1. 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,

2. 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.

3. 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

4. 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 The New Bioethics. Equity and Value in Precision Medicine

5. 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 The New Bioethics. Equity and Value in Precision Medicine

6. 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

7. 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

8. 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

9. 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

10. 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

11. Familial hypercholesterolaemia
Autosomal dominant
Atherosclerotic disease
Increased risk of early onset heart disease
Frequency 1: 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)

12. 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 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 < 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

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

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

15. Cascade screening for FH in NL
(20 years)
individuals diagnosed with FH
Population =
1: 600 inhabitants have been diagnosed with FH
of these in 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 AMC Amsterdam
The screening program has made a significant contribution to the prevention of cardiovascular disease

16. RIVM Briefrapport

17. Between 14 and 34 million individuals worldwide have FH
Eur Heart J 2013;34;

18. 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 life-years and 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.

19. 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.

20. 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?

21. 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

22. Mainstreaming genetic services George A et al, http://www. nature
Mainstreaming genetic services George A et al, 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

23. Oncologist and Genetics team attune

24. 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

27. 4th Oct 2017: European Health Award!
Modules in English, Dutch, Italian, Portuguese, Icelandic, Czech

28. Houwink 2015 PLOS one

29. 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

30. 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

31. 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)

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

33. Genomics for all in the 21st century?
VUmc Basispresentatie
Genomics for all in the 21st century?

34. Who gets referred?
Van der Giessen 2017 JOCG

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

36. 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

37. 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)