Optimizing drug outcomes through pharmacogenetics: a case for preemptive genotyping.

Routine integration of genotype data into drug decision making could improve patient safety, particularly if many relevant genetic variants can be assayed simultaneously before prescribing the target drug. The frequency of opportunities for pharmacogenetic prescribing and the potential adverse events (AEs) mitigated are unknown. We examined the frequency with which 56 medications with known outcomes influenced by variant alleles were prescribed in a cohort of 52,942 medical home patients at Vanderbilt University Medical Center (VUMC). Within a 5-year window, we estimated that 64.8% (95% confidence interval (CI): 64.4-65.2%) of individuals were exposed to at least one medication with an established pharmacogenetic association. Using previously published results for six medications with severe, well-characterized, genetically linked AEs, we estimated that 383 events (95% CI, 212-552) could have been prevented with an effective preemptive genotyping program. Our results suggest that multiplexed, preemptive genotyping may represent an efficient alternative approach to current single-use ("reactive") methods and may also improve safety.

Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project.

The promise of "personalized medicine" guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision-support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health-care provider, identification of relevant genetic variations for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.

Predicting clopidogrel response using DNA samples linked to an electronic health record.

Variants in ABCB1 and CYP2C19 have been identified as predictors of cardiac events during clopidogrel therapy initiated after myocardial infarction (MI) or percutaneous coronary intervention (PCI). In addition, PON1 has recently been associated with stent thrombosis. The reported effects of these variants have not yet been replicated in a real-world setting. We used BioVU, the Vanderbilt DNA repository linked to de-identified electronic health records (EHRs), to find data on patients who were on clopidogrel treatment after an MI and/or a PCI; among these, we identified those who had experienced one or more recurrent cardiac events while on treatment (cases, n = 225) and those who had not experienced any cardiac event while on treatment (controls, n = 468). We found that CYP2C19*2 (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.16-2.06, P = 0.003) and ABCB1 (HR 1.28, 95% CI 1.04-1.57, P = 0.018), but not PON1 (HR 0.91, 95% CI 0.73-1.12, P = 0.370), were associated with recurrent events. In this population, genetic signals for clopidogrel resistance in ABCB1 and CYP2C19 were replicated, supporting the use of EHRs for pharmacogenomic studies. Our data do not show an association between PON1 and recurrent cardiovascular events.

Development of a large-scale de-identified DNA biobank to enable personalized medicine.

Our objective was to develop a DNA biobank linked to phenotypic data derived from an electronic medical record (EMR) system. An "opt-out" model was implemented after significant review and revision. The plan included (i) development and maintenance of a de-identified mirror image of the EMR, namely, the "synthetic derivative" (SD) and (ii) DNA extracted from discarded blood samples and linked to the SD. Surveys of patients indicated general acceptance of the concept, with only a minority ( approximately 5%) opposing it. As a result, mechanisms to facilitate opt-out included publicity and revision of a standard "consent to treatment" form. Algorithms for sample handling and procedures for de-identification were developed and validated in order to ensure acceptable error rates (<0.3 and <0.1%, respectively). The rate of sample accrual is 700-900 samples/week. The advantages of this approach are the rate of sample acquisition and the diversity of phenotypes based on EMRs.

Temporal gene regulation during HIV-1 infection of human CD4+ T cells.

CD4(+) T-cell depletion is a characteristic of human immunodeficiency virus type 1 (HIV-1) infection. In this study, modulation of mRNA expression of 6800 genes was monitored simultaneously at eight time points in a CD4(+) T-cell line (CEM-GFP) during HIV infection. The responses to infection included: (1) >30% decrease at 72 h after infection in overall host-cell production of monitored mRNA synthesis, with the replacement of host-cell mRNA by viral mRNA, (2) suppression of the expression of selected mitochondrial and DNA repair gene transcripts, (3) increased expression of the proapoptotic gene and its gene p53-induced product Bax, and (4) activation of caspases 2, 3, and 9. The intense HIV-1 transcription resulted in the repression of much cellular RNA expression and was associated with the induction of apoptosis of infected cells but not bystander cells. This choreographed host gene response indicated that the subversion of the cell transcriptional machinery for the purpose of HIV-1 replication is akin to genotoxic stress and represents a major factor leading to HIV-induced apoptosis.

Use of keyword hierarchies to interpret gene expression patterns.

MOTIVATION: High-density microarray technology permits the quantitative and simultaneous monitoring of thousands of genes. The interpretation challenge is to extract relevant information from this large amount of data. A growing variety of statistical analysis approaches are available to identify clusters of genes that share common expression characteristics, but provide no information regarding the biological similarities of genes within clusters. The published literature provides a potential source of information to assist in interpretation of clustering results. RESULTS: We describe a data mining method that uses indexing terms ('keywords') from the published literature linked to specific genes to present a view of the conceptual similarity of genes within a cluster or group of interest. The method takes advantage of the hierarchical nature of Medical Subject Headings used to index citations in the MEDLINE database, and the registry numbers applied to enzymes.

Are medical informatics and nursing informatics distinct disciplines? The 1999 ACMI debate.

The 1999 debate of the American College of Medical Informatics focused on the proposition that medical informatics and nursing informatics are distinctive disciplines that require their own core curricula, training programs, and professional identities. Proponents of this position emphasized that informatics training, technology applications, and professional identities are closely tied to the activities of the health professionals they serve and that, as nursing and medicine differ, so do the corresponding efforts in information science and technology. Opponents of the proposition asserted that informatics is built on a re-usable and widely applicable set of methods that are common to all health science disciplines, and that "medical informatics" continues to be a useful name for a composite core discipline that should be studied by all students, regardless of their health profession orientation.

Assurance: the power behind PCASSO security.

The need for security protection in Internet-based healthcare applications is generally acknowledged. Most healthcare applications that use the Internet have at least implemented some kind of encryption. Most applications also enforce user authentication and access control policies, and many audit user actions. However, most fall short on providing strong assurances that the security mechanisms are behaving as expected and that they cannot be subverted. While no system can claim to be totally "bulletproof," PCASSO provides assurance of correct operation through formal, disciplined design and development methodologies, as well as through functional and penetration testing. Through its security mechanisms, backed by strong system assurances, PCASSO is demonstrating "safe" use of public data networks for health care.

PCASSO: a design for secure communication of personal health information via the internet.

The Internet holds both promise and peril for the communications of person-identifiable health information. Because of technical features designed to promote accessibility and interoperability rather than security, Internet addressing conventions and transport protocols are vulnerable to compromise by malicious persons and programs. In addition, most commonly used personal computer (PC) operating systems currently lack the hardware-based system software protection and process isolation that are essential for ensuring the integrity of trusted applications. Security approaches designed for electronic commerce, that trade known security weaknesses for limited financial liability, are not sufficient for personal health data, where the personal damage caused by unintentional disclosure may be far more serious. To overcome these obstacles, we are developing and evaluating an Internet-based communications system called PCASSO (Patient-centered access to secure systems online) that applies state of the art security to health information. PCASSO includes role-based access control, multi-level security, strong device and user authentication, session-specific encryption and audit trails. Unlike Internet-based electronic commerce 'solutions,' PCASSO secures data end-to-end: in the server; in the data repository; across the network; and on the client. PCASSO is designed to give patients as well as providers access to personal health records via the Internet.

Advances in information technology. Implications for medical education.

Few kinds of technology have had as broad an impact on the recent affairs of humanity as have information technologies. The appearance and rapid spread in the past several years of innovations such as the Internet's World Wide Web and the emergence of computer networks connecting tens to hundreds of millions of people worldwide have occurred with startling rapidity. These global events portend substantial changes in the delivery of health care, the conduct of biomedical research, and the undergraduate, graduate, and continuing education of health professionals. This report will attempt to succinctly review the following: (1) the characteristics of modern information technologies and recent trends that are most relevant to medical education and to the world in which future practitioners, researchers, and educators will live and work; (2) the implications of these technologies for the development of educational goals (in other words, the specific information technology skills that future health professionals will need); (3) the issues associated with the use of these technologies in the process of education; and (4) implications for near-term action by University of California medical schools and academic medical centers.

Protecting clinical data on Web client computers: the PCASSO approach.

The ubiquity and ease of use of the Web have made it an increasingly popular medium for communication of health-related information. Web interfaces to commercially available clinical information systems are now available or under development by most major vendors. To the extent that such interfaces involve the use of unprotected operating systems, they are vulnerable to security limitations of Web client software environments. The Patient Centered Access to Secure Systems Online (PCASSO) project extends the protections for person-identifiable health data on Web client computers. PCASSO uses several approaches, including physical protection of authentication information, execution containment, graphical displays, and monitoring the client system for intrusions and co-existing programs that may compromise security.

PCASSO: a secure architecture for access to clinical data via the Internet.

Patient Centered Access to Secure Systems Online (PCASSO) is a National Information Infrastructure research project funded by the US National Library of Medicine (NLM). PCASSO is specifically designed to address the problem of enabling secure access to health information over the Internet, not just for healthcare providers and medical researchers, but also for patients to view their own medical records. The project is using familiar Web technologies to support the search and retrieval of information, including patient demographics, medications, lab tests, and transcription reports. State-of-the-art security technologies protect patient privacy and the integrity of patient information. This paper describes the security architecture of the PCASSO system.

Patient-Centered Access to Secure Systems Online (PCASSO): a secure approach to clinical data access via the World Wide Web.

The Internet's World-Wide Web (WWW) provides an appealing medium for the communication of health related information due to its ease of use and growing popularity. But current technologies for communicating data between WWW clients and servers are systematically vulnerable to certain types of security threats. Prominent among these threats are "Trojan horse" programs running on client workstations, which perform some useful and known function for a user, while breaching security via background functions that are not apparent to the user. The Patient-Centered Access to Secure Systems Online (PCASSO) project of SAIC and UCSD is a research, development and evaluation project to exploit state-of-the-art security and WWW technology for health care. PCASSO is designed to provide secure access to clinical data for healthcare providers and their patients using the Internet. PCASSO will be evaluated for both safety and effectiveness, and may provide a model for secure communications via public data networks.