Navigating the Research-Clinical Interface in Genomic Medicine: Analysis From the CSER Consortium

Purpose: The Clinical Sequencing Exploratory Research (CSER) Consortium encompasses nine National Institutes of Health– funded U-award projects investigating translation of genomic sequencing into clinical care. Previous literature has distinguished norms and rules governing research versus clinical care. This is the first study to explore how genomics investigators describe and navigate the research–clinical interface. Methods: A CSER working group developed a 22-item survey. All nine U-award projects participated. Descriptive data were tabulated and qualitative analysis of text responses identified themes and characterizations of the research–clinical interface. Results: Survey responses described how studies approached the research–clinical interface, including in consent practices, recording results, and using a research versus clinical laboratory. Responses revealed four characterizations of the interface: clear separation between research and clinical care, interdigitation of the two with steps to maintain separation, a dynamic interface, and merging of the two. All survey respondents utilized at least two different characterizations. Although research has traditionally been differentiated from clinical care, respondents pointed to factors blurring the distinction and strategies to differentiate the domains. Conclusion: These results illustrate the difficulty in applying the traditional bifurcation of research versus clinical care to translational models of clinical research, including in genomics. Our results suggest new directions for ethics and oversight

Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk

<p>Abstract</p> <p>Background</p> <p>Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.</p> <p>Methods</p> <p>In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.</p> <p>Results</p> <p>Here, we have shown that the high enzymatic activity genotype of CCND1^High(AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMT^Medium(MetVal) and the high enzymatic activity of COMT^High(ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMT^High(ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: <b>2.22</b>, 95%CI (1.49–3.28)] and Finland [OR: <b>1.73</b>, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.</p> <p>Conclusion</p> <p>Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.</p

Public vs. Proprietary Science: A Fruitful Tension?

What should be public and what should be private in scientific research? The competitive sprint of public and private laboratories to complete the sequence of the human genome has brought this question to the fore. The same question frames the developing struggle over terms of access to human embryonic stem cell lines and the conflict between Microsoft and the open source movement over how best to promote software development. We expect such conflicts to become more widespread as the role of for-profit research expands in a broader range of scientific fields. Will science progress more swiftly and fruitfully if its findings are in the public domain, or if they may be captured as intellectual property? What kinds of research should be funded publicly and what kinds left for private financing? Is competition between public and private science stimulating and constructive, or is it wasteful and counterproductive? Our aim in this essay is to bring these issues into clearer view. They have been kept in the analytic shadows until recently by the presumption that science and technology are largely distinct enterprises. In fact, the problems arise in areas where science and technology overlap

Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario

<p>Abstract</p> <p>Background</p> <p>Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly <it>MLH1 </it>and <it>MSH2</it>, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population.</p> <p>Methods</p> <p>We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information.</p> <p>Results</p> <p>The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among <it>MLH1 </it>mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in <it>MSH2 </it>carriers (about 54%). The relative risk associated with <it>MLH1 </it>was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30–70), while the HR for <it>MSH2 </it>decreased with age (from 13.1 at age 30 to 5.4 at age 70).</p> <p>Conclusion</p> <p>This study provides a unique population-based study of CRC risks among <it>MSH2</it>/<it>MLH1 </it>mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families.</p

The efficacy of oral azithromycin in clearing ocular chlamydia: mathematical modeling from a community-randomized trachoma trial.

Mass oral azithromycin distributions have dramatically reduced the prevalence of the ocular strains of chlamydia that cause trachoma. Assessing efficacy of the antibiotic in an individual is important in planning trachoma elimination. However, the efficacy is difficult to estimate, because post-treatment laboratory testing may be complicated by nonviable organisms or reinfection. Here, we monitored ocular chlamydial infection twice a year in pre-school children in 32 communities as part of a cluster-randomized clinical trial in Tanzania (prevalence in children was lowered from 22.0% to 4.7% after 3-year of annual treatment). We used a mathematical transmission model to estimate the prevalence of infection immediately after treatment, and found the effective field efficacy of antibiotic in an individual to be 67.6% (95% CI: 56.5-75.1%) in this setting. Sensitivity analyses suggested that these results were not dependent on specific assumptions about the duration of infection. We found no evidence of decreased efficacy during the course of the trial. We estimated an 89% chance of elimination after 10 years of annual treatment with 95% coverage

Protocol of a randomized controlled trial of the Tobacco Tactics website for operating engineers

<p>Abstract</p> <p>Background</p> <p>Recent research indicates that 35 percent of blue-collar workers in the US currently smoke while only 20 percent of white-collar workers smoke. Over the last year, we have been working with heavy equipment operators, specifically the Local 324 Training Center of the International Union of Operating Engineers, to study the epidemiology of smoking, which is 29% compared to 21% among the general population. For the current study funded by the National Cancer Institute (1R21CA152247-01A1), we have developed the Tobacco Tactics website which will be compared to the state supported 1-800-QUIT-NOW telephone line. Outcome evaluation will compare those randomized to the Tobacco Tactics web-based intervention to those randomized to the 1-800-QUIT-NOW control condition on: a) 30-day and 6-month quit rates; b) cotinine levels; c) cigarettes smoked/day; d) number of quit attempts; and e) nicotine addiction. Process evaluation will compare the two groups on the: a) contacts with intervention; b) medications used; c) helpfulness of the nurse/coach; and d) willingness to recommend the intervention to others.</p> <p>Methods/Design</p> <p>This will be a randomized controlled trial (N = 184). Both interventions will be offered during regularly scheduled safety training at Local 324 Training Center of the International Union of Operating Engineers and both will include optional provision of over-the-counter nicotine replacement therapy and the same number of telephone contacts. However, the Tobacco Tactics website has graphics tailored to Operating Engineers, tailored cessation feedback from the website, and follow up nurse counseling offered by multimedia options including phone and/or email, and/or e-community. Primary Analysis of Aim 1 will be conducted by using logistic regression to compare smoking habits (e.g., quit rates) of those in the intervention arm to those in the control arm. Primary analyses for Aim 2 will compare process measures (e.g., medications used) between the two groups by linear, logistic, and Poisson regression.</p> <p>Discussion</p> <p>Dissemination of an efficacious work-site, web-based smoking cessation intervention has the potential to substantially impact cancer rates among this population. Based on the outcome of this smaller study, wider scale testing in conjunction with the International Environment Technology Testing Center which services Operating Engineers across North America (including US, Mexico, and Canada) will be conducted.</p> <p>Trial registration</p> <p>NCT01124110</p

Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014