Genetics Research and the Public Health

Genetics, Research and the Public Health The Case for Public Health Genetics Dr Ron Zimmern MA, FRCP, FFPHM Director, Public Health Genetics Unit, Cambridge NHS R & D Forum, Keele University 12 July 2004 Structure of Talk 1. 2. 3. 4. 5. Public health genetics Concepts in public health genetics Competencies and the knowledge base The research agenda in public health genetics Policy considerations Definitions Public Health The art and science of promoting health and preventing disease through the organised efforts of society Public Health Genetics The application of advances in genetics and molecular biology on promoting health and preventing disease Framework for the Integration of Genetic Science into Health Services KnowledgeBase Genetic & Molecular Science Modern Biology Population Science Humanities & Social Science (ELSI) Public Health Genetics Genetic Testing HTA and HSR Regulation and QA Epidemiology Policy Analysis Analysis & Assessment Evaluation & Assurance ELSI Action & Policy Development Building Infrastructure for the Decades Ahead Research Clinical, laboratory and public health practice Practice Analysis and Assessment 1. Human genome epidemiology The systematic application of epidemiological methods and approaches in population based studies of the impact of human genetic variation on health and disease • prevalence of genotype • measures of effect – relative risk, absolute risk, population attributable fraction • gene-gene and gene-environment interaction 1. Policy analysis • science, commercial, information, educational, financial • public involvement • ELSI implications HEALTH WEALTH Action and Policy Development Development of health service capacity to integrate genomics into health care and building infrastructure • manpower planning • education and training • research and development • partnerships and interdisciplinarity • working with the commercial sector Evaluation and Assurance I. Health Technology Assessment The ACCE Framework for genetic test evaluation 1. A nalytical validity 2. C linical validity 3. C linical utility 4. E thical, legal and social Two specific technical problems • Distinction between diagnostic tests, and predictive and susceptibility tests • Clinical validity and the population context I. Health Services Research Effectiveness and cost-effectiveness of service delivery Regulatory Issues Three Levels 1. Statutory legislation regulation codes of practice Issues in Regulation 1. 2. 3. Regulation of laboratories and regulation of tests Regulation of products and regulation of service Genetic tests • • • How are they to be defined? Are they special and should they be regulated in a different manner? Simple tests and complex tests? 1. Resource Allocation NICE and HTA commissioners 4. 5. 6. Regulation of over the counter tests and regulation of professionally ordered tests “In house” tests and tests “placed on the market” Adquacy of existing regulations • • The EU Directive Consumer legislation and regulation 1. Clinical governance education Concepts in Public Health Genetics Genetics 1. Genetics as inheritence single gene disorders inherited in a mendelian fashion genetic services familial association 2. Genetics as cell and molecular biology the genetic component of all human traits and diseases the basis of development modern biology Determinants of Health Genetic Genetic Endowment Biological INDIVIDUALS Physical Natural Environment POPULATIONS Political Social Structural Environment Behavioural Individual Behaviour Gene-Environment Interrelationship GENES ENVIRONMEN T Population and High Risk Approaches Geoffrey Rose Complementary approaches Shift of population distribution Systolic B/P 90 100 110 120 130 140 150 160 170 180 Inherited and Complex Diseases Inherited diseases Cystic fibrosis Duchenne muscular dystrophy Huntington’s disease Familial polyposis coli Familial hypercholesterolaemia Phenylketonuria Complex diseases Diabetes Cardiovascular Cancer Alzheimer’s Hypertension Schizophrenia Rheumatoid arthritis Learning disability Penetrance Gene (Genotype) Other Genes Genetic Risk Gene-gene interaction Disease Risk Gene-environment interaction Environment Disease (Phenotype) Development of Disease 0 10 20 30 40 50 60 70 80 90 Environmental Factors Induction Period Latent Period Genetic Component Idea from Khoury and Cohen (1988) J Clin Epid 41, 1181 Clinical Onset Death Gene-environment Interaction Heart disease PKU Cancer Cystic fibrosis Fragile X Multiple Diabetes sclerosis Asthma Rheumatoid arthritis Schizophrenia Alzheimers TB Obesity Motor vehicle accident Duchenne muscular dystrophy Struck by Meningococcus lightning Autism Totally Genetic Totally Environmental Risk, Genes, and Environment Prev=5% RR=20 Environmental Exposure Prev=95% RR=1.05 TOTAL RR = 2.0 Complexity in Genetic Science 1. Gene-gene interaction 2. Control of transcription 3. Alternative splicing 4. Post translational modification 5. Temporal effects Genetic Exceptionalism Genetic exceptionalism is the claim that genetic information is sufficiently different from other types of health information that it deserves special protection or other exceptional measures Genetic Exceptionalism Arguments For 1. Concern about “genetic prophecy” - can predict our medical future 2. Concern for “kin”- relevant to other family members 3. Concern for “discrimination” - stigmatisation 4. Concern for “identification”unique nature and stability of DNA Arguments against 1. Counter-arguments to the “arguments for” 2. The “two-bucket” theory of disease 3. Danger of genetic determinism Adapted from TH Murray: Genetic Exceptionalism and Future Diaries (1997) The Impact of Genetics A better understanding of disease mechanisms A new categorisation of disease based on genotype A faster and more rational drug discovery process Greater diagnostic potential through genetic testing Opportunities for the prediction and prevention of disease Novel therapeutic interventions and pharmacogenetics Susceptibility Testing and Prevention 1. 2. 3. 4. 1. Genotype-phenotyope correlation Public acceptability Effective interventions Behaviour and compliance Societal implications - justice and discrimination Competencies and the Knowledge Base Genetic Literacy and Society 1. Specialists in public health genetics 2. 3. 4. 5. Health professionals and health service managers Media Commercial, legal and financial community Policy makers 6. 7. 8. Politicians Patients General public Professonal Competence Knowledge Base Genetic Science Public Health Science Humanities and Social Science Public Policy Technical Skills THE SCIENCE Health Needs Assessment Programme Planning Data Analysis Review and Evaluation Management Financial Planning PROFESSIONAL COMPETENCE IN PUBLIC HEALTH GENETICS Interpersonal Skills THE ART Political Sensitivity Ethnicity Cultural differences Personal Development Knowledge Base for Public Health Genetics GENETIC SCIENCE • • Basic concepts of mendelian genetics Family histories and pedigrees Risk assessment and communication Principles of genetic epidemiology Principles of molecular genetics Genetic testing and screening Genetics of common disorders Gene-environment interaction POPULATION SCIENCES HUMANITIES • Sociology • • • • Epidemiology Biostatistics Environmental health sciences Infectious diseases • • • • • • • Anthropology Law Economics Ethics Metaphysics and epistemology Theology Political philosophy • • • • • • • Social and behavioural sciences Health economics Health services research Management science • • • • • Information science IP and commercialisation Proposals for Public Health Genetics in UK 1. Establish a sub-specialty of public health genetics 2. Establish competencies and training programme 3. Establish 12 posts in the UK over next 5 to 6 years 9 in England; 1 in Wales; 1 in Scotland and 1 in N. Ireland 1. Establish links with NHS R & D agenda and specialised commissioning 2. Establish an understanding of the commercial sector and its relevance for public health Education in Genetics for Health Professionals • Strategy for increasing the knowledge and understanding of genetics across the health care professions physicians, nurses, pharmacists, dieticians, public health professionals, health service managers • • • Commitment of Wellcome Trust to background report Strategy commissioned jointly by Wellcome Trust and DH Wide involvement of professional and public stakeholders Addressing Genetics, Delivering Health Main Findings Importance of genetics accepted but most practitioners are still at the stage of unconscious incompetence Genetics is worthy of a special initiative Developing genetics education will be a huge undertaking, unprecedented in its scale and complexity Main Recommendations There should be a National Steering Group to ensure strategic leadership and commitment There should be an Education Centre to provide focus, coordination and energy to the work A major programme should be established to raise awareness, develop genetics in formal and informal curriculum and educate by support to clinical practice Substantial resources will be required £2-3million pa simply to provide a supporting infrastructure The Research Agenda in Public Health Genetics Epidemiology, Health Technology Assessment, Health Services Research Ethical, Legal and Social Research Epidemiological Research 1. DNA banks population based disease based A stored collection of genetic samples, in the form of blood or tissue, that can be linked with medical and geanological or lifestyle information from a specific population, gathered using a process of generalised consent. Austin et al (2003) UK BioBank, DeCode (Iceland), Estonia, Latvia, CartaGene (Canada) 1. Primary research linkage studies genetic association studies gene-environment interaction 1. Secondary research systematic reviews meta-analysis Methodology for appraising association studies Meta-analysis of lipoprotein lipase and heart disease Meta-analysis of CYP2D9 and Warfarin Estimates of family history risk in common conditions CCR5 ∆32 Variant and Protection from HIV-1 Infection • CCR5 - immune system cell surface receptor Co-receptor for entry of HIV-1 Common CCR5 gene variant, ∆32 allele: • • Present in over10% of Caucasians Virtually absent in African and East Asian populations ∆32 heterozygotes partly protected from infection and show slower disease progression to AIDS Chasman DI et al. (2004) JAMA 291, 2821-2827 • ∆32 homozygotes largely protected from HIV-1 infection Metabolic Gene Variants and Cigarette Smoking Combined associations of maternal smoking during pregnancy and CYP1A1 and GSTT1 gene polymorphisms with infant birth weight. • • Smoking in pregnancy linked with low birthweight Toxins in smoke metabolised by CYP1A1 and GSTT1 enzymes • • • AA= homozygous wild-type, Aa = heterozygous variant type, aa= homozygous variant type. Certain CYP1A1 and GSTT1 gene variants influence ability to detoxify smoke Smokers showed the greatest reduction in birth weight (av.1285g) Non-smokers with same genotype showed no decrease in birth weight Adverse effects of smoking modified by maternal genotype Wang X et al. (2002). JAMA. 287, 195-202 Gene Expression Signatures and Cancer Prognosis • • 295 young women with breast cancer Expression of 70 genes previously identified as representing prognostic profile analysed Subjects assigned to good or poor prognosis groups based on profile Prognostic profiles compared favourably with current diagnostic criteria (St Gallen or NIH consensus) for predicting metastasis • • van de Vijver MJ (2002). N Engl J Med. 347, 1999-2009 Research Activities in the PHGU (1) 1. Health Technology Assessment Use of molecular genetic testing in FH Evaluating the ACCE methodology for genetic tests Gene expression arrays and cancer 2. Health Service Research Pathways of care in the genetic testing of childhood learning disability Establishment of a database for health economic studies in genetic services Nutrigenomics Research Activities in the PHGU (2) 3. ELSI Research IPR and DNA patents Regulatory bodies for genetic technologies Legal aspects of stem cell research Genetic Disease Conceptual Analysis Moral & Political Theory Social Aspect Medical Law IPR and Commercial -isation Regulatory Governance of medical databases Genetic research in ICUs: capacity and consent The law and human tissue Causation in epidemiological research Conceptual analysis of disease with special reference to genetics Regulation, information and genetics Genetic Tests HumanTissue Stem Cells Personal Data & Genetic Databases PGx Consent & Confidentiality Policy Considerations A Framework: The Nuffield Genetics Scenario Project Two drivers 1. 2. Science and its capacity to improve human health Public attitudes towards genetics The regulatory framework External Drivers Public attitudes Science Six policy issues 1. 2. 3. 4. 5. 6. The regulatory framework Educational strategies The science base Commercial considerations Information and confidentiality Financial framework for health Political and policy machine The science base Educational strategies Commercial Financial Framework Info and confidentiality Heatlth Services Ethical, legal & social Science and Its Capacity to Improve Human Health Science and its capacity to improve human health Pace at which genetic science will impact on health and health services uncertain Is the science too complex? Will it be too expensive? Can it deliver? • • economic constraints scientific constraints Pace - optimists and realists Public Attitudes Towards Genetics Public attitudes towards genetics Widespread misunderstanding about genetics • genetic determinism • genetic risk Role of media and of scientists Legacy of eugenics Public disquiet about genetic discrimination YES OPTIMUM SITUATION DESIRED SCENARIO PUBLIC ACCEPT NO NO SCIENCE DELIVERS YES YES Basic science progresses No proven clinical benefit Public eager and accept but science cannot deliver SCENARIO 1 Science does not deliver PUBLIC ACCEPTS NO NO SCIENCE DELIVERS YES YES Stage II Public acceptance declines due to failure of science to provide benefits SCENARIO 1 Science does not deliver PUBLIC ACCEPTS NO NO SCIENCE DELIVERS YES YES SCENARIO 2 Public do not accept PUBLIC ACCEPTS Science delivers but public do not accept Luddite views Stop advances in knowledge NO NO SCIENCE DELIVERS YES YES SCENARIO 2 Public do not accept PUBLIC ACCEPTS NO NO Stage II Continued demonization of science destroys science base SCIENCE DELIVERS YES Conclusion 1. 2. 3. 4. 5. 6. 7. 8. 9. Genetic factors are important determinants of health and disease in human populations Genes are not (in most instances) deterministic of disease, interacting as they do with each other and with environmental factors Genetic exceptionalism should be resisted Genetic science and its impact on health is ill understood and steps should be taken to improve genetic literacy among health professionals and across society as a whole Genetic factors should be taken into account in epidemiological studies Those involved in HSR and HTA should develop an understanding of genetic science in view of its growing impact on health service provision Public health genetics should be developed as an essential element of the public health workforce The impact of genetics on society will depend as much on public acceptance as on scientific developments The application of genetics to benefit human health will be determined as much by geenral policy considerations (science, commerce, regulation) as to specific changes in service provision within the NHS www.cgkp.org.uk www.phgu.org.uk www.cmgp.org.uk