Do we all have an actionable genome?

Transcription

1 Do we all have an actionable genome? Evidence from, and implications for, registries and electronic health records Professor Harry Hemingway, MD, FFPH, FRCP Director Farr Institute of Health Informatics Research, London Director Institute of Health Informatics, University College London, London, UK REGISTER IN DER MEDIZIN: WO STEHT DIE SCHWEIZ? 1 Februar 2018, UniS Bern

2 justify any research application that does not include genomic analysis Annual Report, Chief Medical Officer of England, Dame Sally Davies 2017

3 Mining healthcare data save 100,000 lives next year Larry Page, 2014 Unsustainable health/social care: Costs outstrip GDP growth King s Fund The new era of data based and more precise medicine White House 2015 Global Challenges Broken models of drug development and trials Eroom s law Informatics- the clean water of 21 st c. public health Dame Anne Johnson, 2016

4 Data

5 21 st Century challenge for HEALTH SYSTEMS: value from data Better health outcomes for individuals and populations [adapted from] Jameson NEJM 2015

6 21 st Century challenge for HEALTH SYSTEMS: value from data at scale Near term patient benefit, with precision Diagnosis Screening Treatment Prognostics Decision support Longer term benefit for drug development, innovation and society All driven by an emerging clinical research paradigm: Evidence Generating Medicine at scale

7 SCALE and DEPTH ecosystem of data Research cohort + DNA Scale: Total population size (millions) 15,000,000 5,000, ,000 50,000 CALIBER Phenome wide MONDRIAAN G W A S Geisinger Health system + DNA Health system - Disease-based + DNA Disease-based - INTERVAL UK Biobank UK BIOBANK Registries Longitudinal EHR Genome array Res pheno Depth: phenotypic and omic Hemingway et al Eur heart J 2017 Exomes Multi-omics Research Imaging + Sequencing (exomes)

8 RESOURCES WITH GENOME SEQUENCE + EHR PHENOME SEQUENCE Research cohort e.g UK Biobank Health system e.g.geisinger Current N participants 500k 50k Research measures MRI, wearables minor Open access Yes ++ no Scalable No, fixed yes Health system embedded no yes Return clin actionable results no yes

9 15,000,000 CALIBER Population-based Hospital-based Disease-based Total population size (millions) 5,000, ,000 50,000 UK CV registries NICOR Swedish CV registries SWEDEHEART ESC EOPR ABUCASIS MONDRIAAN NIHR HIC HERMES GENIUS CHD AFGEN BioVU MVP RPGEH Kadoorle * With genetic information UCLEB Proposed PMI Cohort Initiative INTERVAL Geisinger UK BIOBANK EPIC CVD emerge Registries Longitudinal EHR Genomics Multi-omics Imaging + Sequencing (exomes) Phenotypic depth

10 Each of us differs in our genome sequence A lot of us are getting sequenced estimated 200 million people by 2025 Consider 4 areas in which genome sequence may be actionable 100 complete knockouts genes with Loss of Function Evans et al., JAMA, 2017

11 1. Rare monogenic diseases N=5000

12 1. Rare monogenic diseases N=5, Common complex diseases N=10,000

13 1. Rare monogenic diseases N=5, Common complex diseases N=10, Drugs N=1400

14 1. Rare monogenic diseases N=5, Common complex diseases N=10, Drugs N= Behaviours N=umpteen

15 Aka Omics: as the ultimate complex intervention?

16 1. MONOGENIC DISEASES

17 One monogenic disease: Familial Hypercholesterolaemia (FH) Autosomal recessive with many variants described in LDLR, APOB, and PCSK9 How common is FH? No previous large scale WES studies Geisinger Health System EHR + Regeneron whole exome sequencing N = 229 / 50,726 patients had one or more of 35 known and predicted pathogenic variants Prevalence higher x 2 than previous estimates or prevalence: 1:256 Abul-Husn Geisinger-Regeneron et al Science 2016

18 Health System Wide Screening for FH with whole exome sequencing (WES) reveals undertreatment n=50,276 Abul-Husn et al Science 2016

19 But there are monogenic diseases ( protein coding genes) What is the combined prevalence of all monogenic diseases? 8 % estimated in Europe most detectable with this same test of whole genome sequencing Some of these gene variants are considered clinically actionable even if the patient has NO family history and NO symptoms i.e. healthy population

20 28 monogenic diseases are currently recommended actionable secondary findings by American College of Medical Genetics Disease name and MIM number Gene via GTR Action Familial hypercholesterolemia (MIM ) APOB (MIM ) LDLR (MIM ) Drugs: Statins, cascade screening Adenomatous polyposis coli (MIM ) APC (MIM ) Endoscopic: surveillance Aortic aneurysm, familial thoracic 4 (MIM ) Breast-ovarian cancer, familial 1 (MIM ) MYH11 (MIM ) BRCA1 (MIM ) Imaging: surveillance Surgery: Prophylactic Long QT syndrome 2 (MIM ) KCNH2 (MIM ). for all 28 diseases. Hunter Genetics In Medicine 2016 Device: implantable cardiodefibrillator

21 HOW COMMON ARE THESE 28 MONOGENIC DISEASES CLINICALLY ACTIONABLE VARIANTS? Until recently we didn t know most exomes done on patients SELECTED on basis of disease Whole exome sequencing in Geisinger health system: Patients were NOT SELECTED on the basis of having a rare disease or for having family history 49/1415 = 3.5% prevalence Dewey et al DiscovEHR Geinsinger-RegeneronScience 2016

22 Registers play a key role In understanding whether a gene variant is truly pathogenic and actionable As whole genome sequencing becomes a clinical test this need increases

23 2. COMMON COMPLEX DISEASES

24 Actions from genomic variants for Complex Diseases Based on causal understanding of mechanisms of disease(s) Including genomic approaches to drug target validation (e.g. ezetimbie and NPC1L1 NEJM 2014) Based on massive abilities to predict onset and progression of many diseases (irrespective of causal relevance)

25 One disease: coronary disease Primary prevention with statins is based on absolute risk (Framingham risk scores, Q risk etc) Based on <20 factors: age, sex, smoking, BP, chol What if we used millions of pieces of information (genetic variants) instead? Change clinical decision making, by classifying individuals above treatment threshold (10% risk) at earlier age?

26 One disease: coronary disease 20% of the general population with higher GRS, exceed risk threshold at much younger age Based on 1.7 million genetic variants Inouye et al UK Biobank Cardiometabolic Consortium

27 Potential for earlier diagnosis of MANY diseases: e.g. cancer? liquid biopsies -cell free tumour DNA (2001 genomic positions) + 8 proteins Cohen et al Science 2018

28 Registers play a key role Guess where CancerSEEK is mounting its 50k patient trial? DNA samples are collected and discarded unanalysed by the billion each day. Need long term support Need linkage between registers

29 3 DRUGS

30 Actions from genomic variants for DRUG response To avoid harms (safety) and deliver benefits (efficacy) Right patient: cystic fibrosis and ivacaftor Right drug: Stevens Johnson Synd, abacavir trial Right dose: bleeding, warfarin trial Right time: early in prevention e.g. Inouye 2018 Across a wide range of drugs taken at different stages in the lifecourse

31 One Drug Gentotype Interaction: randomised evidence of effectiveness? Gage et al GIFT JAMA 2017

32 Five Drug-Genotype Interactions

33 Five Drug-Genotype Interactions How common are these variants? >90% of healthy population How common is exposure to one of these drugs in a 60 year old over a 5 year period?

34 130 drugs have an FDA label saying consider genetic testing (only 1400 approved drugs) Clinical Pharmacogenetics Consortium (CPIC) Give recommendations in the setting of the genetic result Pre-emptive pharmacogenetics: variants already in the Register or EHR with decision support ready if and when a drug is

35 4. Behaviours

36 Actions from genomic variants for health related behaviours To avoid harms (safety) and deliver benefits (efficacy) Right behaviour: Right dose: Right time: early in prevention Across wide range of behaviours (not one at a time) over the 5000 hover hours per year Asch NEJM 2012

37 Smoking pharmacogenetics of nicotine and nicotine replacement therapy (NRT) e.g. does NRT effectiveness differ by genotype NRT Bupropion Varenicline 1 Lerman, Am J Prev Med. 2007

38 What Diet and Exercise works best for your genes? 1. Download your 23and me file 2. Search for the best SNPs below rockstarresearch.com

39 Registers play a key role Bringing together the always on data about behaviours from mobile and wearables with clinical data

40 1. Rare monogenic diseases N=5, Common complex diseases N=10, Drugs N= Behaviours N=umpteen

41 Preventive Genomics: Pilot Randomised Trial Returning results from Whole Genome Sequencing in primary care 1. Monogenic disease carrier status n=28 diseases 2. Complex diseases risks n=8 Genetic Risk Scores 3. Drug-gene interactions n=5 drug-gene pairs 4. Behaviours n=0 Vassy JL, et al MedSeq Project. Ann Intern Med. 2017

42 Preventive Genomics: Pilot Randomised Trial 51 patients WGS vs 50 patients family history only Monogenic disease risk 22% vs 0% New clinical actions recommended 34% vs 16% Behaviours change at 6 months 41% vs 30% Vassy JL, et al MedSeq Project. Ann Intern Med. 2017

43 UK Approach?

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45 Conclusion: Do we all have an actionable genome? Without large scale integrated registers and EHRs with embedded genomics we will never know!

46 b

47 Thank you