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Biomedical subjects

Sarah L Sawyer

Publications and source records attributed to Sarah L Sawyer.

6 recordsLinked to original sources
PubMed2025

Mainstreaming of clinical genetic testing: A conceptual framework.

PURPOSE: Demand for genetic testing is increasing across medicine, whereas the genetics workforce remains stable. In response, mainstreaming models are being introduced, in which nongeneticist clinicians are increasingly involved in the genetic testing pathway. Because a standardized approach would facilitate evaluation and optimal patient care, a unified framework is warranted. METHODS: Through a focus group with clinical genetics experts, a conceptual framework for the mainstreaming of clinical genetic testing is proposed. Through a consensus process, experts elucidated the steps in the diagnostic care pathway and defined a set of variables that influence which mainstreaming model is best suited to specific patient care scenarios. RESULTS: A total of 35 individuals representing 20 distinct clinical genetics services and all Canadian provinces participated in the development of the framework. The framework describes 4 generalizable mainstreaming models of care, each with varying levels of involvement of the clinical genetics service in the diagnostic care pathway. CONCLUSION: This framework will help guide clinical teams in the design and evaluation of mainstreaming efforts. It is critical that these programs are evaluated and shared in a standardized way so that we can implement strategies that allow optimal utilization of genetics resources and improve patient care.

Humans↗
PubMed2006

Nonsynonymous SNPs: validation characteristics, derived allele frequency patterns, and suggestive evidence for natural selection.

We experimentally investigated more than 1,200 entries in dbSNP that would change amino-acids (nsSNPs), using various subsets of DNA samples drawn from 18 global populations (approximately 1,000 subjects in total). First, we mined the data for any SNP features that correlated with a high validation rate. Useful predictors of valid SNPs included multiple submissions to dbSNP, having a dbSNP validation statement, and being present in a low number of ESTs. Together, these features improved validation rates by almost 10-fold. Higher-abundance SNPs (e.g., T/C variants) also validated more frequently. Second, we considered derived alleles and noted a considerably (approximately 10%) increased average derived allele frequency (DAF) in Europeans vs. Africans, plus a further increase in some other populations. This was not primarily due to an SNP ascertainment bias, nor to the effects of natural selection. Instead, it can be explained as a drift-based, progressive increase in DAF that occurs over many generations and becomes exaggerated during population bottlenecks. This observation could be used as the basis for novel DAF-based tests for comparing demographic histories. Finally, we considered individual marker patterns and identified 37 SNPs with allele frequency variance or FST values consistent with the effects of population-specific natural selection. Four particularly striking clusters of these markers were apparent, and three of these coincide with genes/regions from among only several dozen such domains previously suggested by others to carry signatures of selection.

Alleles↗
PubMed2005

Linkage disequilibrium patterns vary substantially among populations.

A major initiative to create a global human haplotype map has recently been launched as a tool to improve the efficiency of disease gene mapping. The 'HapMap' project will study common variants in depth in four (and to a lesser degree in up to 12) populations to catalogue haplotypes that are expected to be common to all populations. A hope of the 'HapMap' project is that much of the genome occurs in regions of limited diversity such that only a few of the SNPs in each region will capture the diversity and be relevant around the world. In order to explore the implications of studying only a limited number of populations, we have analyzed linkage disequilibrium (LD) patterns of three 175-320 kb genomic regions in 16 diverse populations with an emphasis on African and European populations. Analyses of these three genomic regions provide empiric demonstration of marked differences in frequencies of the same few haplotypes, resulting in differences in the amount of LD and very different sets of haplotype frequencies. These results highlight the distinction between the statistical concept of LD and the biological reality of haplotypes and their frequencies. The significant quantitative and qualitative variation in LD among populations, even for populations within a geographic region, emphasizes the importance of studying diverse populations in the HapMap project to assure broad applicability of the results.

Asian People↗
PubMed2004

Haplotype block structures show significant variation among populations.

Recent studies suggest that haplotypes tend to have block-like structures throughout the human genome. Several methods were proposed for haplotype block partitioning and for tagging single-nucleotide polymorphism (SNP) identification. In population genetics studies, several research groups compared block structures across human populations. However, the measures used to quantify population similarity are either less than satisfactory or nonexistent. In this article, we propose several similarity measures to facilitate the comparisons of haplotype structures, namely block boundaries and tagging SNPs, across populations. With these measures, we can more objectively compare haplotype block structures and tagging SNP sets between different populations. In addition, these measures allow us to compare the results of different methods for block partition and tagging SNP identification. When we applied these measures to a real data set on chromosome 10 in 16 worldwide populations, we found that in this genome region: 1) haplotype block boundaries vary among populations, with European and some African populations showing similar boundaries but other populations showing other patterns; 2) tagging SNP sets are generally similar for populations with similar haplotype block structures but differ if the block structures differ; and 3) all but one of the block finding methods we tested yield consistent results, although variations exist regarding consistency. Our tentative results show that at least in the genome region studied, it is unlikely that a common haplotype pattern exists for all human populations: many populations, even in the same geographical region, may have different haplotype patterns.

Chromosome Mapping↗
PubMed2003

Scoring insertion-deletion polymorphisms by dynamic allele-specific hybridization.

Genome variation provides researchers with thousands of markers with which to study human demographic history and phenotypes. Insertion-deletion (indel) polymorphism is an important and abundant form of human genome variation, and convenient methods for genotyping indels are therefore needed. Here we evaluate dynamic allele-specific hybridization (DASH) for its ability to score indels. Evaluation of six model indel DASH assays based on synthetic oligonucleotides showed that length differences of 1-5 bp were accurately scored. Only single probes were required to assay indels of 3-4 bp or less, while longer indels tended to require the use of both allele probes serially. The best results were obtained by central placing of the probe over the indel. Model study findings were confirmed by running indel DASH assays upon PCR-amplified targets representing four polymorphisms from Alzheimer's disease candidate genes APBB1 and LRP1. These indels were genotyped in a set of 121 patients and 156 controls. While no disease association was found, the data quality confirmed that DASH is a robust and useful procedure for genotyping indels of the size range typically found in the human genome.

Alleles↗