Professor Dame Anna Dominiczak Regius Chair of Medicine Vice-Principal and Head of College of Medical, Veterinary & Life Sciences Genomics and other Omics

DNA Genomics mRNA Transcriptomics miRNAs Protein Proteomics

Metabolites Metabolomics small molecules

Pjanic M et al. Curr Cardiol Rep 2016;18:102 The Perfect Storm

Age(Yrs) ’s Aging Population

100 2031 90 1951 Global economic impact of 80 Males Females 70 the chronic diseases -- cancer, 60 diabetes, mental illness, heart 50 disease, and respiratory 40 disease -- $47 trillion over the 30 next 20 years. 20 10 (World Economic Forum) 0 60,000 40,000 20,000 0 20,000 40,000 60,000 Population Headcount Trial & Error Medicine

% patient population that responds to drug class

90% top selling Diabetes 57% blockbuster medicines Arthritis 50% only work for 30–50% of patients Cancer 25% Precision Medicine Input Value Tools Outputs Affected Disease Strata population • Diagnostics to better predict disease state, prognosis, response Clinical to treatment Presentation • Mechanism of disease leading to Medical new therapies Imaging

Genetic / Therapeutic Molecular Response

Capturing this potential requires partnership between researchers, industry (BioPharma and Diagnostics) NHS and patients. No one group has all the necessary skills/resources.

5 Linkage of Scottish Health Records

Dental SMR13 Mental Health SMR04 Community care SMR50

Neonatal Record SMR11 Out patients SMR00 Hospital Admissions SMR01

GP consultations BIRTH

Maternity DEATH Immunisation Prescribing Screening Cancer registry

Child health surveillance Cancer registrations SMR06

CHI = Community Health Index Omics technologies available for integrated analyses

Genome Transcriptome Proteome Metabolome

Enzymes DNA RNA Metabolites Protein 3 N~2x104 N~4x104 N~106 N~5x10 Precision Medicine Scotland – Innovation Centre

6 Exemplars: Ovarian, Oesophageal & Pancreatic Cancers, Rheumatoid Arthritis, Multiple Sclerosis, IBD/COPD Precision Oncology Therapeutic Development

Andrew Biankin Regius Professor of Surgery Director, Wolfson Wohl Cancer Research Centre University of Rheumatioid Arthritis

• Involved: • Prof Iain McInnes (UoG; PI) • Dr Duncan Porter (GGHB) • Prof Paul McKeigue (UoE) • SMS-IC SMART Lab • Sistemic • ThermoFisher • Aridhia • Delivers: • Pharmacogenomic relationship for response/non response to methotrexate in RhA • Utility: • Allows clinicians to prescribe MTX only in cases where evidence base predicts it will work • Creates more compelling arguments for use of biological therapy in early RhA Glasgow – Swedish GWAS of HTN

n=2000 Hypercontrols Cases n=2000 • Malmö Diet and Cancer Study • Nordic Diltiazem Study (MDC) (NORDIL) • BP< 120/80mmHg • 2 consecutive BPs > • at least 50 years of age 160/100mmHg • free from cardiovascular events • diagnosis < 60 years of age during 10yr follow-up • not on hypertensive medication

Bottom 9.2% Top 1.7%

80 100 120 140 160 180 200 Systolic BP (mmHg)

Padmanabhan S et al. PLoS Genetics 2010;6:e1001177 Uromodulin regulates sodium homeostasis in the kidney

-log10(p) Meta-analysis p=1.5x10-13 rs13333226

80 Recombinationrate (cM/Mb) 8 ) rs13333226 0.8 P p=1.14x10-07 10 0.5 60

6

log - r2 40 4

20

Observed ( Observed 2

0 0 GP2 FLJ20581 UMOD LOC123876 PDILT Chromosome 20200 20300 Chromosome 16 position (kb) Padmanabhan S et al. PLoS Genetics 2010;6:e1001177 Uromodulin

Previously called Tamm– Horsfall protein

Expressed exclusively by the thick ascending limb of the loop of Henle and released into urine from the apical cell membrane.

The thick ascending limb of Henle is impermeable to water and is the site where 25% of filtered Na+ is reabsorbed.

In physiological range it is the most abundant urinary protein.

It is a protective factor for UTI and renal stones. Molecular pathways affecting sodium transport

25%

Padmanabhan et al, Circ Res 2015;116:937 UMOD & Precision Medicine

Hypertension Strata by UMOD rs13333226

High-UMOD Hypertension Low-UMOD Hypertension

Increased UMOD excretion Decreased UMOD excretion Salt sensitivity Salt resistance Increased eGFR Normal eGFR Increased proximal tubular Na Greater BP response to loop reabsorption diuretics Poor BP response to loop diuretics

AA genotype – 67% AG/GG genotype – 33% early add-on loop diuretics in Uncontrolled Hypertension genotype guided algorithm to determine use of loop diuretic those with AA genotype Precision Medicine Clinical Trial

Dundee Repurposing of Torasemide based on genetic make up Clinical Research Centre Health Informatics Centre&Memo CRUK laboratoriesScreening

Uncontrolled Hypertension

Bloods Bloods Bloods Bloods BP>140/90 Bloods • Centres: Glasgow, Edinbaurgh,

Glasgow

AmbulatoryBlood AmbulatoryBlood AmbulatoryBlood AmbulatoryBlood

Dundee AmbulatoryBlood

Pressure MonitoringPressure MonitoringPressure MonitoringPressure MonitoringPressure MonitoringPressure U&E • Integrated100 Subjects CRF 0 14days 28days 56days 84days 112days Queen Elizabeth University Hospital Royal Infirmary Edinburgh Beatson Oncology Centre 2 week run-in Wellcome CRF Discontinue diuretics if prescribed Torasemide 5mg OD Institute Med Cell Biol Recruitment End Nov Commenced May 2017 2019 ‘Science and Innovation Audits 15 Digital Technology and helplocal Data-driven Innovation organisations map Precision Medicine their research and Innovation in Scotland 6 1 22 12 innovation 23 strengths, and 18 21 identify 17 16 10 7 areas of potential 3 2 11 19 global competitive advantage.’ 8 21 4 14 21 13 20 24 25 5 9

21

87 Precision Medicine: the economic opportunity

“The global market value: 2016 - $43bn 2025 - $134bn ”

In Scotland PM could save the NHS - £1.5bn over 5 years www.gla.ac.uk/precisionmedicine/SIA Potential value of Precision Medicine in Scotland 140 119 120 10% reduction in burden 107 50% reduction in burden Value of health 100 (2016-2066) UK £billion 80 72

60 41 40 32 24 21 20 14 6 8 0 Cancer Diabetes Heart disease Lung disease Musculoskeletal • Uses methodology adapted from Dzau et al, The Lancet (2015) • Annual Burden of Disease from The Scottish Burden of Disease Study, 2015 available from http://www.scotpho.org.uk/media/1474/sbod2015-overview-report-july17.pdf • Assumes 10% and 50% reduction in burden from hypothetical precision medicine innovations in five major disease groups • Additional QALYs valued at £20,000 in line with lower accepted UK threshold ‘Game-changing’ Opportunities for Scotland

1. Next generation clinical decision 2. QEUH as a ‘living laboratory’ to support tools realise the potential of PM and drive economic growth

• Accelerating productivity growth for Scotland

• Improving patient outcomes 87 SIPF full proposal in progress…… • Healthcare cost avoidance Safe Haven AI Platform at ICE - SHAIP Healthcare Enterprise Technology Company ClinicalClinician Cockpit To transform management of chronic disease globally by accelerating biomedical research, high Dataquality Controller health care provision and economic Researchergrowth.

Actionable mutations Genomic profile of tumour Anonymizing Data Portal

TP53 (V274F )

PACS Data Scientist

LIMS KRAS WORKSPACE(G12D) EMR p16/CDKN2A Caldicott (loss)

Safe Haven

Machine Algorithm Learning Portal

Dr Ken Sutherland iCAIRD Industrial Centre for Artificial Intelligence Research in Digital Diagnostics

Cambridge, MA

Imaging Centre of Excellence Imaging Centre of Excellence Key features • led • Pan-Scotland initiative • £10M from Innovate UK

• £6M from industry partners Santa Clara, CA • 6 SME partners involved in exemplars • Brings Philips and SMEs to Clinical Innovation Zone

22 ‘The Living Laboratory’ Proposal

• Environment and ecosystem for Business • Accelerating Growth Real World Implementation of PM productivity growth for Scotland • Proximity to world-class academic/ clinical/ Industry • Healthcare cost industry expertise Use Cases avoidance • Health Innovation Hub • Improving patient outcomes with enabling Accelerating Commercial Innovation infrastructure for innovation and clinical adoption Living Laboratory: Use Case 65+ year old Analysis of Initial Glasgow Cohort 165k Poly-pharmic Individuals ThermoFisher: diversification in Scotland; Coriell: new to Scotland Initial Cohort Analyzed: Aged 65+ on multiple medications

Data de-identified, economic analysis conducted upfront Annual • Average number of medications per member: 8 >£450M pharmaceutical spend • Most prevalent condition: High blood pressure • Most costly condition: Diabetes

Nearly 22% of this cohort (36,000 people) at Annual health risk of medication failure or significant adverse £2.7B care spend reaction from at least 1 medication prescribed

71% taking at least one drug with known genetic implications

Potential Savings ~£85M Predicted cost savings of >£85M over three years upon in 3 years implementation

24 Precision Medicine: Report by the World Innovation Summit for Health (WISH)

Case study 8: Scotland Precision Medicine Ecosystem The SMS-IC will help organizations develop capabilities and assets to create PM solutions that attract commercial investment and have the potential to generate revenue for Scottish partners. This model is intended to accelerate the adoption of genomic services and enable broader academic, industrial and NHS participation across Scotland. Precision Medicine is ready for clinical Datause modality Analysis

Flow of Biological Information

Network Modelling Clinical utility Functional annotation + digital radiology & digital pathology Thank You

Scotland’s Ecosystem for Precision Medicine

Connected Ecosystem

Broad Industry Base

Advanced Exemplars

Academic Leadership

Forward-thinking NHS

Electronic Health Records

Chronic Disease, Patient Trust

Data Integration and Analysis

Rapid NHS Adoption Queen Elizabeth Diagnostics University Hospital (QEUH)

Clinical Trials

Commercial Products

Fast Regulatory Approval Two MRC Molecular Pathology Nodes illumina & SGP

Clinical Innovation Zone (CIZ) for Precision Medicine

• Total of 22,000 sq ft • Purpose-built industry space • Located within QEUH • Facilitated access to clinicians • Flexible space – wet lab, dry lab, office space • Hot-desk facilities for industry • UK Science Parks Association (UKSPA) Thank you for attending the LUCID Conference