VUmc Basispresentatie Genetics and genomics: focus on value 6th October 2017, Cambridge Bradford Hill seminar Clinical Genetics & Amsterdam Public Health research institute VU University Medical Center, Amsterdam Prof.dr. Martina Cornel, www.vumc.com/researchcommunitygenetics

VUmc Basispresentatie Bradford Hill Strength Consistency Specificity Temporality Biological gradient Plausibility Coherence Experiment Analogy Folic acid intake around the start of pregnancy was associated with foetal neural tube defects Case control studies Causality? RCT needed Campaigns to increase intake Own career started in epidemiology of birth defects – many associations reported Important to have theoretical framework Studies Smithells 1976 Vitamin deficiencies and neural tube defects. These findings are compatible with the hypothesis that nutritional deficiencies are significant in the causation of congenital defects of the neural tube in man.

Genetics & Genomics More DNA tests available Price of DNA testing decreases Number of persons for whom DNA testing could potentially be relevent increases Fixed budgets Prioritization needed Mainstreaming needed

Defining value in healthcare In the UK setting, the NHS RightCare Programme has been set up to give a value-based perspective to decision-making in healthcare But what does ‘value’ mean? (collaboration VUMC-BVHC Oxford in PRECeDI project) Gray M et al. 2017 The New Bioethics. Equity and Value in Precision Medicine

Defining value in healthcare Allocative value, determined by how well assets are distributed to different subgroups in a population. Personal value, determined by how well the outcome relates to the preferences and values of each individual. Technical value, determined by how well the allocated resources are used for all the people in need in the population; this is greater than, but includes efficiency, which relates outcomes to the resources used for the patients treated by a service. Gray M et al. 2017 The New Bioethics. Equity and Value in Precision Medicine

Shift from quality to value “The intense focus on quality of service for the patients treated has diverted our attention from the impact of our services not just on those patients who have referred themselves or have been referred, but on all the people in the population” (Muir Gray) People who would benefit most from the specialist service People receiving specialist service All people with the condition

VUmc Basispresentatie Neonatal screening Participation >99% Timeliness: 98.5% bloodsample taken within 168 hours in 2014, 98.6% in 2013, reference value 99% 597 infants referred for 183 true positives (2013). PPV 30.7% Number needed to screen = 940 Cost 80€ per infant 14.5 million/year in total

How can principles of value based health care help? VUmc Basispresentatie How can principles of value based health care help? Prioritize within Health Care, change management Select Key Performance Indicators/ Criteria Mirror information to monitor progress: examples from Neonatal screening – key performance indicators? Familial Hypercholesterolaemia – many “values” published

Summary so far Genetics and genomics is generating many opportunities Human resources are limited Value based health care principles can help the staff of your service to decide what to do first

What to prioritize? considerations of medical benefit, health need and costs evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient specific likelihood of being affected by the condition tested for Severin et al. European Journal of Human Genetics (2015) 23, 729–735

Familial hypercholesterolaemia Autosomal dominant Atherosclerotic disease Increased risk of early onset heart disease Frequency 1:200-500 individuals Diagnosis: (1) increased serum cholesterol (>5 or 8 mmol/l) (2) DNA test One mutation in one of following genes (heterozygous): Low density lipoprotein (LDR) receptor Apolipoprotein B (APOB) Proprotein convertase subtilisin kexin type 9 (PCSK9)

Better prognosis with statin treatment Nordestgaard et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease Consensus Statement of the European Atherosclerosis Society Eur Heart J. 2013 Dec 1; 34(45): 3478–3490. Fig 9: Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < 0.001 for difference). Based on 413 and 1537 Dutch subjects with heterozygous familial hypercholesterolaemia on or off statin treatment. CHD, coronary heart disease; FH, familial hypercholesterolaemia. Adapted from Versmissen et al.3

Screening? Cascade screening! VUmc Basispresentatie Screening? Cascade screening! After identification of an index patient, invite all first degree relatives (parents, brothers, sisters, children)

Screening? Cascade screening! VUmc Basispresentatie Screening? Cascade screening! father If some of the first degree relatives test positive, invite their first degree relatives. brother

Cascade screening for FH in NL 1994-2014 (20 years) 28.000 individuals diagnosed with FH Population = 17.000.000 1: 600 inhabitants have been diagnosed with FH 15.000 of these in 2004-2014 when FH cascade screening was an official national screening program. Coordinated by Nat Inst Public Health & Environment, identification of patients by STOEH (Foundation for the Detection of Familial Hypercholesterolaemia) (now LEEFH) DNA testing @ AMC Amsterdam The screening program has made a significant contribution to the prevention of cardiovascular disease

RIVM Briefrapport 2014-0152

Between 14 and 34 million individuals worldwide have FH Eur Heart J 2013;34;3478-90.

Cost effectiveness Australia, J Clin Lipidol. 2014, Ademi et al. The model estimated that screening for FH would reduce the 10-year incidence of CHD from 50.0% to 25.0% among people with FH. Of every 100 people screened, there was an overall gain of 24.95 life-years and 29.07 quality-adjusted life years (discounted). The incremental cost-effectiveness ratio was in Australian dollars, $4155 per years of life saved and $3565 per quality-adjusted life years gained.

Nherera 2011 The ICER was estimated at £3666/QALY. …Probabilistic sensitivity analysis showed that this approach is 100% cost-effective using the conventional benchmark for cost-effective treatments in the NHS of between £20,000 and £30,000 per QALY gained. Cascade testing of relatives of patients with DFH and PFH is cost-effective when using a combination of DNA testing for known family mutations and LDL-cholesterol levels in the remaining families. The approach is more cost-effective than current primary prevention screening strategies.

Summary Value Based Health Care can help to provide mirror information at population level – for FH screening already triple value Personal value Autonomy, self management Technical value Better outcomes for acceptable cost For program we know population based results Allocative value More valuable than other interventions for this group of people? Shift resources?

What to prioritize? Whole genome sequencing FH cascade screening Often research Likelihood to find causal pathogenic variant Treatment available and accessible cost Health need for unsolved cases Known for decades But we do not always do what we know Likelihood for sibs, children 50% Treatment cheap, effective

Mainstreaming genetic services George A et al, http://www. nature Mainstreaming genetic services George A et al, http://www.nature.com/articles/srep29506 PHG foundation, Genetics and mainstream medicine, 2011 Clinical geneticists explain to oncologists, surgeons, gynaecologist and get them involved Train them and then start with genetic testing via them Participation in multidisciplinairy teams of clinicial geneticists/ low barriers to referral Follow-up of satisfaction of patients and doctors Measure impact of mainstreaming, the reach of population of interest Mainstreaming Cancer Genetics Programme

Oncologist and Genetics team attune http://www.nature.com/articles/srep29506

The next steps If we accept that primary care workers, public health physicians, oncologists etc. can offer genetic testing… training is needed Genetics knowledge often not relevant for practical issues Baars et al Genetics in Medicine 2005

4th Oct 2017: European Health Award! www.primarycaregenetics.org https://www.ehfg.org/projects-events/european-health-award/ Modules in English, Dutch, Italian, Portuguese, Icelandic, Czech

Houwink 2015 PLOS one

What is the goal of education? Satisfaction (did you like to go to my course?) Knowledge (pre- and post module quiz) Skills interpretation of family history knowing where to find what you need (just in time) Improve % of adequate tests, referrals Improve % of FH patients recognized and treated Health gain

Summary so far Many opportunities Decide on priorities Train those colleagues who will help Based on needs assessment Evaluate more than satisfaction and knowledge If value is impact on patients – evaluate impact on patients If value is impact on populations – evaluate impact on populations

Do we do the good thing for all? THE human genome (reference) was based on a few white male individuals There is a need for researchers and health care professionals to support achievable milestones that will enhance global ancestral diversity in genomic research for the 21st century, and integrate the resulting knowledge into health care that benefits everyone (Cornel & Bonham 2017 JOCG)

After Watson: the first female genome Marjolein Kriek (not Crick as in Watson & Crick) Clinical geneticist WGS Leiden 2008 Statue in Nijmegen

Genomics for all in the 21st century? VUmc Basispresentatie Genomics for all in the 21st century? http://ehsdailyadvisor.blr.com/2010/07/5-steps-for-successfully-managing-diversity/

Who gets referred? Van der Giessen 2017 JOCG

Who is included in research? Popejoy and Fullerton 2016 Nature Genomics is failing on diversity

Global value “Attention needed for all the people in the population” (Muir Gray) People who would benefit most from the specialist service People receiving specialist service All people with the condition

Summary: Genetics & Genomics: Focus on value VUmc Basispresentatie Summary: Genetics & Genomics: Focus on value Don’t forget about low hanging fruit such as FH Do what we know (especially if medical benefit, health need and costs are favorable) Train (yourself and colleagues who can help) Focus on all populations Use mirror information (VBHC)