Secretary's Advisory Committee Research Articles

Research in athletes with sickle cell trait: just do it

the sickle cell trait (SCT) genotype, a condition found in an estimated 300 million people worldwide and 8–9% of African Americans is characterized by the heterozygous inheritance of a single defective beta globin gene. Inherited in the homozygous form, the beta globin gene mutation leads to

Strategies for Implementing Screening for Critical Congenital Heart Disease

Although newborn screening for critical congenital heart disease (CCHD) was recommended by the US Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children to promote early detection, it was deemed by the Secretary of the HHS as not ready for adoption pending an implementation plan from HHS agencies. To develop strategies for the implementation of safe, effective, and efficient screening. A work group was convened with members selected by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children, the American Academy of Pediatrics, the American College of Cardiology Foundation, and the American Heart Association. On the basis of published and unpublished data, the work group made recommendations for a standardized approach to screening and diagnostic follow-up. Key issues for future research and evaluation were identified. The work-group members found sufficient evidence to begin screening for low blood oxygen saturation through the use of pulse-oximetry monitoring to detect CCHD in well-infant and intermediate care nurseries. Research is needed regarding screening in special populations (eg, at high altitude) and to evaluate service infrastructure and delivery strategies (eg, telemedicine) for nurseries without on-site echocardiography. Public health agencies will have an important role in quality assurance and surveillance. Central to the effectiveness of screening will be the development of a national technical assistance center to coordinate implementation and evaluation of newborn screening for CCHD.

The Road to Universal Pulse-Oximetry Screening: Are We There Yet?

Congenital heart disease is the most common birth defect and represents nearly 40% of all deaths caused by congenital anomalies.1 Critical congenital heart disease (CCHD), which encompasses the more severe forms, is present in 2.5 to 3 in 1000 live births.2 In general, prenatal ultrasound or physical examination alone can easily miss newborns with CCHD.3,4 Failure to diagnose CCHD early in life can result in high morbidity and mortality rates, because symptoms frequently present after closing of the pulmonary ductus arteriosus, after nursery discharge. Pulse-oximetry screening is a low-cost, painless, noninvasive test that increases the ability to identify newborns with CCHD before they clinically decompensate.5,–,8 In 2009 the American Heart Association and American Academy of Pediatrics published a scientific statement regarding the role of pulse oximetry in examining newborns for CCHD.9 Despite presenting strong support for this method, they stopped shy of recommending universal screening and called for further studies on implementation. In September 2010, the US Department of Health and Human Services (HHS) Secretary's Advisory Committee on Heritable Disorders in Newborns and Children recommended that CCHD be added to the uniform screening panel. However, … Address correspondence to Sandra Cuzzi, MD, Division of Hospitalist Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, DC 20010. E-mail: scuzzi{at}childrensnational.org

Coming soon: NIH genetic test registry

Coming soon: NIH genetic test registry

Health disparities and health equity: the issue is justice.

Eliminating health disparities is a Healthy People goal. Given the diverse and sometimes broad definitions of health disparities commonly used, a subcommittee convened by the Secretary's Advisory Committee for Healthy People 2020 proposed an operational definition for use in developing objectives and targets, determining resource allocation priorities, and assessing progress. Based on that subcommittee's work, we propose that health disparities are systematic, plausibly avoidable health differences adversely affecting socially disadvantaged groups; they may reflect social disadvantage, but causality need not be established. This definition, grounded in ethical and human rights principles, focuses on the subset of health differences reflecting social injustice, distinguishing health disparities from other health differences also warranting concerted attention, and from health differences in general. We explain the definition, its underlying concepts, the challenges it addresses, and the rationale for applying it to United States public health policy.

Newborn screening policy development: The Secretary's Advisory Committee on heritable disorders in newborns and children

Newborn screening policy development: The Secretary's Advisory Committee on heritable disorders in newborns and children

Impact of gene patents and licensing practices on access to genetic testing and carrier screening for Tay-Sachs and Canavan disease

Genetic testing for Tay-Sachs and Canavan disease is particularly important for Ashkenazi Jews, because both conditions are more frequent in that population. This comparative case study was possible because of different patenting and licensing practices. The role of DNA testing differs between Tay-Sachs and Canavan diseases. The first-line screening test for Tay-Sachs remains an enzyme activity test rather than genotyping. Genotyping is used for preimplantation diagnosis and confirmatory testing. In contrast, DNA-based testing is the basis for Canavan screening and diagnosis. The HEXA gene for Tay-Sachs was cloned at the National Institutes of Health, and the gene was patented but has not been licensed. The ASPA gene for Canavan disease was cloned and patented by Miami Children's Hospital. Miami Children's Hospital did not inform family members and patient groups that had contributed to the gene discovery that it was applying for a patent, and pursued restrictive licensing practices when a patent issued in 1997. This led to intense controversy, litigation, and a sealed, nonpublic 2003 settlement that apparently allowed for nonexclusive licensing. A survey of laboratories revealed a possible price premium for ASPA testing, with per-unit costs higher than for other genetic tests in the Secretary's Advisory Committee on Genetics, Health, and Society case studies. The main conclusion from comparing genetic testing for Tay-Sachs and Canavan diseases, however, is that patenting and licensing conducted without communication with patients and advocates cause mistrust and can lead to controversy and litigation, a negative model to contrast with the positive model of patenting and licensing for genetic testing of cystic fibrosis.

A New Horizon for Newborn Screening

MANY OF US remember a time when mental retardation (MR) affected significant numbers of children and adults. Before the 1960s, phenylketonuria (PKU) and several other preventable causes of developmental delay severely disabled thousands of children each year. Brosco, Mattingly, and Sanders (2006) reported that between 1950 and 2000, detection and treatment programs for seven conditions associated withMR (congenital syphilis, Rh hemolytic disease of newborns, measles, Haemophilus influenzae B meningitis, congenital hypothyroidism, PKU, and congenital rubella syndrome) reduced their prevalence from 16.5% to 0.005% as causes of MR in the United States. Although this is an impressive drop, Brosco et al. noted that these conditions represent only a small part of the overall prevalence of MR today. Nevertheless, this valuable review affirms the direction taken in the 1960s, led by President Kennedy with the establishment of federal programs using the findings of scientific research to ameliorate disease and disability. In 2005, the American Academy of Pediatrics supported a report from the American College of Medical Genetics recommending that state newborn screening programs adopt testing for a basic panel of 29 congenital conditions (many of them rare metabolic disorders) with the addition of 25 treatable conditions, all detectable using tandem mass spectrometry, a technology capable of rapidly and cheaply screening hundreds of dried blood spots available since the 1990s (American Academy of Pediatrics Newborn Screening Authoring Committee, 2008). This report was also endorsed by the U.S. Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children, and over the past few years, nearly all the states have instituted expanded newborn screening aimed at finding and treating affected

Public Health Goals for Persons With Disabilities: Looking Ahead to 2020

Much of this article first appeared as testimony of Dr. Iezzoni before the U.S. Senate Health, Education, Labor, and Pensions Committee, Washington, DC, January 27, 2009. Dr. Iezzoni serves on the Secretary's Advisory Committee on National Health Promotion and Disease Prevention Objectives for 2020. This article represents her personal views and not the views of the committee.

Secretary's Advisory Committee on Genetics, Health, and Society—Public Consultation Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests (Draft Report for Public Comment) [excerpts

Biotechnology Law ReportVol. 28, No. 3 DOCUMENTSSecretary's Advisory Committee on Genetics, Health, and Society—Public Consultation Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests (Draft Report for Public Comment) [excerpts]Published Online:1 Aug 2009https://doi.org/10.1089/blr.2009.9956AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byShould We Change EU Law to Disallow DNA Patents?SSRN Electronic JournalDoes IP Need IP? Accommodating Intellectual Production Outside the Intellectual Property ParadigmSSRN Electronic Journal Volume 28Issue 3Jun 2009 Information© 2009 Mary Ann Liebert, Inc.To cite this article:Secretary's Advisory Committee on Genetics, Health, and Society—Public Consultation Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests (Draft Report for Public Comment) [excerpts].Biotechnology Law Report.Jun 2009.417-442.http://doi.org/10.1089/blr.2009.9956Published in Volume: 28 Issue 3: August 1, 2009PDF download

Every Child Is Priceless: Debating Effective Newborn Screening Policy

To the Editor: Ethics, Evidence, and Cost in Newborn Screening, by Mary Ann Baily and Thomas H. Murray, and Expanding Newborn Screening: Process, Policy and Priorities, by Virginia Moyer, Ned A. Calonge, Steven M. Teutsch, and Jeffrey Botkin (May-June 2008) raise significant questions, but I will identify only a few that to me appear most important. Baily and Murray are very critical of the decision-making process reflected in the report issued by the American College of Medical Genetics, but some of their comments suggest that they have not carefully reviewed the report, which is over three hundred pages. For example, although the experts who drafted this report felt that benefit from newborn screening should be considered more expansively, all of the conditions recommended by the ACMG report for the core panel are serious conditions, and all are judged to benefit from specific, traditional treatments. No condition was added because of the expanded benefit espoused in the group's recommendations. In reaching these conclusions, the broadly based panel reviewed what published information exists (due to the rarity of the conditions), as well as expert opinions. It is particularly unfortunate that these authors have singled out the expansion of the excellent newborn screening panel in Mississippi and positioned this discussion in a fashion that could suggest that this expansion might have been related to the increase in infant mortality because scarce resources have been allocated to newborn screening. Baily and Murray's review of the very complex cost accounting of newborn screening is not enlightening. One cannot put a price the life of an infant saved by early identification and treatment of MCADD deficiency. Infants with other illnesses who are not identified as newborns and become seriously ill prior to diagnosis are commonly hospitalized and generate enormous expenses for treatment. And although not well documented, the long-term follow-up treatments of diagnosed children are probably similar to the costs of repeated hospitalizations of undiagnosed infants under treatment--excepting, of course, those who die early without treatment. Baily and Murray bring up the often-discussed issue of children who may even be harmed by unnecessary interventions. However, those of us in the field have long felt that there is little evidence of serious harm to infants who are unnecessarily treated. A recent article in Pediatrics (Jeffrey P. Brosco et al., Adverse Medical Outcomes of Early Newborn Screening Programs for Phenylketonuria, July 2008) substantiates this opinion. The authors further fail to recognize that even at the time they wrote their article, the newborn screening panels had already been brought closer into harmony with the panel suggested in the ACMG's report, which was also recommended by the Secretary's Advisory Committee Hereditary Disorders in Newborns and Children, as well as the American Academy of Pediatrics. There is a line of thinking that holds that we should not begin newborn screening until all of the pieces of our health care system are in place. I certainly agree that we should strive for this goal, but in our current health care environment, requiring this would mean that we provide essentially no preventive health care. I personally object strenuously to Baily and Murray's suggestion that families play too large a role in advancing newborn screening. We all agree that such programs should be based the best evidence of benefit, but no group has a greater right and responsibility to work behalf of children with these serious conditions than their families, who know firsthand both the burden and the benefits. I find the article by Moyer and colleagues surprising since it is presented on behalf of the United States Preventive Services Task Force. The federal mission statement says that the Agency for Healthcare Research and Quality supports health services research initiatives that seek to improve the quality of health care in America. …

Gene patents and personalized medicine - what lies ahead?

Gene patents have generally not impeded biomedical research, but some problems that arise in genetic diagnostics can be attributed to exclusively licensed gene patents. Gene patents for therapeutics have often been litigated but have received surprisingly little public outcry. In stark contrast, genetic diagnostics have been highly controversial but rarely litigated: no case has gone to trial and there is little case law to guide policy. Most recently the Secretary's Advisory Committee for Genetics Health and Society (SACGHS) released a draft report examining how patenting and licensing affect access to clinical genetic testing in the US. The SACGHS reported that patents neither greatly hindered nor facilitated patient access to genetic testing; both the harms and the benefits of patents on genetic diagnostics have been exaggerated. Problems do occur when patents are exclusively licensed to a single provider and no alternative is available. Courts have been changing the thresholds for what can be patented, and how strongly patents can be enforced. Technologies for sequencing, genotyping and gene expression profiling promise to guide clinical decisions in managing common chronic diseases and infectious diseases, and will likely be an integral part of personalized medicine. Developing such genomic tests may require mapping a complex intellectual property landscape and cutting through thickets of patented DNA sequences and related methods. Our preliminary studies have found patent claims that, if strictly enforced, might block the use of multi-gene tests or full-genome sequence data. Yet new technologies promise to reduce the costs of complete genomic sequencing to prices that are comparable to current genetic tests for a single condition. Courts, companies, and policy makers seem unlikely to allow intellectual property to obstruct such technological advance, but prudent policy will depend on careful analysis and foresight. The SACGHS report signals that the US government is paying attention, and increases the odds that policy will foster socially beneficial uses of genetic testing while preserving intellectual property incentives and mitigating the problems that arise from legal monopolies.

Analysis: Secretary's Advisory Committee on Genetics, Health, and Society Report falls short

On April 30, 2008, the Secretary's Advisory Committee on Genetics, Health, and Society released its Report, "US System of oversight of genetic testing: a response to the charge of the Secretary of HHS." Positive features of this Report include recommendations for increased funding for the development and characterization of reference materials and methods; enhanced support for the growth and improvement of public reference sequence databases; encouragement for the implementation of electronic medical records; promotion of the efforts of clinical utility-oriented study groups such as the Evaluation of Genomic Applications in Practice and Prevention Working Group; and enforcement of the prohibitions against clinical testing by laboratories that lack Clinical Laboratory Improvement Amendments certification. The Committee reaffirmed recommendations set forth in its publication, "Coverage and reimbursement of genetic tests and services," that would expand Medicare coverage and increase payment rates for appropriately performed genetic tests. However, in its Report, the Secretary's Advisory Committee on Genetics, Health, and Society used an overly broad definition of genetic testing that is neither scientifically sound nor practically workable. This definition led to the Committee's inability to distinguish genetic tests from other complex laboratory assays. The Report has fallen short by unnecessarily advocating for Food and Drug Administration review of all laboratory developed tests and proposing the creation of a mandatory registry for all clinical laboratory tests.

US system of oversight for genetic testing: a report from the Secretary's Advisory Committee on Genetics, Health and Society.

As genetic testing technology is integrated into healthcare, increasingly detailed information about individual and population genetic variation is available to patients and providers. Health professionals use genetic testing to diagnose or assess the risk of disease in individuals, families and populations and to guide healthcare decisions. Consumers are beginning to explore personalized genomic services in an effort to learn more about their risk for common diseases. Scientific and technological advances in genetic testing, as with any newly introduced medical technology, present certain challenges to existing frameworks of oversight. In addition, the growing use of genetic testing will require a significant investment in evidence-based assessments to understand the validity and utility of these tests in clinical and personal decisionmaking. To optimize the use of genetic testing in healthcare, all sectors of the oversight system need to be strengthened and yet remain flexible in order to adapt to advances that will inevitably increase the range of genetic tests and methodologies.

Newborn Screening for Cystic Fibrosis: A Lesson in Public Health Disparities

In the US, Newborn screening (NBS) for cystic fibrosis (CF) has rapidly expanded since the Secretary's Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children1 voted to recommend to the Secretary of the Department of Health and Human Services the uniform NBS panel proposed by the American College of Medical Genetics (ACMG)/Health Resources and Services Administration (HRSA) committee.2 The decision to include CF as one of the 29 core conditions in the uniform panel was strengthened by data presented at a CDC workshop in 2003.

Human Research Protections: Time for Regulatory Reform?

Ever greater numbers of us will be asked at some point in our lives to participate in a research study. We might be invited to participate in surveys and focus groups, asked to let researchers conduct studies with our tissue or medical information, or recruited for clinical trials that test whether drugs, medical devices, or biologics--like vaccines and genetic materials--are safe or effective. One company involved in recruiting human subjects estimated that the number of participants needed to fill industry-sponsored trials grew from 2.8 million in 1999 to 19.8 million in 2005. (1) There is also a growing need for children, the elderly, and people with certain diseases to enroll in studies that test interventions targeted to those populations. The very fact that record numbers of people are being recruited for research makes thoughtful attention to how we safeguard human subjects of the utmost importance. On top of that, though, there are problems with the current regulatory system. Some requirements may be overprotective and excessively bureaucratic. And yet there are also gaps that may leave many research participants without adequate protection. Some of the gaps exist because regulations have not kept pace with recent developments, such as stem cell and other biotech research, and the globalization of clinical trials. Increasing numbers of American-based trials are being conducted abroad, and participants in those trials may be less well protected than participants in trials conducted domestically. There are also gaps in the empirical data about the research enterprise, including such basic information as the number of adults and children who enroll in trials. Other gaps are caused by disagreements about the extent to which research with humans should be regulated. Thus, there are no specific rules for research with persons who are cognitively impaired, even though several advisory bodies have recommended them, and there are significant exceptions to the requirements for informed consent and prior approval of studies. Today these exceptions are widely accepted, yet there have been and continue to be dissenters. As Robert Veatch has noted, researchers often wanted to pursue research unhindered, and the authors of the regulations listened. (2) Many commentators are now calling for regulatory reform, and the Department of Health and Human Services' Secretary's Advisory Committee for Human Research Protections is considering whether changes are needed and where. The challenge is to start from the solid foundation of ethical principles and to identify both the regulatory gaps that should be filled and the regulatory overburden that does not meaningfully protect research participants. The Foundations Until the late twentieth century, research with humans was not subject to federal regulations. Informal scientific norms guided researchers as to whether and how they should conduct experiments with humans. The medical norm to do no harm and the notion of the virtuous researcher justified the scientific community's preference for self-regulation and its resistance to government oversight. In the 1970s, Congress enacted legislation that resulted in limited federal regulation in response to the public outcry over several unethical research studies. Scientists had conducted research on children and sick adults without obtaining consent or under coercive circumstances. The United States Public Health Service's Tuskegee Syphilis Study was perhaps the best known of these studies. Today, regulations issued by the Department of Health and Human Services and the Food and Drug Administration spell out the rules researchers must follow when conducting human studies. Although the DHHS regulations apply only to federally funded studies, many institutions conducting federally sponsored human research apply the DHHS rules to all of their research with humans, regardless of the source of funding. …

Screening and Caring for Children with Rare Disorders

Newborn screening is a public health program that identifies genetic, metabolic, hormonal, and functional disorders in infants and provides comprehensive follow-up care. Without these disorders can result in devastating health consequences, and sometimes death. Newborn screening began in the mid-1960s, but has dramatically expanded in recent years. This is primarily due to new technology to reliably identify rare disorders, and to a 2005 report by the American College of Medical Genetics, commissioned by the United States Health Resources and Services Administration, that recommended mandatory newborn screening for a core panel of twenty-nine disorders. This report moves toward a national uniform newborn screening panel for serious disorders that have effective preventive interventions and treatments. It was enthusiastically endorsed by the Secretary's Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children, the American Academy of Pediatrics, and the March of Dimes. Two articles in this issue criticize the process of decisionmaking and the criteria for inclusion of disorders in the ACMG report and argue that resources spent on newborn screening might be better spent on other child health initiatives. The ACMG process for developing the recommended panel of tests was the creation of a multidisciplinary committee and solicitation of broad expert opinion. Its criteria for including a disorder were: identification of the disorder before symptoms occur through a sensitive, specific test performed shortly after birth; and of early detection, timely intervention, and treatment. These criteria seem consistent with the ethics of mandatory newborn screening debated over the last forty years. Reasonable people may disagree on the definition of demonstrated benefit and efficacious treatment, but the ACMG group took those concerns quite seriously. Since the report's release, forty-two states--acting on the judgments of advisory committees comprised of health experts and community members--have adopted screening panels that include at least twenty-one of the twenty-nine core disorders. Critics argue that expert opinion is not enough to determine public health practice, and that only evidence-based data are sufficient to set screening standards. However, the threshold for evidence-based public health practice for screening for rare diseases is intrinsically different from evidence-based clinical practice, and from the approach applied to screening common chronic conditions like cancer or diabetes. …

Defining purpose: a key step in genetic test evaluation

The introduction of new genetic tests, like other medical innovations, can be conceptualized as a three-step process. Tests are proposed for use based on research findings and clinical reasoning; an evaluation occurs; and judgments are made about clinical use and reimbursement (Fig. 1). The evaluation may be informal, as when a clinician determines whether a new test will be helpful in a particular patient encounter, or formal, as when a practice guideline panel utilizes a defined methodology to assess a test or a health care funder utilizes a set of criteria to determine test coverage. Although genetic tests are often described in terms of technology, a full evaluation requires that the test be considered as a clinical process in which the laboratory assay, or other testing procedure, is done to acquire information about a particular health condition, in a defined population, for a specific clinical purpose.1 Genetic tests have a wide range of health care applications. They are used to confirm the presence of a genetic condition, identify reproductive risks, and select preventive therapy. Testing occurs in newborn screening programs and in primary, specialty, and prenatal care, and may be initiated on the basis of clinical symptoms, family history, or population demographics. Genetic tests also utilize a range of technologies, and vary considerably in their predictive value. This diversity poses a challenge for the evaluation process. Several groups have considered methods for genetic test evaluation,2–5 and model programs for systematic evaluation have been established in the United States (Evaluation of Genomic Applications in Practice and Prevention6) and the UK (the UK Genetic Testing Network7). To date, however, the evaluation process has not fully addressed the clinical diversity of genetic tests. The Evaluation of Genomic Applications in Practice and Prevention project has focused on genetic tests related to common disorders and drug therapy, whereas the United Kingdom Genetic Testing Network has primarily addressed tests for single gene disorders. An effort by the Secretary’s Advisory Committee on Genetic Testing to categorize genetic tests into those requiring higher versus lower levels of scrutiny was not successful.8 To address the challenge of genetic test diversity, we propose an outcome-orientated taxonomy for defining test purpose. A focus on health outcomes allows the definition of a small and informative set of purposes for genetic testing, despite the range of technologies and clinical settings in which testing occurs. Defining test purpose in turn clarifies the benefits to be expected from the testing process, and provides guidance to clinicians and policy makers concerning the evidence needed to support test use. Defining test purpose, therefore, is an important first step in genetic test evaluation.

Determining Risk in Pediatric Research with No Prospect of Direct Benefit: Time for a National Consensus on the Interpretation of Federal Regulations

United States federal regulations for pediatric research with no prospect of direct benefit restrict institutional review board (IRB) approval to procedures presenting: 1) no more than “minimal risk” (§ 45CFR46.404); or 2) no more than a “minor increase over minimal risk” if the research is commensurate with the subjects' previous or expected experiences and intended to gain vitally important information about the child's disorder or condition (§ 45CFR46.406) (DHHS 2001). During the 25 years since their adoption, these regulations have helped IRBs balance subject protections with the pursuit of scientific knowledge to advance children's welfare. At the same time, inconsistency in IRB application of these regulations to pediatric protocols has been widespread, in part because of the ambiguity of the regulatory language. During the past decade, three federally-charged committees have addressed these ambiguities: 1) the National Human Research Protections Advisory Committee (NHRPAC) (Washington, DC), 2) the Institute of Medicine (IOM) Committee on the Ethical Conduct of Clinical Research Involving Children (Washington, DC); and 3) the United States Department of Health and Human Services Secretary's Advisory Committee for Human Research Protections (SACHRP) (Washington, DC). The committees have reached similar conclusions on interpretation of language within regulations § § 45CFR46.404 and 406; these conclusions are remarkably consistent with recent international recommendations and those of the original National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) report from which current regulations are based. Drawing on the committees' public reports, this article identifies the ethical issues posed by ambiguities in regulatory language, summarizes the committees' deliberations, and calls for a national consensus on recommended criteria.

How Big Is Big Enough for Epidemiology?

W A /hen I was approached by the Editor to write this commentary, I had mixed feelings. On the one hand, grappling with the many complex issues that surround the role of and studies in epidemiology (B/VBE) has increasingly become important given the number of national and international initiatives, both underway and proposed, to conduct such studies. On the other hand, the debate on these issues raises disquieting images reminiscent of both Tom Hanks' movie and Jonathan Swift's Gulliver's Travels. As you may recall from the movie Big, the protagonist-Josh, a 13-year-old boy-is transformed by a coin-operated fortune teller named Zoltar into a grown man. Innocent and inexperienced as he is, Josh finds that, although the experience of being grown-up does have some advantages, he longs to return to being a kid. From Swift we recall the perils and rewards of being too in Lilliput and too small in Brobdingnag and hope that we will not become epidemiologic Yahoos. Without the aid of Zoltar, the fortune teller, we have no way of predicting the consequences of epidemiology becoming big, but Swift's satirical insight does forewarn us that one size definitely does not fit all and that size may impact our vision. Over the last few years, I have attended or participated in numerous conferences and symposia on the topic of big epidemiology, have discussed the prospects and limitations of such studies with many colleagues, have participated in some of the planning for a prospective national study, and have followed the considerations of groups such as the Secretary's Advisory Committee on Genetics, Health, and Society and its Task Force on Large Population Studies. Although I do not want to assert that I am an expert on the subject, I have developed considerable appreciation for all sides of the story and have become more and more skeptical about the need, feasibility, and desirability of such studies. I am also concerned that there may be potential for serious unintended conse quences of very large epidemiologic studies at this time. I will not try to address all of these issues in this commentary and I admit from the outset that simple answers'to complex issues are always somewhat suspect. Of immediate concern is what we mean by or epidemiology. For the purposes of my comments, I am going to focus on studies with 100,000 plus participants. However, even that does not narrow the field enough, as we can imagine-and there already are examples of case-control studies, cohort studies, population-based registries, collections of biologic samples on a grand scale as in BIOBANK and deCode, and other designs. Thus, one cannot really assess the promises and problems associated with epidemiology without being very clear about what kinds of studies we are discussing. For much of what follows I mostly focus on and longitudinal studies, because they present perhaps the biggest challenges. Big epidemiology should not be confused with interdisciplinarity or multidisci plinarity. Paralleling the trends in many other disciplines, many of us have found that problems of great epidemiologic and public health interest require the input and tools of multiple disciplines, regardless of study size.