Showing papers by "Muin J. Khoury published in 2005"

How many genes underlie the occurrence of common complex diseases in the population

Abstract: Conclusions Our results suggest that a limited number of disease susceptibility genes with common variants can explain a major proportion of common complex diseases in the population. Our findings should help focus the search for common genetic variants that provide the most important predispositions to complex human diseases.

Do We Need Genomic Research for the Prevention of Common Diseases with Environmental Causes

Abstract: Concerns have been raised about the value of genomic research for prevention and public health, especially for complex diseases with risk factors that are amenable to environmental modification. Given that gene-environment interactions underlie almost all human diseases, the public health significance of genomic research on common diseases with modifiable environmental risks is based not necessarily on finding new genetic "causes" but on improving existing approaches to identifying and modifying environmental risk factors to better prevent and treat disease. Such applied genomic research for environmentally caused diseases is important, because 1) it could help stratify disease risks and differentiate interventions for achieving population health benefits; 2) it could help identify new environmental risk factors for disease or help confirm suspected environmental risk factors; and 3) it could aid our understanding of disease occurrence in terms of transmission, natural history, severity, etiologic heterogeneity, and targets for intervention at the population level. While genomics is still in its infancy, opportunities exist for developing, testing, and applying the tools of genomics to clinical and public health research, especially for conditions with known or suspected environmental causes. This research is likely to lead to population-wide health promotion and disease prevention efforts, not only to interventions targeted according to genetic susceptibility.

A Network of Investigator Networks in Human Genome Epidemiology

Abstract: The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; offer methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort. Copyright

Genomics and the prevention and control of common chronic diseases: emerging priorities for public health action.

Abstract: The completion of the Human Genome Project in 2003 continues to raise expectations on near-term applications of human genome discoveries in personalized disease prevention, especially in the area of common chronic diseases (1,2). In fact, almost daily we are confronted with stories of scientific discoveries of human genetic variants that are suggested to affect our risks for one or more of the major common chronic diseases. (See Table 1 for an illustrative sample of news stories published online during December 2004 [3].) Yet the immediate significance of most of these discoveries remains elusive. Despite the scientific excitement and the predictions for personalized prevention and drug treatment, the promise of human gene discovery for health promotion and disease prevention is yet to be fulfilled (4). Table 1 Examples of News Stories on Human Genome Discoveries Relevant to Common Chronic Diseasesa Increasingly, public health practitioners from academic, government, and other organizations have taken a proactive leadership role in assessing the relevance of this technology to population health and to community-based interventions (a new field often referred to as public health genetics, or genomics) (5). This issue of Preventing Chronic Disease contains several articles illustrating various processes developed and applied by schools of public health and state health departments to evaluate the role of genomics and its relevance to the prevention of chronic diseases in the population (6-11). Johnson et al (6) demonstrate the feasibility and success of using family history as a simple genomic tool to inform and motivate high-risk families to make long-term lifestyle behavior changes for preventing a variety of chronic diseases. Annis et al (7) show that existing population-based databases contain valuable genomic information and can serve as a reliable source for chronic disease program recommendations for early detection, prevention, and risk assessment. Irwin et al (8) examine the genomic content of state Comprehensive Cancer Control programs and show that many states have genomic components in their written plans. Importantly, about 67% of programs that included family history in their plans have already begun implementing their stated goals. Harrison et al (9) describe a process for synthesizing genomics information and for sharing knowledge and lessons learned. Novel educational approaches, such as the one presented by Theisen et al (10), and innovative training tools, such as those highlighted by Bodzin et al (11), will be crucial in efforts to provide continuing education for the public and health care professionals. A central theme in all of these papers is the importance of family history as a tool for chronic disease prevention and health promotion.

The epidemiologic approach to pharmacogenomics.

Abstract: The epidemiologic approach enables the systematic evaluation of potential improvements in the safety and efficacy of drug treatment which might result from targeting treatment on the basis of genomic information. The main epidemiologic designs are the randomized control trial, the cohort study, and the case-control study, and derivatives of these proposed for investigating gene-environment interactions. However, no one design is ideal for every situation, and methodological issues, notably selection bias, information bias, confounding and chance, all play a part in determining which study design is best for a given situation. There is also a need to employ a range of different designs to establish a portfolio of evidence about specific gene-drug interactions. In view of the complexity of gene-drug interactions, pooling of data across studies is likely to be needed in order to have adequate statistical power to test hypotheses. We suggest that there may be opportunities (i) to exploit samples from trials already completed to investigate possible gene-drug interactions; (ii) to consider the use of the case-only design nested within randomized controlled trials as a possible means of reducing genotyping costs when dichotomous outcomes are being investigated; and (iii) to make use of population-based disease registries that can be linked with tissue samples, treatment information and death records, to investigate gene-treatment interactions in survival.

Family History Assessment to Detect Increased Risk for Colorectal Cancer: Conceptual Considerations and a Preliminary Economic Analysis

Abstract: Background: Although the rationale for earlier screening of persons with a family history of colorectal cancer is plausible, there is no direct evidence that earlier assessment is either effective or cost-effective. Objective: To estimate the clinical and economic effect of using family history assessment to identify persons for colorectal cancer screening before age 50. Methods: We developed a decision model to compare costs and outcomes for two scenarios: ( a ) standard population screening starting at age 50; ( b ) family history assessment at age 40, followed by screening colonoscopy at age 40 for those with a suggestive family history of colorectal cancer. The analysis was conducted using the health insurer perspective. Results: Using U.S. population estimates, 22 million would be eligible for family history assessment, and one million would be eligible for early colonoscopy; 2,834 invasive cancers would be detected, and 29,331 life years would be gained. The initial program cost would be $900 million. The discounted cost per life year gained of family history assessment versus no assessment equals $58,228. The results were most sensitive to the life expectancy benefit from earlier screening, the cost of colonoscopy, and the relative risk of colon cancer in those with a family history. Conclusions: The cost-effectiveness of family history assessment for colorectal cancer approaches that of other widely accepted technologies; yet, the results are sensitive to several assumptions where better data are needed. Because of the relatively high prevalence of family history in the population, careful analysis and empirical data are needed.

The journey to personalized medicine

Abstract: During the Renaissance, the realization that the sun, and not the earth, was the center of our solar system helped lead to a re-evaluation of man’s role in the universe. The engraving in Figure 1 has been interpreted by some as representing a medieval astronomer breaking through the prevailing earth-centric-bound thinking in order to peer at the workings of the Ptolemaic universe beyond. While this re-evaluation moved man from an inaccurate, but perhaps more comfortable, belief that the world revolved around the earth to understanding that man and the earth were far less significant, the discovery also stimulated a hope that a better understanding of science would improve the human condition. Moving into the 21st century, the completion of the Human Genome Project has ushered in a similarly hopeful feeling that advances in genomics will rearrange our view of medicine and health in a way equally profound as that experienced during the Renaissance. In the last century, the science of medicine has made great strides in reducing human suffering, developing a wide armamentarium of antibiotics and medications for acute and chronic infections and diseases, and vaccines that helped eradicate a major disease (smallpox) and reduced the toll of many others (such as polio and measles). However, while these advances helped highlight the importance of a scientific approach to human disease, the end of the century also brought substantial concerns over the future and the feasibility of the continued advancement of medical science. Antibiotic resistance became particularly worrisome, accorded in large part to the widespread and perhaps indiscriminate use of antibiotics. A number of highly touted drugs (including the cyclooxygenase-2 [COX-2] inhibitors and the 5-hydroxytryptamine 3 [5-HT3] receptor antagonists) were brought to market and warmly embraced by a public looking for relief from painful and debilitating illnesses, only to be withdrawn due to concerns over their safety profile. Similarly, the rhesus rotavirus vaccine had been under development for over 10 years and shown to be effective against rotavirus, a diarrheal disease that kills close to 1 million children each year worldwide. Shortly after introduction, however, the vaccine was withdrawn from the US market because of concerns over its association with intussusception, a form of bowel obstruction in young children.