Last data update: May 20, 2024. (Total: 46824 publications since 2009)
Records 1-4 (of 4 Records) |
Query Trace: Bradley LA[original query] |
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Use of genomic profiling to assess risk for cardiovascular disease and identify individualized prevention strategies--a targeted evidence-based review.
Palomaki GE , Melillo S , Neveux L , Douglas MP , Dotson WD , Janssens AC , Balkite EA , Bradley LA . Genet Med 2010 12 (12) 772-84 PURPOSE: To address the key question of whether using available "cardiogenomic profiles" leads to improved health outcomes (e.g., reduction in rates of myocardial infarction and stroke) and whether these profiles help in making medical or personal decisions. METHODS: A targeted evidence-based review based on published Evaluation of Genomic Applications in Practice and Prevention methodologies. RESULTS: No study addressed the overarching question directly. Evidence for the analytic validity of genomic profiles was inadequate for most genes (scale: convincing, adequate, and inadequate), but based on gray data, the analytic sensitivity and specificity might be adequate. For the 29 candidate genes (58 separate associations reviewed), the credibility of evidence for clinical validity was weak (34 associations) to moderate (23 associations), based on limited evidence, potential biases, and/or variability between included studies. The association of 9p21 variants with heart disease had strong credibility with odds ratios of 0.80 (95% confidence interval: 0.77-0.82) and 1.25 (95% confidence interval: 1.21-1.30), respectively, for individuals with no, or two, at-risk alleles versus those with one at-risk allele. Using a multiplicative model, we combined information from 24 markers predicting heart disease and from 13 markers for stroke. The areas under the curves (64.7% and 55.2%, respectively), and overall screening performance (detection rates of 24% and 14% at a 10% false-positive rate, respectively) do not warrant use as stand-alone tests. CONCLUSION: Even if genomic markers were independent of traditional risk factors, reports indicate that cardiovascular disease risk reclassification would be small. Improvement in health could occur with earlier initiation or higher adherence to medical or behavioral interventions, but no prospective studies documented such improvements (clinical utility). |
Association between 9p21 genomic markers and heart disease: a meta-analysis.
Palomaki GE , Melillo S , Bradley LA . JAMA 2010 303 (7) 648-56 CONTEXT: Associations between chromosome 9p21 single-nucleotide polymorphisms (SNPs) and heart disease have been reported and replicated. If testing improves risk assessments using traditional factors, it may provide opportunities to improve public health. OBJECTIVES: To perform a targeted systematic review of published literature for effect size, heterogeneity, publication bias, and strength of evidence and to consider whether testing might provide clinical utility. DATA SOURCES: Electronic search via HuGE Navigator through January 2009 and review of reference lists from included articles. STUDY SELECTION: English-language articles that tested for 9p21 SNPs with coronary heart/artery disease or myocardial infarction as primary outcomes. Included articles also provided race, numbers of participants, and data to compute an odds ratio (OR). Articles were excluded if reporting only intermediate outcomes (eg, atherosclerosis) or if all participants had existing disease. Twenty-five articles were initially identified and 16 were included. A follow-up search identified 6 additional articles. DATA EXTRACTION: Independent extraction was performed by 2 reviewers and consensus was reached. Credibility of evidence was assessed using published Venice criteria. DATA SYNTHESIS: Forty-seven distinct data sets from the 22 articles were analyzed, including 35 872 cases and 95 837 controls. The summary OR for heart disease among individuals with 2 vs 1 at-risk alleles was 1.25 (95% confidence interval [CI], 1.21-1.29), with low to moderate heterogeneity. Age at disease diagnosis was a significant covariate, with ORs of 1.35 (95% CI, 1.30-1.40) for age 55 years or younger and 1.21 (95% CI, 1.16-1.25) for age 75 years or younger. For a 65-year-old man, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 13.2% vs 11%. For a 40-year-old woman, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 2.4% vs 2.0%. Nearly identical but inverse results were found when comparing 1 vs 0 at-risk alleles. Three studies showed net reclassification indexes ranging from -0.1% to 4.8%. CONCLUSION: We found a statistically significant association between 9p21 SNPs and heart disease that varied by age at disease onset, but the magnitude of the association was small. |
Outcomes of interest in evidence-based evaluations of genetic tests.
Botkin JR , Teutsch SM , Kaye CI , Hayes M , Haddow JE , Bradley LA , Szegda K , Dotson WD , EGAPP Working Group . Genet Med 2010 12 (4) 228-35 Genetic tests are increasingly available for use in traditional clinical practice settings and through direct-to-consumer marketing. The need for evidence-based information and guidance on their appropriate use has never been more apparent. The independent Working Group of the Evaluation of Genomic Applications in Practice and Prevention Initiative commissions evidence-based reviews and develops recommendations to inform decision making surrounding the implementation of genetic tests and other applications of genomic technologies into clinical practice. A critical component of this analysis involves the identification and appropriate weighting of relevant health outcomes from genetic testing. Impacts of testing on morbidity and mortality are central considerations although research to document such outcomes can be challenging to conduct. In considering the broader impacts of genetic tests on the individual, familial and societal levels, psychosocial outcomes often take on increasing importance, and their systematic evaluation is a challenge for traditional methods of evidence-based review. Incorporating these types of outcomes in evidence-based processes is possible, however, and necessary to extract balanced and complete (or as complete as available data will allow) information on potential benefits and on potential harms. The framework used by the Evaluation of Genomic Applications in Practice and Prevention Working Group in considering, categorizing, and weighting health-related outcomes as applied to genomic technologies is presented here. |
Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review.
Palomaki GE , Bradley LA , Douglas MP , Kolor K , Dotson WD . Genet Med 2009 11 (1) 21-34 This evidence-based review addresses the question of whether testing for UGT1A1 mutations in patients with metastatic colorectal cancer treated with irinotecan leads to improvement in outcomes (e.g., irinotecan toxicity, response to treatment, morbidity, and mortality), when compared with no testing. No studies were identified that addressed this question directly. The quality of evidence on the analytic validity of current UGT1A1 genetic testing methods is adequate (scale: convincing, adequate, inadequate), with available data indicating that both analytic sensitivity and specificity for the common genotypes are high. For clinical validity, the quality of evidence is adequate for studies reporting concentration of the active form of irinotecan (SN-38), presence of severe diarrhea, and presence of severe neutropenia stratified by UGT1A1 common genotypes. The strongest association for a clinical endpoint is for severe neutropenia. Patients homozygous for the *28 allele are 3.5 times more likely to develop severe neutropenia compared with individuals with the wild genotype (risk ratio 3.51; 95% confidence interval 2.03-6.07). The proposed clinical utility of UGT1A1 genotyping would be derived from a reduction in drug-related adverse reactions (benefits) while at the same time avoiding declines in tumor response rate and increases in morbidity/mortality (harms). At least three treatment options for reducing this increased risk have been suggested: modification of the irinotecan regime (e.g., reduce initial dose), use of other drugs, and/or pretreatment with colony-stimulating factors. However, we found no prospective studies that examined these options, particularly whether a reduced dose of irinotecan results in a reduced rate of adverse drug events. This is a major gap in knowledge. Although the quality of evidence on clinical utility is inadequate, two of three reviewed studies (and one published since our initial selection of studies for review) found that individuals homozygous for the *28 allele had improved survival. Three reviewed studies found statistically significant higher tumor response rates among individuals homozygous for the *28 allele. We found little or no direct evidence to assess the benefits and harms of modifying irinotecan regimens for patients with colorectal cancer based on their UGT1A1 genotype; however, results of our preliminary modeling of prevalence, acceptance, and effectiveness indicate that reducing the dose would need to be highly effective to have benefits outweigh harms. An alternative is to increase irinotecan dose among wild-type individuals to improve tumor response with minimal increases in adverse drug events. Given the large number of colorectal cancer cases diagnosed each year, a randomized controlled trial of the effects of irinotecan dose modifications in patients with colorectal cancer based on their UGT1A1 genotype is feasible and could clarify the tradeoffs between possible reductions in severe neutropenia and improved tumor response and/or survival in patients with various UGT1A1 genotypes. |
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