Associate Director, Stanford Center for Biomedical Ethics (2003 - Present)
Dr. Cho's major areas of interest include: ethical and social issues in genetic research, stem cell research, bioweapons and microbial genome research, the effects of gene patenting on clinical genetic testing and research, and the impacts of academic-industry ties on biomedical research.
The U.S. Office for Human Research Protections has proposed that end points of randomized trials comparing the effectiveness of standard medical practices are risks of research that would require disclosure and written informed consent, but data are lacking on the views of potential participants.To assess attitudes of U.S. adults about risks and preferences for notification and consent for research on medical practices.Cross-sectional survey conducted in August 2014.Web-based questionnaire.1095 U.S. adults sampled from an online panel (n = 805) and an online convenience river sample (n = 290).Attitudes toward risk, informed consent, and willingness to participate in 3 research scenarios involving medical record review and randomization of usual medical practices.97% of respondents agreed that health systems should evaluate standard treatments. Most wanted to be asked for permission to participate in each of 3 scenarios (range, 75.2% to 80.4%), even if it involved only medical record review, but most would accept nonwritten (oral) permission or general notification if obtaining written permission would make the research too difficult to conduct (range, 70.2% to 82.7%). Most perceived additional risk from each scenario (range, 64.0% to 81.6%).Use of hypothetical scenarios and a nonprobability sample that was not fully representative of the U.S. population.Most respondents preferred to be asked for permission to participate in observational and randomized research evaluating usual medical practices, but they are willing to accept less elaborate approaches than written consent if research would otherwise be impracticable. These attitudes are not aligned with proposed regulatory guidance.National Center for Advancing Translational Sciences at the National Institutes of Health.
View details for DOI 10.7326/M15-0166
View details for Web of Science ID 000355015200018
View details for PubMedID 25868119
The complexity of biomedical research has increased considerably in the last decade, as has the pace of translational research. This complexity has generated a number of novel ethical issues for clinical investigators, institutional review boards (IRBs), and other oversight committees. In response, many academic medical centers have created formal research ethics consultation (REC) services to help clinical investigators and IRBs navigate ethical issues in biomedical research. Key functions of a REC service include assisting with research design and implementation, providing a forum for deliberative exploration of ethical issues, and supplementing regulatory oversight. As increasing numbers of academic research institutions establish REC services, there is a pressing need for consensus about the primary aims and policies that should guide these activities. Establishing clear expectations about the aims and policies of REC services is important if REC programs are to achieve their full potential. Drawing on the experiences of a Clinical and Translational Science Award Research Ethics Consultation Working Group, this article describes three major ethical and professional practice challenges associated with the provision of REC: (1) managing multiple institutional roles and responsibilities, (2) managing sensitive information, and (3) communicating with consultation requestors about how these issues are managed. The paper also presents several practical strategies for addressing these challenges and enhancing the quality of REC services.
View details for DOI 10.1097/ACM.0000000000000640
View details for Web of Science ID 000353879700022
View details for PubMedID 25607942
As exome and whole genome sequencing become clinically available, the potential to receive a large number of clinically relevant but incidental results is a significant challenge in the provision of genomic counseling. We conducted three focus groups of a total of 35 individuals who were members of ASHG and/or NSGC, assessing views towards the return of genomic results. Participants stressed that patient autonomy was primary. There was consensus that a mechanism to return results to the healthcare provider, rather than patient, and to streamline integration into the electronic health record would ensure these results had the maximal impact on patient management. All three focus groups agreed that pharmacogenomic results were reasonable to return and that they were not felt to be stigmatizing. With regard to the return of medically relevant results, there was much debate. Participants had difficulty in consistently assigning specific diseases to 'bins' that were considered obligatory versus optional for disclosure. Consensus was reached regarding the importance of informed consent and pretest counseling visits to clarify what the return of results process would entail. Evidence based professional guidelines should continue to be developed and regularly revised to assist in consistently and appropriately providing genomic results to patients.
View details for DOI 10.1007/s10897-013-9611-5
View details for PubMedID 23728783
Large-scale sequencing information may provide a basis for genetic tests for predisposition to common disorders. In this study, participants in the Coriell Personalized Medicine Collaborative (N = 53) with a personal and/or family history of Major Depressive Disorder or Bipolar Disorder were interviewed based on the Health Belief Model around hypothetical intention to test one's children for probability of developing a mood disorder. Most participants (87 %) were interested in a hypothetical test for children that had high ("90 %") positive predictive value, while 51 % of participants remained interested in a modestly predictive test ("20 %"). Interest was driven by beliefs about effects of test results on parenting behaviors and on discrimination. Most participants favored testing before adolescence (64 %), and were reluctant to share results with asymptomatic children before adulthood. Participants anticipated both positive and negative effects of testing on parental treatment and on children's self-esteem. Further investigation will determine whether these findings will generalize to other complex disorders for which early intervention is possible but not clearly demonstrated to improve outcomes. More information is also needed about the effects of childhood genetic testing and sharing of results on parent-child relationships, and about the role of the child in the decision-making process.
View details for DOI 10.1007/s10897-014-9710-y
View details for PubMedID 24651919
Objective:To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake.Study Design:A national sample of 1861 US-based adults was surveyed using a validated online survey instrument. The survey was administered by a commercial survey research company. Respondents were randomized to receive a survey about prenatal testing for trisomy 13 and 18 or trisomy 21. Participants were asked to select among testing modalities, including cffDNA testing, and rank the features of testing that they considered most important to decision making.Result:There was substantive interest in the use of cffDNA testing rather than traditional screening mechanisms, with a minority of respondents reporting that they would support the use of both methods in combination. The lower rates of false-negative and false-positive test results and the ability to use the test earlier in the pregnancy were the most highly rated benefits of cffDNA testing. Participants expressed strong support for diagnostic confirmation via invasive testing after a positive result from either screening or cffDNA testing. However, almost one-third of participants reported that they would not endorse the use of either invasive or non-invasive prenatal testing.Conclusion:There appears to be support for uptake of non-invasive prenatal tests. Clinical guidelines should therefore go forward in providing guidance on how to integrate non-invasive methods into the current standard of care. However, our findings indicate that even when accuracy, which is rated by patients as the most important aspect of prenatal testing, is significantly improved over existing screening methods and testing is offered non-invasively, the number of individuals who reported that they would decline any testing remained the same. Attention should therefore be directed at ensuring that the right of informed refusal of prenatal testing is not impacted by new, non-invasive methods.
View details for DOI 10.1038/jp.2014.30
View details for Web of Science ID 000336945800004
View details for PubMedID 24603453
The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy.
View details for DOI 10.1371/journal.pbio.1001699
View details for PubMedID 24223516
OBJECTIVE: The goal of this study is to provide an ethical framework for clinicians and companies providing noninvasive prenatal testing using cell-free fetal DNA or whole fetal cells. METHOD: In collaboration with a National Institutes of Health-supported research ethics consultation committee together with feedback from an interdisciplinary group of clinicians, members of industry, legal experts, and genetic counselors, we developed a set of best practices for the provision of noninvasive prenatal genetic testing. RESULTS: Principal recommendations include the amendment of current informed consent procedures to include attention to the noninvasive nature of new testing and the potential for a broader range of results earlier in the pregnancy. We strongly recommend that tests should only be provided through licensed medical providers and not directly to consumers. CONCLUSION: Prenatal tests, including new methods using cell-free fetal DNA, are not currently regulated by government agencies, and limited professional guidance is available. In the absence of regulation, companies and clinicians should cooperate to adopt responsible best ethical practices in the provision of these tests. © 2013 John Wiley & Sons, Ltd.
View details for DOI 10.1002/pd.4144
View details for Web of Science ID 000330248700008
View details for PubMedID 23613322
Cell-free fetal DNA-based noninvasive prenatal testing (NIPT) could significantly change the paradigm of prenatal testing and screening. Intellectual property (IP) and commercialization promise to be important components of the emerging debate about clinical implementation of these technologies. We have assembled information about types of testing, prices, turnaround times, and reimbursement of recently launched commercial tests in the United States from the trade press, news articles, and scientific, legal, and business publications. We also describe the patenting and licensing landscape of technologies underlying these tests and ongoing patent litigation in the United States. Finally, we discuss how IP issues may affect clinical translation of NIPT and their potential implications for stakeholders. Fetal medicine professionals (clinicians and researchers), genetic counselors, insurers, regulators, test developers, and patients may be able to use this information to make informed decisions about clinical implementation of current and emerging noninvasive prenatal tests.
View details for DOI 10.1002/pd.4101
View details for Web of Science ID 000319222400003
View details for PubMedID 23686656
The field of behavioral genetics has engendered a host of moral and social concerns virtually since its inception. The policy implications of a genetic basis for behaviors are widespread and extend beyond the clinic to the socially important realms of education, criminal justice, childbearing, and child rearing. The development of new techniques and analytic approaches, including whole-genome sequencing, noninvasive prenatal genetic testing, and optogenetics, has clearly changed the study of behavioral genetics. However, the social context of biomedical research has also changed profoundly over the past few decades, and in ways that are especially relevant to behavioral genetics. The ever-widening scope of behavioral genetics raises ethical, legal, social, and policy issues in the potential new applications to criminal justice, education, the military, and reproduction. These issues are especially critical to address because of their potentially disproportionate effects on vulnerable populations such as children, the unborn, and the incarcerated. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is . Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
View details for DOI 10.1146/annurev-genom-090711-163743
View details for Web of Science ID 000326658500023
View details for PubMedID 23452225
There are little data revealing how genetic counselors talk about disability in the prenatal setting. We performed a qualitative analysis of 93 existing transcripts from simulated patient (SP) genetic counseling sessions conducted in 2003–4 through the Genetic Counseling Video Project. We found that most genetic counselors (95%) focused on the physical aspects of disability while fewer (27%) discussed the social aspects. In addition, few genetic counselors (38%) asked patients about personal experiences with disability. When discussing options available if a pregnancy were diagnosed with a disability, most genetic counselors mentioned termination (86%) while fewer mentioned the continuation of the pregnancy (37%) or adoption (13%). Only half of the genetic counselors asked the SP if she had thought about how she might use the results of prenatal screening. To better facilitate informed decision-making that is consistent with patient values, we recommend genetic counselors engage prenatal patients in a deeper discussion about their ability and willingness to parent a child with a disability.
View details for DOI 10.1007/s10897-012-9484-z
View details for Web of Science ID 000311509200012
View details for PubMedID 22898882
The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field. Ongoing research portends the arrival of a wide range of cffDNA tests. However, it is not yet clear how these tests will be integrated into well-established prenatal testing strategies in the USA, as the timing of such testing and the degree to which new non-invasive tests will supplement or replace existing screening and diagnostic tools remain uncertain. We argue that there is an urgent need for policy-makers, regulators and professional societies to provide guidance on the most efficient and ethical manner for such tests to be introduced into clinical practice in the USA.
View details for DOI 10.1093/humrep/des286
View details for Web of Science ID 000310218300001
View details for PubMedID 22863603
View details for PubMedID 22830179
Existing attempts to explain why secondary researchers might have any obligation to return findings to the contributors of genetic samples falter because of the lack of any direct interaction between the secondary researchers and the contributors. The partial-entrustment account of these obligations defended here circumvents this problem by explaining how a chain of special responsibilities can be forged even in the absence of any direct interaction.Genet Med 2012:14(4):467-472.
View details for DOI 10.1038/gim.2012.12
View details for Web of Science ID 000302565600017
View details for PubMedID 22361900
Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using "biobank" here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.
View details for DOI 10.1038/gim.2012.23
View details for Web of Science ID 000302565600003
View details for PubMedID 22436882
Research ethics consultation services are designed to help scientists address ethical and societal issues that may not be considered in the context of existing regulatory frameworks, such as institutional review boards. Here, we identify some types of biomedical research for which the research process can benefit from consultation with ethicists.
View details for DOI 10.1126/scitranslmed.3002734
View details for Web of Science ID 000299539500001
View details for PubMedID 22277965
There are little data revealing how genetic counselors talk about disability in the prenatal setting. We performed a qualitative analysis of 93 existing transcripts from simulated patient (SP) genetic counseling sessions conducted in 2003-4 through the Genetic Counseling Video Project. We found that most genetic counselors (95%) focused on the physical aspects of disability while fewer (27%) discussed the social aspects. In addition, few genetic counselors (38%) asked patients about personal experiences with disability. When discussing options available if a pregnancy were diagnosed with a disability, most genetic counselors mentioned termination (86%) while fewer mentioned the continuation of the pregnancy (37%) or adoption (13%). Only half of the genetic counselors asked the SP if she had thought about how she might use the results of prenatal screening. To better facilitate informed decision-making that is consistent with patient values, we recommend genetic counselors engage prenatal patients in a deeper discussion about their ability and willingness to parent a child with a disability.
View details for PubMedID 22297411
To provide a preliminary assessment of obstetric healthcare provider opinions surrounding implementation of cell-free fetal DNA testing.A 37-question pilot survey was used to address questions around the translation and use of non-invasive prenatal testing using cell-free fetal DNA. The survey was distributed and collected at a Continuing Medical Education course on obstetrics and gynecology.Of 62 survey respondents, 73% were female and 87% held MD/DO degrees. Respondents generally agreed that patients want prenatal diagnostic information to help make decisions about a pregnancy and that cell-free fetal DNA testing would encourage the testing of more patients for more conditions. However, there was an overall lack of knowledge or conviction about using this technology. Genetic counseling and professional society approval were deemed important to implementation, whereas the possibility of direct-to-consumer testing and government regulation produced mixed responses. Respondents indicated that they would be more likely to offer cell-free fetal DNA testing for chromosomal abnormalities and single-gene disorders, but would be cautious with respect to determination of sex and behavioral or late-onset conditions.Preliminary assessment indicates uncertainty among obstetric providers about the details of implementing cell-free fetal DNA testing and suggests expanded research on perspectives of this stakeholder group.
View details for DOI 10.1002/pd.2835
View details for Web of Science ID 000298261200009
View details for PubMedID 21793012
Cell-free fetal nucleic acids circulating in the blood of pregnant women afford the opportunity for early, noninvasive prenatal genetic testing. The predominance of admixed maternal genetic material in circulation demands innovative means for identification and analysis of cell-free fetal DNA and RNA. Techniques using polymerase chain reaction, mass spectrometry, and sequencing have been developed for the purposes of detecting fetal-specific sequences, such as paternally inherited or de novo mutations, or determining allelic balance or chromosome dosage. Clinical applications of these methods include fetal sex determination and blood group typing, which are currently available commercially although not offered routinely in the United States. Other uses of cell-free fetal DNA and RNA being explored are the detection of single-gene disorders, chromosomal abnormalities, and inheritance of parental polymorphisms across the whole fetal genome. The concentration of cell-free fetal DNA may also provide predictive capabilities for pregnancy-associated complications. The roles that cell-free fetal nucleic acid testing assume in the existing framework of prenatal screening and invasive diagnostic testing will depend on factors such as costs, clinical validity and utility, and perceived benefit-risk ratios for different applications. As cell-free fetal DNA and RNA testing continues to be developed and translated, significant ethical, legal, and social questions will arise that will need to be addressed by those with a stake in the use of this technology. Target Audience: Obstetricians & Gynecologists and Family Physicians Learning Objectives: After participating in this activity, physicians should be better able to evaluate techniques and tools for analyzing cell-free fetal nucleic acids, assess clinical applications of prenatal testing, using cell-free fetal nucleic acids and barriers to implementation, and distinguish between relevant clinical features of cell-free fetal nucleic acid testing and existing prenatal genetic screening and diagnostic procedures.
View details for DOI 10.1097/OGX.0b013e31822dfbe2
View details for Web of Science ID 000295319900021
View details for PubMedID 21944155
Medical schools are being approached by direct-to-consumer genotyping companies about genotyping faculty or trainees as a method to "teach" them about the potential implications of genotyping. In thinking about the future incorporation of genotyping into a graduate level genetics course, the purpose of this study was 2-fold: first, to assess knowledge, attitudes, and beliefs of students toward personal genomics as it related to themselves as both as customers and future physicians and as it related to consumers at large, and second, to determine the impact of the course (as taught without genotyping) on knowledge, attitudes, and beliefs.We surveyed first-year medical students and graduate students before and after a core genetics course.After the course, students were less likely to believe that genotyping information would be useful to physicians, patients, or consumers; genotyping would provide information to improve their own personal health; or personal genomic testing services are diagnostic of medical conditions. They were more likely to answer knowledge questions accurately after the course but still had difficulty with clinical interpretation. Despite these changes, a slight majority of students were, and remained, interested in undergoing genotyping themselves. Of note, the number who believed genotyping "would help them understand genetic concepts better than someone else's data" decreased. General curiosity was the most commonly chosen reason for interest in undergoing genotyping, and approximately 50% of respondents expressed concern about confidentiality of results.In conclusion, even without the genotyping process, an educational program about genotyping increased knowledge, particularly about the clinical limitations of genotyping, but student interest in genotyping did not significantly change. Institutions thinking about offering genotyping to their students as part of a learning experience should consider the pros and cons of doing so.
View details for DOI 10.1097/GIM.0b013e31820562f6
View details for Web of Science ID 000290435700005
View details for PubMedID 21270640
View details for PubMedID 21137125
The recent decision in the case Association for Molecular Pathology et al. v. United States Patent and Trademark Office et al. shocked the biotechnology industry. Although the case could be overturned on appeal, it will probably change how gene patents are written. The effects of the decision might be most strongly felt in the short term by clinical laboratories that develop new genetic tests based on single genes. However, evidence suggests that patents are less effective as an incentive to innovate in the field of genetic diagnostics than for pharmaceuticals. In addition, as genomic technologies move towards whole-genome analysis, policy arguments for patent protection for single genes become less compelling. It is clear that the intellectual property model challenged by the Myriad decision will have to be replaced if new genetic technologies are to achieve their full potential in promoting 'the progress of science and useful arts'.
View details for DOI 10.1016/j.tibtech.2010.08.005
View details for Web of Science ID 000283703300002
View details for PubMedID 20832881
With the completed sequence of the human genome has come the prospect of substantially improving the quality of life for millions through personalized medicine approaches. Still, any advances in this direction require research involving human subjects. For decades science and ethics have enjoyed an allegiance reflected in a common set of ethical principles and procedures guiding the conduct of research with human subjects. Some of these principles emphasize avoiding harm over maximizing benefit. In this paper we revisit the priority given to these ethical principles - particularly the principles that support a cautious approach to science - and propose a reframing of the 'social contract' between science and society that emphasizes reciprocity and meeting public needs.
View details for DOI 10.1159/000319473
View details for Web of Science ID 000281518700009
View details for PubMedID 20805701
To investigate life scientists' views of accountability and the ethical and societal implications of research.Qualitative focus group and one-on-one interviews.45 Stanford University life scientists, including graduate students, postdoctoral fellows and faculty.Two main themes were identified in participants' discussions of accountability: (1) the "how" of science and (2) the "why" of science. The "how" encompassed the internal conduct of research including attributes such as honesty and independence. The "why," or the motivation for conducting research, was two-tiered: first was the desire to positively impact the research community and science itself, and second was an interest in positively impacting the external community, broadly referred to as society. Participants noted that these motivations were influenced by the current systems of publications, grants and funding, thereby supporting a complex notion of boundary-setting between science and non-science. In addition, while all participants recognised the "how" of science and the two tiers of "why," scientists expressed the need to prioritise these domains of accountability. This prioritisation was related to a researcher's position in the academic career trajectory and to the researcher's subsequent "perceived proximity" to scientific or societal concerns. Our findings therefore suggest the need for institutional change to inculcate early-stage researchers with a broader awareness of the implications of their research. The peer review processes for funding and publication could be effective avenues for encouraging scientists to broaden their views of accountability to society.
View details for DOI 10.1136/jme.2009.031781
View details for Web of Science ID 000272210500012
View details for PubMedID 19948933
Research ethics consultation programs are being established with a goal of addressing the ethical, societal, and policy considerations associated with biomedical research. A number of these programs are modelled after clinical ethics consultation services that began to be institutionalized in the 1980s. Our objective was to determine biomedical science researchers' perceived need for and utility of research ethics consultation, through examination of their perceptions of whether they and their institutions faced ethical, social or policy issues (outside those mandated by regulation) and examination of willingness to seek advice in addressing these issues. We conducted telephone interviews and focus groups in 2006 with researchers from Stanford University and a mailed survey in December 2006 to 7 research universities in the U.S.A total of 16 researchers were interviewed (75% response rate), 29 participated in focus groups, and 856 responded to the survey (50% response rate). Approximately half of researchers surveyed (51%) reported that they would find a research ethics consultation service at their institution moderately, very or extremely useful, while over a third (36%) reported that such a service would be useful to them personally. Respondents conducting human subjects research were more likely to find such a service very to extremely useful to them personally than respondents not conducting human subjects research (20% vs 10%; chi(2) p<0.001).Our findings indicate that biomedical researchers do encounter and anticipate encountering ethical and societal questions and concerns and a substantial proportion, especially clinical researchers, would likely use a consultation service if they were aware of it. These findings provide data to inform the development of such consultation programs in general.
View details for DOI 10.1371/journal.pone.0004659
View details for Web of Science ID 000265489900002
View details for PubMedID 19252737
The availability of personalized genomic tests, ordered directly by consumers, is rapidly growing. These tests are unlike other genetic or biochemical tests in the sheer amount of data they provide, but interpretation of these genome-wide analyses for health remains uncertain because of the lack of information about environmental and other factors, and because for the vast majority of genetic loci the associations with disease are weak. Although these tests could provide value to customers by offering tools for social networking or genealogy, there are questions about whether and how to regulate these tests and about the extent to which they provide medical information.
View details for DOI 10.1186/gm17
View details for PubMedID 19341488
The challenge of genome medicine is not to make a significant move into the clinic over the next five years. The floodgates of genomic research have been opened, and the hopes are that the rising tide will spill over into medical practice in the form of diagnostic tests, risk assessment tools and therapeutics. The ability to perform genome-wide analyses using several different approaches has already provided tantalizing new clues to disease causation and therapeutic targets. Companies have sprung up to use these new technologies to provide information to individuals about predicted health and disease, and about behavioral traits. As exciting as these prospects are, it is far too soon to promise clinically useful information from genomic analyses. We have far to go to assure basic levels of analytical validity or clinical validity of the diagnostic or predictive tools on offer, and to determine their clinical utility in the medical context.
View details for DOI 10.1186/gm7
View details for PubMedID 19348694
View details for PubMedID 19119757
Human genetic and genomic research can yield information that may be of clinical relevance to the individuals who participate as subjects of the research. It has been common practice among researchers to notify participants during the informed consent process that no individual results will be disclosed, "incidental" or otherwise. However, as genetic information obtained in research becomes orders of magnitude more voluminous, increasingly accessible online, and more informative, this precedent may no longer be appropriate. There is not yet consensus on the responsibilities of researchers to disclose individual research results to research participants. Empirical research suggests that participants want to know individual research results. On the other hand, the increased resolution and power afforded by new genomic analyses may lead to findings of statistical, but not necessarily clinical, significance. This paper addresses the issues to be considered in deciding whether and how to disclose "incidental" findings or other findings of clinical significance that arise in the course of human genomic and genetic research. What research results should be offered, and what should not be offered? For which research should individual results be offered to research participants, when should they be offered, how, and to whom?
View details for Web of Science ID 000256411400006
View details for PubMedID 18547195
View details for Web of Science ID 000252455400013
The recent completion of the first two individual whole-genome sequences is a research milestone. As personal genome research advances, investigators and international research bodies must ensure ethical research conduct. We identify three major ethical considerations that have been implicated in whole-genome research: the return of research results to participants; the obligations, if any, that are owed to participants' relatives; and the future use of samples and data taken for whole-genome sequencing. Although the issues are not new, we discuss their implications for personal genomics and provide recommendations for appropriate management in the context of research involving individual whole-genome sequencing.
View details for PubMedID 18087293
A decade of empirical work in brain imaging, genomics, and other areas of research has yielded new knowledge about the frequency of incidental findings, investigator responsibility, and risks and benefits of disclosure. Straightforward guidance for handling such findings of possible clinical significance, however, has been elusive. In early work focusing on imaging studies of the brain, we suggested that investigators and institutional review boards must anticipate and articulate plans for handling incidental findings. Here we provide a detailed analysis of different approaches to the problem and evaluate their merits in the context of the goals and setting of the research and the involvement of neurologists, radiologists, and other physicians. Protecting subject welfare and privacy, as well as ensuring scientific integrity, are the highest priorities in making choices about how to handle incidental findings. Forethought and clarity will enable these goals without overburdening research conducted within or outside the medical setting.
View details for Web of Science ID 000252719500010
View details for PubMedID 18227420
Institutional ethics consultation services for biomedical scientists have begun to proliferate, especially for clinical researchers. We discuss several models of ethics consultation and describe a team-based approach used at Stanford University in the context of these models. As research ethics consultation services expand, there are many unresolved questions that need to be addressed, including what the scope, composition, and purpose of such services should be, whether core competencies for consultants can and should be defined, and how conflicts of interest should be mitigated. We make preliminary recommendations for the structure and process of research ethics consultation, based on our initial experiences in a pilot program.
View details for DOI 10.1080/15265160802109322
View details for Web of Science ID 000257030400004
View details for PubMedID 18570086
We are a multidisciplinary group of Stanford faculty who propose ten principles to guide the use of racial and ethnic categories when characterizing group differences in research into human genetic variation.
View details for DOI 10.1186/gb-2008-9-7-404
View details for Web of Science ID 000258773600005
View details for PubMedID 18638359
As with many new diagnostic technologies, the recent rapid emergence of array comparative genome hybridization in clinical genetics provides the power to observe new biological phenomena before their clinical significance is well understood. This raises ethical issues for clinicians when applying the technologies. However, at this early stage of research and development on array comparative genome hybridization, the ethical implications of the conduct of research, as well as how research findings are presented and interpreted, should also be considered by the research, clinical, and ethics communities. These considerations are especially important in the use of array comparative genome hybridization to study complex and common traits. We examined recent publications on autism as an example of the application of array comparative genome hybridization to a complex phenotype. Our goal was to identify points to consider for researchers, clinicians, and patients/families to ensure responsible and ethical design, presentation, and interpretation of these kinds of studies.
View details for DOI 10.1097/GIM.0b013e3181485688
View details for Web of Science ID 000249640800010
View details for PubMedID 17873651
Use of race and ethnicity terms in genetic research continues to generate controversy. Despite differing opinions about their basis or relevance, there is some agreement that investigators using these terms should: explain why the terms or categories were used, define them carefully, and apply them consistently. An important question is whether these recommendations are reflected in practice. Here we addressed this question based on 330 randomly selected articles published between 2001 and 2004 that reported on genetic research and used one or more words from a defined list of race, ethnicity, or population terms. The recommendation that authors using race or ethnicity terms explain the basis for assigning them to study populations was met infrequently (9.1%), and articles that used race and ethnicity as variables were no more likely than those that used them only to label a sample to provide these details. No article defined or discussed the concepts of race or ethnicity. With limited exceptions, current practice does not reflect repeated recommendations for using race or ethnicity terms in genetic research. This study provides a baseline against which to measure future trends.
View details for DOI 10.1002/ajmg.a.31575
View details for Web of Science ID 000246168100009
View details for PubMedID 17345638
The use of racial categories in biomedicine has had a long history in the United States. However, social hierarchy and discrimination, justified by purported scientific differences, has also plagued the history of racial categories. Because "race" has some correlation with biological and genetic characteristics, there has been a call not to "throw the baby out with the bathwater" by eliminating race as a research or clinical category. I argue that race is too undefined and fluid to be useful as a proxy for biology or genetics.
View details for Web of Science ID 000240230700004
View details for PubMedID 17144171
As one of the most compelling technologies for imaging the brain, functional MRI (fMRI) produces measurements and persuasive pictures of research subjects making cognitive judgments and even reasoning through difficult moral decisions. Even after centuries of studying the link between brain and behavior, this capability presents a number of novel significant questions. For example, what are the implications of biologizing human experience? How might neuroimaging disrupt the mysteries of human nature, spirituality, and personal identity? Rather than waiting for an ethical agenda to emerge from some unpredictable combination of the concerns of ethicists and researchers, the attention of journalists, or after controversy is sparked by research that cannot be retracted, we queried key figures in bioethics and the humanities, neuroscience, media, industry, and patient advocacy in focus groups and interviews. We identified specific ethical, legal and social issues (ELSI) that highlight researcher obligations and the nonclinical impact of the technology at this new frontier.
View details for DOI 10.1080/15265160500506274
View details for Web of Science ID 000235709700040
View details for PubMedID 16500831
To examine the role of the practitioner, informed consent, and genetic counseling in genetic testing decisions and to assess their relative influence on women's decision to have clinical BRCA1/2 testing.Qualitative study using in-depth open-ended interviews with 68 women who had considered clinical BRCA1/2 testing.Slightly less than half of the women who had considered BRCA1/2 testing were found to have had a clear and preexisting desire to test or not to test, irrespective of practitioner attitude or advice.The decision to accept or decline genetic testing is the result of a complex process that goes beyond interactions between health care providers and patients, indicating a caution against exclusive reliance on informed consent or counseling encounters.
View details for DOI 10.1159/000091484
View details for Web of Science ID 000236688200002
View details for PubMedID 16612057
Concern over stigma as a consequence of genetic testing has grown in response to the recent increase in genetic research and testing resulting from the Human Genome Project. However, whether a genetic or hereditary basis necessarily confers a stigma to a condition remains unexamined.We performed a qualitative interview study with 86 individuals with one of four conditions: deafness or hearing loss, breast cancer, sickle cell disease, and cystic fibrosis. The first two groups were divided approximately between people who ascribed their conditions to a genetic or hereditary cause and those who did not.Respondents interpreted genetic or hereditary causes and nongenetic causes in a variety of ways. Subjects with breast cancer reported the most consistently negative interpretation of genetic cause. This response concerned future ill health, not an enduring sense of stigma. Deaf and hard of hearing subjects provided the most consistently positive comments about a genetic or hereditary basis to their condition, casting familial hearing loss as a vital component of group and individual identity. Respondents with sickle cell disease and cystic fibrosis offered similar and positive interpretations of the genetic cause of their condition insofar as it meant their conditions were not contagious.Although some subjects report feeling stigmatized as a result of their condition, this stigmatization is not uniformly associated with the condition's cause, genetic or otherwise. Instead, stigma emerges from a variety of sources in the context of the lived experience of a particular condition.
View details for DOI 10.1097/01.gim.0000195894.67756.8b
View details for Web of Science ID 000234850900005
View details for PubMedID 16418597
This article examines what it means to patent a gene. Numerous ethical concerns have been raised about the effects of such patents on clinical medical practice as well as on research and development. We describe what kinds of inventions are covered by human gene patents, give several examples and summarize the small body of empirical research performed in the US examining the effects of these patents. There is little evidence that early fears about gene patenting placing substantial restraints on research and clinical medicine have come to fruition. Nonetheless, there are areas of concern, and policy makers, physicians and the public should be alert to ensure that the net social benefits of patenting human genes are maintained.
View details for DOI 10.1159/000087956
View details for Web of Science ID 000232839300002
View details for PubMedID 16244473
Data on human genetic variation help scientists to understand human origins, susceptibility to illness and genetic causes of disease. Destructive episodes in the history of genetic research make it crucial to consider the ethical and social implications of research in genomics, especially human genetic variation. The analysis of ethical, legal and social implications should be integrated into genetic research, with the participation of scientists who can anticipate and monitor the full range of possible applications of the research from the earliest stages. The design and implementation of research directs the ways in which its results can be used, and data and technology, rather than ethical considerations or social needs, drive the use of science in unintended ways. Here we examine forensic genetics and argue that all geneticists should anticipate the ethical and social issues associated with nonmedical applications of genetic variation research.
View details for DOI 10.1038/ng1434
View details for Web of Science ID 000224854000004
View details for PubMedID 15510102
Alleviating health disparities in the United States is a goal with broad support. Medical research undertaken to achieve this goal typically adopts the well-established perspective that racial discrimination and poverty are the major contributors to unequal health status. However, the suggestion is increasingly made that genetic research also has a significant role to play in alleviating this problem, which likely overstates the importance of genetics as a factor in health disparities. Overemphasis on genetics as a major explanatory factor in health disparities could lead researchers to miss factors that contribute to disparities more substantially and may also reinforce racial stereotyping, which may contribute to disparities in the first place. Arguments that promote genetics research as a way to help alleviate health disparities are augmented by several factors, including research funding initiatives and the distinct demographic patterns of health disparities in the United States.
View details for Web of Science ID 000222184600028
View details for PubMedID 15213210
As industry sponsorship of clinical research grows, investigators' personal financial relationships with those sponsors are under increasing scrutiny. The federal government, some states, and many universities have enacted conflict-of-interest policies to monitor and regulate investigators' financial relationships. Little is known, however, about investigators' awareness of or support for these policies or their attitudes toward regulatory efforts. To explore the possible implications of conflict-of-interest policies for clinical researchers, the authors interviewed active clinical investigators at two institutions where the conflict-of-interest policies differ. The most striking feature of the interviews was the range of perceptions and attitudes expressed by clinical investigators and their implications for administrators, professional societies, and policymakers concerned with conflicts of interest. Fewer than half of the interviewed investigators could accurately describe their campus' conflict-of-interest policy. Many investigators felt that professional societies, the public, and individual investigators were appropriate monitors of conflicts of interest. Many investigators recognized the general risks associated with conflicts of interest, but felt that they personally were not at risk. A fundamental challenge facing administrators and policymakers is to demonstrate to all investigators, both clinical and nonclinical, that the potential for bias, pressure and conflict is relevant to all investigators with industry relationships.
View details for Web of Science ID 000220070500002
View details for PubMedID 12915362
Pharmacogenomics is the emerging study of why individuals respond differently to drugs. It aims to replace the current 'one size fits all' therapeutic approach with 'personalized medicine' that will use pharmacogenomic tests to predict drug response. In a simple conceptualization, these tests challenge privacy as a result of two factors: how comprehensive is the test and how is the access to samples or digital information controlled. Point-of-care tests are likely to be limited in scope, fit seamlessly into medical records and do not raise qualitatively new ethical and privacy challenges. In order to define practically relevant pharmacogenomic predictive patterns however, large-scale clinical trials and research on human specimens will be required, resulting in large databases of genomic information. The genomic scans' magnitude, stability, implications to kin and ease of dissemination together represent a qualitatively different challenge compared to traditional, self-limited and often temporally transient medical information.
View details for Web of Science ID 000181475000001
View details for PubMedID 12605543
The growth of patents that include genetic sequences has been accompanied by concern about their impact on the ability of physicians to provide clinical genetic testing services and to perform research. Therefore, we conducted a survey of clinical laboratory directors that perform DNA-based genetic tests to examine potential effects. We performed a telephone survey between July and September in 2001 of all laboratory directors in the United States who were members of the Association for Molecular Pathology or who were listed on the GENETESTS:org website. One hundred thirty-two of 211 (63%) laboratory directors were interviewed. Ten of these were excluded because they did not conduct DNA-based genetic tests. Almost all performed genetic tests for clinical purposes. Half performed tests for research purposes as well. Twenty-five percent of respondents reported that they had stopped performing a clinical genetic test because of a patent or license. Fifty-three percent of respondents reported deciding not to develop a new clinical genetic test because of a patent or license. In total, respondents were prevented from performing 12 genetic tests, and all of these tests were among those performed by a large number of laboratories. We found 22 patents that were relevant to the performance of these 12 tests. Fifteen of the 22 patents (68%) are held by universities or research institutes, and 13 of the 22 patents (59%) were based on research funded by the United States Government. Overall, respondents reported that their perceptions of the effects of patents on the cost, access, and development of genetic tests, or data sharing among researchers, were negative. In contrast, most respondents felt that patents did not have an effect on the quality of testing. We conclude that patents and licenses have had a significant effect on the ability of clinical laboratories to develop and provide genetic tests. Furthermore, our findings suggest that clinical geneticists feel that their research is inhibited by patents. The effects of patents and licenses on patients' access to tests, and the costs and quality thereof, remains to be determined.
View details for Web of Science ID 000180631100002
View details for PubMedID 12552073
In the use of magnetic resonance imaging (MRI) in medicine and in the conduct of MRI research, conflicts of interest are routinely generated. These conflicts are not necessarily unique to MRI and are not necessarily considered malpractice or misconduct. It is important, however, for clinicians and researchers to understand what constitutes a conflict of interest and how to mitigate the potential adverse effects of those conflicts on patients and on the integrity of research. It also is important for medical professionals to understand the changes in the clinical and research environments that make conflicts of interest more prevalent and more of a concern to policy makers. Finally, it is important for medical professionals who work with MRI to understand some of the characteristics of MRI that might increase the prevalence of conflicts of interest in clinical practice and research.
View details for PubMedID 12055451
Biomedical researchers often assume that sponsors, subjects, families, and disease-associated advocacy groups contribute to research solely because of altruism. This view fails to capture the diverse interests of many participants in the emerging research enterprise. In the past two decades, patient groups have become increasingly active in the promotion and facilitation of genetics research. Simultaneously, a significant shift of academic biomedical science toward commercialization has occurred, spurred by U.S. federal policy changes. The concurrent rise in both the roles that subjects play and the commercial interests they have presents numerous ethical challenges. We examine the interests of different research participants, finding that these interests are not addressed by current policies and practices. We conclude that all participants should be given a voice in decisions affecting ownership, access to, and use of commercialized products and services, and that researchers and institutions should negotiate issues relating to control of research results and the sharing of benefits before the research is performed.
View details for Web of Science ID 000174252100013
View details for PubMedID 11870592
View details for PubMedID 11832913
View details for PubMedID 11908751
The biotechnology industry has become firmly established over the past twenty years and gene patents have played an important part in this phenomenon. However, concerns have been raised over the patentability of human genetic material, through public protests and international statements, but to little effect. Here we discuss some of these concerns, the patent authorities' response to them, and ways in which to address these issues and to move the debate forward using current legal structures.
View details for Web of Science ID 000165763700016
View details for PubMedID 11252752
Despite federal regulations on faculty conflicts of interest in federally funded research, academic-industry ties are common, and evidence exists that financial considerations bias the research record. Public scrutiny of these ties is increasing, especially in cases where researchers have financial interests in the corporate sponsors of their clinical research.To review policies on conflict of interest at major biomedical research institutions in the United States.Cross-sectional survey and content analysis study conducted from August 1998 to February 2000.The 100 US institutions with the most funding from the National Institutes of Health in 1998 were initially sampled; policies from 89 institutions were available and included in the analysis.Process for disclosure, review, and management of conflicts of interest and specified management strategies or limitations, according to the institutions' faculty/staff conflict of interest policies.Content of the conflict of interest policies varied widely across institutions. Fifty-five percent of policies (n = 49) required disclosures from all faculty while 45% (n = 40) required them only from principal investigators or those conducting research. Nineteen percent of policies (n = 17) specified limits on faculty financial interests in corporate sponsors of research, 12% (n = 11) specified limits on permissible delays in publication, and 4% (n = 4) prohibited student involvement in work sponsored by a company in which the faculty mentor had a financial interest.Most policies on conflict of interest in our sample of major research institutions in the United States lack specificity about the kinds of relationships with industry that are permitted or prohibited. Wide variation in management of conflicts of interest among institutions may cause unnecessary confusion among potential industrial partners or competition among universities for corporate sponsorship that could erode academic standards. It is in the long-term interest of institutions to develop widely agreed-on, clear, specific, and credible policies on conflicts of interest. JAMA. 2000;284:2203-2208.
View details for Web of Science ID 000090052600028
View details for PubMedID 11056591
View details for PubMedID 10617419
It was our purpose to determine the characteristics of practitioners in the United States who were among the first to inquire about and use the BRCA1 and BRCA2 (BRCA1/2) genetic tests outside of a research protocol. Questionnaires were mailed to all practitioners who requested information on or ordered a BRCA1/2 test from the University of Pennsylvania (UPenn) Genetic Diagnostics Laboratory (GDL) between October 1, 1995 and January 1, 1997 (the first 15 months the test was available for clinical use). The response rate was 67% of practitioners; 54% (121/225) were genetic counselors, 39% (87/225) were physicians or lab directors. Most physicians were oncologists, pathologists, or obstetrician/gynecologists, but 20% practiced surgery or internal or general medicine. Fifty-six percent (125/225) had ordered a BRCA1/2 test for a patient; most of the rest had offered or were willing to offer testing. Of those who had offered testing, 70% had a patient decline BRCA1/2 testing when offered. Practitioners perceived that patients' fear of loss of confidentiality was a major reason for declining. Nearly 60% of practitioners reported that their patients had access to a genetic counselor, but 28% of physicians who ordered a BRCA1/2 test reported having no such access, despite the GDL's counseling requirement. The proportion of physicians reporting no access to genetic counselors for their patients increased from 22.4% in the first half of the study to 50% in the last half. Many practitioners have an interest in BRCA1/2 testing, despite policy statements that discourage its use outside of research protocols. Practitioner responses suggest that patient interest in testing seems to be tempered by knowledge of potential risks. An apparent increase in patient concern about confidentiality and inability to pay for testing could indicate growing barriers to testing. Although most practitioners reported having access to counseling facilities, perceived lack of such access among an increasing proportion of practitioners indicates that lab requirements for counseling are difficult to enforce and suggests that an increasing proportion of patients may not be getting access to counseling.
View details for Web of Science ID 000078879600004
View details for PubMedID 10096590
All authors may not be equal in the eyes of reviewers. Specifically, well-known authors may receive less objective (poorer quality) reviews. One study at a single journal found a small improvement in review quality when reviewers were masked to author identity.To determine whether masking reviewers to author identity is generally associated with higher quality of review at biomedical journals, and to determine the success of routine masking techniques.A randomized controlled trial performed on external reviews of manuscripts submitted to Annals of Emergency Medicine, Annals of Internal Medicine, JAMA, Obstetrics & Gynecology, and Ophthalmology.Two peers reviewed each manuscript. In one study arm, both peer reviewers received the manuscript according to usual masking practice. In the other arm, one reviewer was randomized to receive a manuscript with author identity masked, and the other reviewer received an unmasked manuscript.Review quality on a 5-point Likert scale as judged by manuscript author and editor. A difference of 0.5 or greater was considered important.A total of 118 manuscripts were randomized, 26 to usual practice and 92 to intervention. In the intervention arm, editor quality assessment was complete for 77 (84%) of 92 manuscripts. Author quality assessment was complete on 40 (54%) of 74 manuscripts. Authors and editors perceived no significant difference in quality between masked (mean difference, 0.1; 95% confidence interval [CI], -0.2 to 0.4) and unmasked (mean difference, -0.1; 95% CI, -0.5 to 0.4) reviews. We also found no difference in the degree to which the review influenced the editorial decision (mean difference, -0.1; 95% CI,-0.3 to 0.3). Masking was often unsuccessful (overall, 68% successfully masked; 95% CI, 58%-77%), although 1 journal had significantly better masking success than others (90% successfully masked; 95% CI, 73%-98%). Manuscripts by generally known authors were less likely to be successfully masked (odds ratio, 0.3; 95% CI, 0.1-0.8). When analysis was restricted to manuscripts that were successfully masked, review quality as assessed by editors and authors still did not differ.Masking reviewers to author identity as commonly practiced does not improve quality of reviews. Since manuscripts of well-known authors are more difficult to mask, and those manuscripts may be more likely to benefit from masking, the inability to mask reviewers to the identity of well-known authors may have contributed to the lack of effect.
View details for Web of Science ID 000074706000013
View details for PubMedID 9676668
In a previous study, we found that masking success was higher at a journal that masked reviewers to author identity. We hypothesized that masking policy or other factors could be associated with masking success.To evaluate differences in success of masking reviewers to author identity at 7 biomedical journals and to identify factors associated with these differences.Written questionnaire.Reviewers at 3 journals with a long-standing policy of masking author identity (Annals of Emergency Medicine, Epidemiology, and Journal of the American Geriatrics Society) and 4 journals without a policy of masking author identity (Annals of Internal Medicine, JAMA, Obstetrics & Gynecology, and Ophthalmology).Masking success (percentage of reviewers successfully masked) and reviewer characteristics associated with masking.There was no significant difference in masking success between journals with a policy of masking (60%) and those without (58%) (P= .92). We found no association between masking success and a policy of masking when adjusted for the reviewer characteristics of age, sex, years of reviewing experience, number of articles published, number of articles reviewed, percentage of time spent in research, editorial experience, or academic rank (odds ratio [OR], 1.3; 95% confidence interval [CI], 0.64-2.8; P=.43). In multivariable analysis of reviewer characteristics, reviewers spending a greater percentage of time in research, the only significant predictor of masking success, were less likely to be successfully masked (OR, 1.01; 95% CI, 1.00-1.02) (P=.04).Masking success appears unrelated to a journal policy of masking, but is associated with reviewers' research experience and could be affected by other characteristics. Using reviewers with less research and reviewing experience might increase masking success, but the effect on review quality is unknown.
View details for Web of Science ID 000074706000014
View details for PubMedID 9676669
This summary corresponds to the translation into Spanish of the Special Communication published in the Journal of the American Medical Association in August 1996, along with the editorial published in the same issue "How to report Randomized Controlled Trials. The Consort Statement". It describes the Consolidated Standards for Preparation of Controlled Clinical Trials, prepared by a work group made up of members of the SORT Group and of the Asilomar Work Group, along with the director of a magazine and the author of the report on a clinical trial. The work was carried out by means of a Delphi process and the result was a check list and a process diagram. The check list is made up of 21 items that mainly refer to methods, results and discussions on the report of a controlled clinical trial, identifying the necessary information in order to be able to evaluate the internal and external value of the report, judging the improvement to be positive for the patient, the editors and the reviewers of the magazines.
View details for PubMedID 9477711
Genetic testing for common conditions will be used increasingly in primary care, but resources for patient counseling are decreasing. It is also necessary that primary care practitioners be better equipped to do basic genetic counseling. Therefore, the quality of informational materials for practitioners and patients is important. It was unknown how often key elements recommended by policy groups were actually included in such material. It was our aim to determine the content of printed informational material for practitioners and patients on genetic testing. We performed (1) a telephone survey of organizations in the United States that developed genetic tests or services and (2) a content analysis of pamphlets obtained from these organizations to determine the presence of 10 critical elements necessary to evaluate the appropriateness and performance of the tests. Almost 95% (169/178) of organizations responded to our survey; 131/169 (78%) reported using informational materials. We analyzed 115 pamphlets collected from 125/131 (95%) organizations. Elements least frequently included in the pamphlets were risks and benefits, patient rights, and intended use or purpose of the test. Most frequently included were descriptions of the conditions detected by the test, and the appropriate patients for testing. Nearly one half of the pamphlets included some statement about the accuracy of the test, but most of these did not specify whether their statements referred to sensitivity, specificity, or predictive value. Overall, pamphlets tended to contain information that would aid in determining a patient's eligibility for a genetic test, but did not contain sufficient information about the tests themselves. Our results suggest that several critical elements need to be added to enhance informed choices by patients and physicians.
View details for Web of Science ID A1997YH57700016
View details for PubMedID 9415691
View details for PubMedID 10462622
To compare the quality, relevance, and structure of drug studies published in symposium proceedings that are sponsored by drug companies with 1) articles from symposia with other sponsors and 2) articles in the peer-reviewed parent journals of symposium proceedings; and to study the relation between drug company sponsorship and study outcome.Cross-sectional studies of clinical drug studies published in symposium proceedings or their parent medical journals.The proportion of articles with no methods sections (which are necessary to assess quality); methodologic quality and clinical relevance scores; and the proportion of articles with outcomes favoring the drug of interest.Symposia sponsored by single drug companies had more articles without methods sections (10%; 108 of 1064) than did symposia that had other sponsors (3%; 58 of 2314) or symposia that had no mentioned sponsor (2%; 29 of 1663) (P < 0.001). The mean methodologic quality and relevance scores of articles were similar both by type of sponsorship and between articles published in symposia sponsored by single drug companies and articles from the parent journals. Significantly more articles with drug company support (98%; 39 of 40) than without drug company support (79%; 89 of 112) had outcomes favoring the drug of interest (P = 0.01).Articles in symposia sponsored by single drug companies were similar in quality and clinical relevance to articles with other sponsors and to articles published in the parent journals. Articles with drug company support are more likely than articles without drug company support to have outcomes favoring the drug of interest.
View details for Web of Science ID A1996TW77300004
View details for PubMedID 8602706
View details for PubMedID 7990245
Mammalian skeletal muscle is generated by two waves of fiber formation, resulting in primary and secondary fibers. These fibers mature to give rise to several classes of adult muscle fibers with distinct contractile properties. Here we describe fast myosin heavy chain (MyHC) isoforms that are expressed in nascent secondary, but not primary, fibers in the early development of rat and human muscle. These fast MyHCs are distinct from previously described embryonic and neonatal fast MyHCs. To identify these MyHCs, monoclonal antibodies were used whose specificity was determined in western blots of MyHCs on denaturing gels and reactivity with muscle tissue at various stages of development. To facilitate a comparison of our results with those of others obtained using different antibodies or species, we have identified cDNAs that encode the epitopes recognized by our antibodies wherever possible. The results suggest that epitopes characteristic of adult fast MyHCs are expressed very early in muscle fiber development and distinguish newly formed secondary fibers from primary fibers. This marker of secondary fibers, which is detectable at the time of their inception, should prove useful in future studies of the derivation of primary and secondary fibers in mammalian muscle development.
View details for Web of Science ID A1994PH54500002
View details for PubMedID 7531198
To develop valid and reliable instruments to assess the methodologic quality and clinical relevance of drug studies.We developed an instrument to assess the methodologic quality of articles reporting clinical research and an instrument to measure nonmethodologic measures of quality, such as clinical relevance, generalizability, and adherence to ethical standards. Each instrument was pretested by seven independent, masked reviewers and modified based on interrater agreement and content validity of individual items. We determined correlational validity of the final methodologic quality instrument by comparing quality scores assigned to 10 articles by means of our instrument and a previously published one.Clinical drug studies published in symposium proceedings and peer reviewed biomedical literature.Interrater reliability of overall quality scores, measured by intraclass correlation (r) and Kendall's coefficient of concordance (W), and interrater reliability of individual items, by percentage agreement.The interrater reliability of the pretest methodologic quality instrument was high (r = .89 [95% confidence interval, .73 to .96]; W = 0.64). Correlational validity of the final instrument was suggested by the high degree of concordance with another previously published one (W = 0.74). The interrater reliability of the pretest clinical relevance instrument was moderate (r = .41 [95% confidence interval, .18 to .64]; W = 0.47). Reviewers confirmed the content validity of both instruments.The two instruments we developed, one measuring methodologic quality and one measuring clinical relevance of articles reporting clinical research, are reliable, valid, and applicable to a variety of research designs.
View details for Web of Science ID A1994NV42400005
View details for PubMedID 8015115
View details for PubMedID 11652321
Myosin heavy chain (MyHC) isoforms show a striking diversity of expression patterns during mammalian development. Using a set of monoclonal antibodies that recognize different epitopes on myosin heavy chain isoforms we show that there exist in human and rat skeletal muscle at least three isoforms of slow twitch myosin heavy chain. To facilitate a comparison of our results to others obtained using different antibodies or species, we have identified cDNAs encoding the epitopes recognized by the three slow antibodies. Using these reagents, we show that the onset of expression of three slow MyHC isoforms is temporally distinct during early gestation. This result suggests that a sequence of MyHC transitions plays an important role in determining muscle fiber function at fetal, neonatal, and adult stages.
View details for Web of Science ID A1993LM14800015
View details for PubMedID 7687223
Vertebrate muscles are composed of an array of diverse fast and slow fiber types with different contractile properties. Differences among fibers in fast and slow MyHC expression could be due to extrinsic factors that act on the differentiated myofibers. Alternatively, the mononucleate myoblasts that fuse to form multinucleated muscle fibers could differ intrinsically due to lineage. To distinguish between these possibilities, we determined whether the changes in proportion of slow fibers were attributable to inherent differences in myoblasts. The proportion of fibers expressing slow myosin heavy chain (MyHC) was found to change markedly with time during embryonic and fetal human limb development. During the first trimester, a maximum of 75% of fibers expressed slow MyHC. Thereafter, new fibers formed which did not express this MyHC, so that the proportion of fibers expressing slow MyHC dropped to approximately 3% of the total by midgestation. Several weeks later, a subset of the new fibers began to express slow MyHC and from week 30 of gestation through adulthood, approximately 50% of fibers were slow. However, each myoblast clone (n = 2,119) derived from muscle tissues at six stages of human development (weeks 7, 9, 16, and 22 of gestation, 2 mo after birth and adult) expressed slow MyHC upon differentiation. We conclude from these results that the control of slow MyHC expression in vivo during muscle fiber formation in embryonic development is largely extrinsic to the myoblast. By contrast, human myoblast clones from the same samples differed in their expression of embryonic and neonatal MyHCs, in agreement with studies in other species, and this difference was shown to be stably heritable. Even after 25 population doublings in tissue culture, embryonic stage myoblasts did not give rise to myoblasts capable of expressing MyHCs typical of neonatal stages, indicating that stage-specific differences are not under the control of a division dependent mechanism, or intrinsic "clock." Taken together, these results suggest that, unlike embryonic and neonatal MyHCs, the expression of slow MyHC in vivo at different developmental stages during gestation is not the result of commitment to a distinct myoblast lineage, but is largely determined by the environment.
View details for Web of Science ID A1993LB63800008
View details for PubMedID 8491773
In this report, we define a muscle-specific marker, beta-enolase, that distinguishes proliferating myoblasts from different stages of development. Enolase exists as multiple isoforms and in the course of cardiac and skeletal muscle development the beta isoform progressively replaces the alpha isoform. In skeletal muscle, this change in gene expression, unlike most developmental changes in myogenic gene expression, is evident in undifferentiated myoblasts. Whereas myoblasts from fetal tissues express alpha-enolase mRNA, beta-enolase is the predominant mRNA expressed by myoblasts from postnatal tissues. Our results are consistent with the idea that distinct precursor myoblasts contribute to the diversity of fiber types characteristic of muscle tissue at different stages of development.
View details for Web of Science ID A1992HY74000029
View details for PubMedID 1339335