Citations

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P < 10 −75 ), ARMS2 ( P < 10 −59 ), C2/CFB ( P < 10 −20 ), C3 ( P < 10 −9 ), and CFI ( P < 10 −6 ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 −11 ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 −7 ; CETP , P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 −3 ) and ABCA1 ( P = 5.6 × 10 −4 ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Purpose Patient adherence is critical in evaluating the effectiveness of an oral therapy. We sought to measure adherence among women randomly assigned to capecitabine in a preplanned substudy of a multicenter clinical trial. Patients and Methods Cancer and Leukemia Group B study CALGB 49907 was a randomly assigned trial comparing standard chemotherapy versus oral chemotherapy with capecitabine in patients age 65 years or older with early-stage breast cancer. We used microelectronic monitoring system (MEMS) caps on participants' capecitabine bottles to record pill bottle openings. Capecitabine was given in two divided daily doses for 14 consecutive days of a 21-day cycle for six cycles. Adherence was calculated as the number of doses taken divided by doses expected, taking into account toxicity-related dosing changes. A participant was defined as adherent if 80% or more of expected doses were recorded by MEMS. Results Overall, 161 patients were enrolled. Median age was 71 years (range, 65 to 89 years); 124 patients (83%) persisted with capecitabine to completion of planned protocol therapy. Adherence was 78% across all cycles, and adherence did not vary by cycle (P = .32). Twenty-five percent of participants took fewer than 80% of expected doses and were nonadherent. In a logistic regression model, participants with node-negative disease (P = .01) and mastectomy (P = .01) were more likely to be nonadherent. Adherence was not related to age, tumor stage, or hormone receptor status. Adherence was not significantly associated with relapse-free survival or grade 3 or 4 toxicity. Conclusion Most older women with early-stage breast cancer were adherent to short-term oral chemotherapy in a randomized clinical trial. Age was not associated with adherence.

Background Often in randomized controlled trials of cancer screening, cause of death is determined by a mortality review committee. However, little is known regarding how findings from mortality review compare to those from death certificates alone. Purpose To examine the results of four different U. S. trials of cancer screening when death certificate data only were used, as compared to results using all available mortality review information. Methods Trials included were the Health Insurance Plan of New York breast screening trial (HIP), the Minnesota trial of fecal occult blood testing, and the Johns Hopkins and Mayo Lung Projects, which each examined chest x-ray and sputum cytology. The sensitivity, specificity, positive and negative predictive values, and Cohen’s kappa for death certificates were calculated for all arms of all trials. Separate intention-to-screen analyses were conducted for each trial using cause of death information from either death certificates alone or full mortality review data. Results Generally there was excellent agreement between the death certificates and the mortality review committee as to the underlying cause of death (kappa >0.85 in all cases); death certificate agreement was similar between arms in all trials. Modest changes in the screening effectiveness estimates were observed when mortality review information was utilized, ranging from a 9% decrease to a 2% increase in the calculated mortality rate ratios. However, in one instance (HIP) a statistically significant benefit of screening was observed when mortality review committee data were used (rate ratio (RR) 0.77, 95% confidence interval (CI) 0.62— 0.95) but not when death certificate data were used (RR 0.82, 95% CI 0.65—1.03). Limitations Although considered to be the gold standard, even carefully conducted mortality review may result in errors in cause of death assignment. Conclusions For each trial, results were similar regardless of the source of cause of death information. Clinical Trials 2010; 7: 69—77. http://ctj.sagepub.com