy every 1 or 2 years for first-degree relatives of individuals diagnosed with Lynch syndrome, and uptake among this group is about 80%. Th...

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This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.

Objective-Calculate first and second trimester reference ranges and within-woman correlations for TSH, free T4, and thyroid antibodies.Study Design-Measure TSH, free T4, and thyroid antibodies in paired sera from 9,562 women in the FaSTER trial of Down syndrome screening.Results-Median first trimester TSH (1.05 mIU/L) is lower than second (1.23 mIU/L); and 98 th centile is higher (4.15 vs. 3.77 mIU/L). Within-woman paired TSH correlations are moderately strong (r 2 =0.64). Among women with first trimester TSH values above the 98 th centile, second trimester values are over the 95 th centile in 68%. Median first trimester free T4 values (1.10 ng/dL) are higher than second (1.01 ng/dL). Paired free T4 measurements correlate weakly (r 2 =0.23). Among women with first trimester free T4 values below the 2 nd centile, second trimester values are below the 5 th centile in 32%. Antibody measurements correlate strongly between trimesters (thyro-peroxidase r 2 =0.79, thyroglobulin r 2 =0.83).Conclusions-TSH and free T4 measurements require gestation-specific reference ranges.

In early pregnancy, a woman's centile TSH level appears to determine susceptibility to the TSH being suppressed at any given hCG level, suggesting that hCG itself may be the primary analyte responsible for stimulating the thyroid gland. hCG affects lower centile TSH values disproportionately.

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.

Purpose: Mutations in BRCA1 or BRCA2 genes increase breast cancer risk. Assuring reliability of information about these mutations is increasingly important to the health care community; mutation testing is becoming more widespread. We describe a methodology for assessing such information. Methods: Our approach integrates four interdependent epidemiologic parameters: (1) the probability of developing breast cancer, (2) the proportion of breast cancer cases with a BRCA1 or BRCA2 mutation, (3) the proportion of women that carries a mutation, and (4) the proportion of women with a mutation that develops cancer. We assess the plausibility of estimates of these parameters from published reports and commonly accessed information sources. Results: Assuming a fixed probability of developing breast cancer, the following estimates for the other three epidemiologic parameters are derived for women by age 70: 1% to 2% of all breast cancer cases are associated with a BRCA1 or BRCA2 mutation; 1 in 300 to 1 in 465 women carry a mutation; and 35 to 65% of mutation carriers develop breast cancer. Within these ranges, however, only selected combinations are plausible. The proportion of mutation-related breast cancer is lower than listed in some common information sources (1 to 2% vs 6%). Also, penetrance is somewhat lower and the carrier rate somewhat higher. Conclusions: The four epidemiologic parameters can be integrated to test their plausibility. BRCA1 and BRCA2 mutations are associated with only one-third as many breast cancer cases in the Guidelines have been developed to aid clinicians in deciding when to offer BRCA1 and BRCA2 mutation testing. 1-6 These guidelines recommend testing in specific circumstances, such as in women whose family history indicates an inherited predisposition to breast cancer. When a mutation is identified in an index case, cascade testing can be offered to other family members, thereby allowing primary prevention options to be considered. Implementation of BRCA1 and BRCA2 mutation testing by primary care providers has been sporadic and driven, in part, by direct-to-consumer advertising. [7][8][9][10][11] At least two information sources about BRCA1 and BRCA2 mutation testing have been developed for use by primary care providers in the United States. 12,13 In addition, two comprehensive reviews on BRCA1 and BRCA2 and hereditary breast cancer are available via internet access to health care providers, as well as the general public. 14,15 The data summarized by these sources are not always complete and/or consistent, either internally or with each other. These data are composed of three epidemiologic parameters: (1) the penetrance of BRCA1 and BRCA2 mutations, (2) the mutation carrier rate in the general population, and (3) the proportion of all breast cancer cases that is associated with a mutation. Almost all estimates quoted for each of these epidemiologic parameters are indirectly derived in the original studies. For example, there have been no published studies where a large population-based samp...

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.