Impact of molecular medicine on pathophysiology,medical practice,and medical education

This article brings an overview of the influence of molecular medicine on pathophysiology, medical practice, and medical education. Various aspects of the growing impact of molecular medicine on clinical practice are discussed: diagnostic and predictive testing, gene and targeted therapy, and pharmacogenomics. Insufficient data from appropriate clinical studies and evidence-based medicine presently limit the applications of molecular medicine in clinical practice. Incorporation of conceptual and clinical aspects of molecular medicine in undergraduate and postgraduate curricula and a continuing education of medical professionals is an urgent imperative for the demands of medical care quality to be met in near future. The emphasis should be put on bedside-orientated molecular medicine. The prerequisite is translational research aimed to translate basic information into the improvement of healthcare of individual patients and the population as a whole.     

Pharmacogenetics or the promise of a personalized medicine: variability in drug metabolism and transport

There is much variability in the manner individuals respond to drugs, such that the management of some drugs is problematic. In France, the incidence of hospital admissions related to adverse drug reactions is estimated to be 3.2 %, at an annual cost of over 300 millions euros. Genetic factors affecting the pharmacokinetics and pharmacodynamics of drugs partly explain interindividual variability in drug response. Pharmacogenetic focuses on the molecular mechanisms involved in drug response, and its ultimate goal is the optimisation of drug treatments, both in terms of efficacy and safety. Numerous polymorphisms in genes encoding drug-metabolising enzymes, transporters and receptors have been described and their consequences on disposition and effect of a substantial number of medications have been elucidated. This review focuses on variability of drug metabolism and transport to define the objectives of pharmacogenetics, the molecular bases of interindividual variation in drug response and the methods used for the evaluation of the individual risk of drug failure or toxicity. Some clinical applications of pharmacogenetics have already been developed in routine medicine resulting in significant improvement in patient treatment. The clinical validation of an increasing number of pharmacogenetic tests, as well as the development of new highly efficient technologies for genotyping (real-time PCR, DNA chips) should further promote pharmacogenetics in clinical practice and lead to the development of a patient-tailored drug therapy.     

Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug‐related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug‐related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.     

Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist?

Adverse drug reactions, due at least in part to interindividual variability in drug response, rank between the 4th and 6th leading causes of death in the USA. The field of 'pharmacogenetics', which is 'the study of variability in drug response due to heredity', should help in reducing drug-caused morbidity and mortality. The recently coined term 'pharmacogenomics' usually refers to 'the field of new drug development based on our rapidly increasing knowledge of all genes in the human genome'. However, the two terms - pharmacogenetics and pharmacogenomics - are often used interchangeably. A classification of more than five dozen pharmacogenetic differences is presented here. Most of these variations occur in drug-metabolizing enzyme (DME) genes, with some presumed to exist in the DME receptor and drug transporter genes, and others have not yet been explained on a molecular basis. A method for unequivocally defining a quantitative phenotype (drug efficacy, toxicity, etc.) is proposed; this is where help from the clinical geneticist can be especially important. Our current appreciation of the degree of variability (including single-nucleotide polymorphisms, SNPs) in the human genome is described, with emphasis on the need to prove that a particular genotype is indeed the cause of a specific phenotype; this topic has been termed 'functional genomics'. Furthermore, the current amount of admixture amongst almost all ethnic groups will obviously make studies of gene-drug interactions more complicated, as will the withholding of ethnic information about DNA samples during any molecular epidemiologic study. DME genes and DME receptor and drug transporter genes can be regarded as 'modifier genes', because they influence disorders as diverse as risk of cancer, bone marrow toxicity resulting from occupational exposure, and Parkinson's disease; for this reason, the clinical geneticist, as well as the medical genetics counselor, should be knowledgeable in the rapidly expanding fields of pharmacogenetics and pharmacogenomics.     

Pharmacogenetics of anticancer drugs

Much progress has been made in treating human malignancies and there are now multiple treatment options with similar efficacy for nearly every type of cancer. However, the narrow therapeutic index of most chemotherapeutic agents and the severe consequences of undertreatment or overdosing have led to research molecular predictive factors of the toxicity and efficacy of cancer treatments. Genetic factors affecting drug metabolism and transport partly explain interindividual variability in drug response. Pharmacogenetic focuses on the molecular mechanisms involved in drug response, and its ultimate goal is the optimisation of the treatments, that combines the optimal efficacy and the minimal risk of severe side effects. Polymorphisms in genes encoding specific drug-metabolising enzymes can result in individuals in the general population being characterised as low, rapid or even ultra-rapid metabolisers. Phenotyping and genotyping tests are now available that determine or predict the metabolic status of an individual and, thus, enable the evaluation of risk of drug failure or toxicity. Some clinical applications of pharmacogenetics (5-FU, irinotecan, thiopurines) have already been developed in routine medicine resulting in significant improvement in patient treatment. The clinical validation of an increasing number of pharmacogenetic tests, as well as the development of new highly efficient technologies for genotyping (real-time PCR, DNA chips...) should further promote pharmacogenetics in clinical practice and lead to the development of a patient-tailored drug therapy.     

Using pharmacogenetics and pharmacogenomics in the treatment of psychiatric disorders: some ethical and economic considerations

Current pharmacotherapies for psychiatric disorders are generally incompletely effective. Many patients do not respond well or suffer adverse reactions to these drugs, which can result in poor patient compliance and poor treatment outcome. Adverse drug reactions and non-response are likely to be influenced by genetic polymorphisms. Pharmacogenetics holds some promise for improving the treatment of mood disorders by utilising information about genetic polymorphisms to match patients to the drug therapy that is the most effective with the fewest side effects. Pharmacogenomics promises to facilitate the development of new drugs for treatment. However, these technologies raise many ethical, economic and regulatory issues that need to be addressed before they can be integrated into psychiatry, and medicine more generally. We discuss ethical and policy issues arising from pharmacogenetic testing and pharmacogenomics research, such as informed consent, privacy and confidentiality, research on vulnerable persons and discrimination; and economic viability of pharmacogenetics and pharmacogenomics. We conclude with recommendations for the regulation and distribution of pharmacogenetic testing services and pharmacogenomic drugs.     

人类单核苷酸多态性及其在医学领域的研究进展

单核苷酸多态性(SNPs)作为第3代遗传标记,在人类基因组中广泛存在,已广泛应用于人类遗传学、基础医学、临床医学、药物基因组学等多学科研究.在此,主要介绍SNPs的分类及特点、常用检测技术、在医学领域的研究进展以及其存在的问题和发展前景.     

The Genome Clinic: A Multidisciplinary Approach to Assessing the Opportunities and Challenges of Integrating Genomic Analysis into Clinical Care

Our increasing knowledge of how genomic variants affect human health and the falling costs of whole‐genome sequencing are driving the development of individualized genetic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to guide health care decisions throughout life, to anticipate, diagnose, and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific, and clinical paradigms. The potential benefits of presymptomatic identification of at risk individuals, improved diagnostics, individualized therapy, accurate prognosis, and avoidance of adverse drug reactions coexist with the potential risks of uninterpretable results, psychological harm, outmoded counseling models, and increased health care costs. Here, we review the challenges of integrating genomic analysis into clinical practice and describe a prototype for implementing genetic medicine. Our multidisciplinary team of bioinformaticians, health economists, ethicists, geneticists, genetic counselors, and clinicians has designed a “Genome Clinic” research project that addresses multiple challenges in genomic medicine—ranging from the development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference, and the ethics of consent.     

Pharmacogenetics and pharmacogenomics in rheumatology

Pharmacogenetics and pharmacogenomics deal with possible associations of a single genetic polymorphism or those of multiple gene profiles with responses to drugs. In rheumatology, genes and gene signatures may be associated with altered efficacy and/or safety of anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs) and biologics. In brief, genes of cytochrome P450, other enzymes involved in drug metabolism, transporters and some cytokines have been associated with responses to and toxicity of non-steroidal anti-inflammatory drugs, corticosteroids and DMARDs. The efficacy of biologics may be related to alterations in cytokine, chemokine and FcγR genes. Numerous studies reported multiple genetic signatures in association with responses to biologics; however, data are inconclusive. More, focused studies carried out in larger patient cohorts, using pre-selected genes, may be needed in order to determine the future of pharmacogenetics and pharmacogenomics as tools for personalized medicine in rheumatology.     

The SickKids Genome Clinic: developing and evaluating a pediatric model for individualized genomic medicine

Our increasing knowledge of how genomic variants affect human health and the falling costs of whole‐genome sequencing are driving the development of individualized genomic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to anticipate, diagnose and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific and clinical paradigms. The potential benefits of pre‐symptomatic identification of at‐risk individuals, improved diagnostics, individualized therapy, accurate prognosis and avoidance of adverse drug reactions coexist with the potential risks of uninterpretable results, psychological harm, outmoded counseling models and increased health care costs. Here we review the challenges, opportunities and limits of integrating genomic analysis into pediatric clinical practice and describe a model for implementing individualized genomic medicine. Our multidisciplinary team of bioinformaticians, health economists, health services and policy researchers, ethicists, geneticists, genetic counselors and clinicians has designed a ‘Genome Clinic’ research project that addresses multiple challenges in pediatric genomic medicine – ranging from development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference and the ethics of consent.     

Integrative medical education: development and implementation of a comprehensive curriculum at the University of Arizona.

Dissatisfaction with the U.S. health care system is increasing despite impressive technologic advances. This dissatisfaction is one factor that has led patients to seek out complementary and alternative medicine (CAM) and led medical schools to start teaching CAM. This paper focuses on the University of Arizona's approach to developing and implementing a comprehensive curriculum in integrative medicine. Integrative medicine is defined much more broadly than CAM. It is healing-oriented medicine that reemphasizes the relationship between patient and physician, and integrates the best of complementary and alternative medicine with the best of conventional medicine. Since its inception in 1996, the Program in Integrative Medicine (PIM) has grown to include a two-year residential fellowship that educates four fellows each year, a distance learning associate fellowship that educates 50 physicians each year, medical student and resident rotations, continuing medical and professional education, an NIH-supported research department, and an active outreach program to facilitate the international development of integrative medicine. The paper describes the PIM curriculum, educational programs, clinical education, goals, and results. Future strategies for assessing competency and credentialing professionals are suggested.     

Pharmacogenomics and its implications for autoimmune disease

A striking failure of modern medicine is the debilitating and lethal consequences of adverse drug reactions (ADRs) which rank as one of the top ten leading causes of death and illness in the developed world with direct medical costs of 137-177 billion US dollars annually in the USA. Although many factors influence the effect of medications (i.e. age, organ function, drug interactions), genetic factors account for 20-95% of drug response variability and play a significant role in the incidence and severity of ADRs. The field of pharmacogenomics seeks to identify genetic factors responsible for individual differences in drug efficacy and adverse drug reactions. Pharmacogenomics has led to several genetic tests that provide clinical dosing recommendations. For autoimmune disease, pharmacogenomics has led to several DNA-based tests to improve drug selection, optimize dosing, and minimize the risk of toxicity. The 'GATC' project is a nation-wide project established in Canada to identify novel predictive genomic markers of severe ADRs in children. An ADR surveillance network has been established in all of Canada's major children's hospitals, serving up to 75% of all Canadian children. The goal of the project is to identify patients experiencing specific ADRs, collect DNA samples, and apply genomics-based technologies to identify ADR-associated genetic markers.     

Returning integrated genomic risk and clinical recommendations: The eMERGE study

PurposeAssessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.MethodsTo enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results.ResultsGIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.ConclusionReturn of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.     

The polymerase chain reaction. History, methods, and applications.

The polymerase chain reaction (PCR) uses in vitro enzymatic synthesis to amplify specific DNA sequences. PCR amplification can produce approximately 100 billion copies of one molecule of DNA in a few hours. PCR has revolutionized research in the biological sciences and medicine, and has influenced criminology and law. Several major scientific discoveries, including purification of DNA polymerase and elucidation of the mechanism of DNA replication, were essential for development of the present PCR technology. An overview of these discoveries and early work on in vitro DNA synthesis are presented. Basic PCR methodology, instrumentation, advanced PCR techniques, and applications are also discussed in this review. Several new amplification systems are mentioned. PCR is an extremely important and simple technology for research and diagnostic analyses of DNA and RNA. PCR technology and other amplification procedures will continue to produce novel applications in basic research and clinical medicine.     

Discrepant DNA analysis in three patients with inherited arrhythmia: molecular genetic test results deserve a second glance

Molecular results provide a basis for diagnosis, risk assessment, medical management and genetic counseling. Unlike other areas of laboratory medicine, molecular genetic tests are rarely repeated. We describe three patients with suspected inherited arrhythmia in whom genetic testing was arranged via clinical and/or research laboratories. In all three instances, initial test results appeared falsely negative, with no deleterious mutations detected by various methodologies in selected long-QT or catecholaminergic polymorphic ventricular tachycardia-related genes. Discordant results emerged upon repeat analysis in separate laboratories. The cases highlight the importance of clinical judgment and assessment of genetic test results and methodology, in addition to the role of re-testing in molecular genetic medicine, particularly in the case of uninformative negative results.     

药物基因组学临床决策支持系统综述

近几年来精准医学成为生物医学的一个热门领域,世界各国都致力于率先在这一领域取得突破性的进展。药物基因组学(PGx),通过基因组学和其他“组学”知识来个性化药物选择和药物使用以避免药物不良反应和最大化药物疗效,是精准医学的重要组成部分,也是目前最有希望在临床上实现日常应用的精准医学领域之一。其中药物基因组学临床决策支持(PGx-CDS)系统,是实现PGx临床应用和知识转化必不可少的工具。目前很多临床医疗机构已经开展PGx服务并部署PGx-CDS系统,同时更多的临床医疗和研究机构正在筹备开展这类服务。对目前已出现并被报道的主要PGx-CDS系统和研究进行文献综述,共涉及11个PGx-CDS系统。通过对这些系统的临床应用场景、系统设计、知识表达、干预方式和应用评估等方面的综合回顾,总结目前PGx-CDS系统的研究进展和发展现状,然后对PGx-CDS系统目前面临的主要挑战和未来发展方向进行讨论,为在国内落地PGx服务和PGx-CDS系统提供借鉴。     

A communication assessment and skill-building exercise (CASE) for first-year residents.

OBJECTIVE: Good communication skills are essential for residents entering postgraduate education programs. However, these skills vary widely among medical school graduates. This pilot program was designed to create opportunities for (1) teaching essential interviewing and communication skills to trainees at the beginning of residency, (2) assessing resident skills and confidence with specific types of interview situations, (3) developing faculty teaching and assessment skills, (4) encouraging collegial interaction between faculty and new trainees, and (5) guiding residency curricular development. DESCRIPTION: During residency orientation, all first-year internal medicine residents (n = 26) at the University of Minnesota participated in the communication assessment and skill-building exercise (CASE). CASE consisted of four ten-minute stations in which residents demonstrated their communication skills in encounters with standardized patients (SPs) while faculty members observed for specific skills. Faculty and SPs were oriented to the educational purposes and goals of their stations, and received instructions on methods of providing feedback to residents. With each station, residents were provided one and a half minutes of direct feedback by the faculty observer and the SP. The residents were asked to deal with an angry family member, to counsel for smoking cessation, to set a patient-encounter agenda, and to deliver bad news. A resident's performance was analyzed for each station, and individual profiles were created. All residents and faculty completed evaluations of the exercise, assessing the benefits and areas for improvement. DISCUSSION: Evaluations and feedback from residents and faculty showed that most of our objectives were accomplished. Residents reported learning important skills, receiving valuable feedback, and increasing their confidence in dealing with certain types of stressful communication situations in residency. The activity was also perceived as an excellent way to meet and interact with faculty. Evaluators found the experience rewarding, an effective method for assessing and teaching clinical skills, a faculty development experience for themselves in learning about structured practical skills exercises, and a good way to meet new interns. The residency program director found individual resident performance profiles valuable for identifying learning issues and for guiding curricular development. Time constraints were the most frequently cited area for improvement. The exercise became feasible by collaborating with the medical school Office of Education-Educational Development and Research, whose mission is to collaborate with faculty across the continuum of medical education to improve the quality of instruction and evaluation. The residency program saved considerable time, effort, and expense by using portions of the medical school's existing student skills-assessment programs and by using chief residents and faculty as evaluators. We plan to use CASE next year with a wider variety of physician-patient scenarios for interns, and to expand the program to include beginning second- and third-year residents. Also, since this type of exercise creates powerful feedback and assessment opportunities for instructors and course directors, and because feedback was so favorable from evaluators, we will encourage participation in CASE as part of our faculty educational development program.     

Information technology,medical education,and anatomy for the twenty-first century

Medicine is experiencing an escalating explosion of information. With more data available about more topics, the key questions are how to access and make sense of the medical information jungle. Skill in choosing and applying information is essential for both medical education and practice and will require new approaches to mastering data. Medical education, like medicine itself, will continue to be driven by technology, and we can expect our students to be increasingly computer literate. Thus the role of medical education will become more one of how to use this information than of obtaining the information itself. What medical education must focus on is the processing of information for appropriate medical care. This, in turn, depends upon practitioners having contexts in which the relevance and significance of information can be evaluated. New imaging technologies and molecular advances demand a broader understanding of both health and disease. With the information explosion “on line,” how can a student use this to understand the structure and function of the human body in four dimensions? Anatomy, the structural basis for life, provides a unique and necessary perspective on the human body from the molecular to the macroscopic. A solid foundation in anatomy is the best preparation for an effective physical examination and for safe, efficient basic clinical procedures. Finally, anatomy laboratories provide a context for learning other important aspects of medicine—group process, clinical problem solving, and a sensitivity to human mortality. Advocating for these unique features of our discipline in medical education is the task facing anatomists as we end this millennium. The challenges and opportunities for us have never been greater, if we don't throw out the baby with the bath water. © 1996 Wiley-Liss, Inc.     

Assessment in Clinical Psychology: A Perspective on the Past, Present Challenges, and Future Prospects

Assessment emerged during the early twentieth century with the development of tests for assessing characteristics such as intelligence, personality, and suitability for employment. The long, interwoven relationship between clinical psychology and assessment began to change during the 1970s when many clinical psychologists became more involved in behavioral therapy and moved away from psychological testing and with the expanding role of managed care in the mental health services. Clinical assessment broadened into forensic, medical, and personnel applications with psychologists expanding professional roles. The status of assessment was reviewed and some challenges were highlighted. The potential for assessment to contribute to the understanding of mental health problems through collaborative cross-cultural study of psychopathology was suggested with the growing development of clinical psychology internationally.     

Predictive data mining in clinical medicine: current issues and guidelines

BACKGROUND: The widespread availability of new computational methods and tools for data analysis and predictive modeling requires medical informatics researchers and practitioners to systematically select the most appropriate strategy to cope with clinical prediction problems. In particular, the collection of methods known as 'data mining' offers methodological and technical solutions to deal with the analysis of medical data and construction of prediction models. A large variety of these methods requires general and simple guidelines that may help practitioners in the appropriate selection of data mining tools, construction and validation of predictive models, along with the dissemination of predictive models within clinical environments. PURPOSE: The goal of this review is to discuss the extent and role of the research area of predictive data mining and to propose a framework to cope with the problems of constructing, assessing and exploiting data mining models in clinical medicine. METHODS: We review the recent relevant work published in the area of predictive data mining in clinical medicine, highlighting critical issues and summarizing the approaches in a set of learned lessons. RESULTS: The paper provides a comprehensive review of the state of the art of predictive data mining in clinical medicine and gives guidelines to carry out data mining studies in this field. CONCLUSIONS: Predictive data mining is becoming an essential instrument for researchers and clinical practitioners in medicine. Understanding the main issues underlying these methods and the application of agreed and standardized procedures is mandatory for their deployment and the dissemination of results. Thanks to the integration of molecular and clinical data taking place within genomic medicine, the area has recently not only gained a fresh impulse but also a new set of complex problems it needs to address.