Gabriel Scally

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Welcome

• Gabriel Scally
• Regional Director of Public Health
• NHS South West

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Genomics and population health

• David Melzer
• Epidemiology Public Health

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outline

• The promise of sequencing the genome
• Overview of findings
• Flood of discovery for common disease and traits
• Interpreting gene status
• Implications for PH
• Biological insights into population distributions
  and the need for population based approaches
• Regulatory challenge

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2005 - How the Human Genome Era Will Usher in a
Health Care Revolution -Personalized Medicine
(NHGRI)

• Prevention
• Identify those at risk before they developed
  disease
• Diagnosis
• Treatment Pharmacogenetics
• Personalising the drug and dose
• Avoiding idiosyncratic side effects
• (gene therapy)
• Prognosis

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DNA RNA protein 3 billion base pairs, 20K
genes
Mendel biography, Mawer S, Adams NY 2006
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Genetic variation between humans

• gt10 million variants in human genome databases
• Most common Single Nucleotide Polymorphisms
  (SNPs)

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Sickle cell mutation changing one amino acid
Public health genetics unit, 2006
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HeritabilityThe degree to which a characteristic
is determined by genetics (as opposed to
environment).

• stroke, diabetes, prostate cancer, cardiovascular
  disease, depression and bone degeneration
• approx 25 - 33 heritability

Sciences et Avernir, 2007
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GWA studies e.g. UK Wellcome Trust Case Control
Consortium
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WTCCC study - Type 2 diabetes - Oxford and Exeter
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FTO AA genotype is associated with a 3kg
increase in adipose tissue
P 3 x 10-35
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FTO gene status meaning?May 27th, 2008

• Susannah said
• I was astonished, and over the moon.
• and meanwhile my fat friend here to Trinny
  I dont know what youre going to do?!
• Turning to the fat people who did not have the
  gene, Susannah said
• "So if we don't have it and we're still fat, it
  must be because we're just greedy pigs who eat
  too many pies!"

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Obesity epidemic
Mu Boyan 2009
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LDL cholesterol SNPs in the InCHIANTI study

• Frequency of respondents by LDL cholesterol
  allele count, with box-plots of the distribution
  of serum LDL cholesterol levels. Dotted lines
  indicate intervention levels of greater than 130
  mg/dl for borderline high levels and greater than
  160mg/dl for high levels.
• Murray et al European Heart Journal 2009

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population distributions
Arbitrary risk thresholds inescapable?
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Flood of SNP discoveries 300
(Melzer, BMJ Feb 08)
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Age related Macular Degeneration

• Most common risk of blindness in older people in
  developed countries
• Population attributable risk 43 for CFH
• Complement Factor H
• Plus
• 20 - smoking
• 36 for LOC387715

From Mayo Clinic website
Schmidt S, Am. J. Hum. Genet. 200678852864.
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New biologyFilaggrin mutations, dermatitis and
asthma

• Nature Genetics 38, 399 - 400 (2006) Skin barrier
  function and allergic risk
• Thomas J Hudson  Figure 1. Skin barrier function
  and allergic risk.An intact epithelial barrier
  (a) prevents allergens from reaching antigen
  presenting cells (APCs) in subepithelial tissues.
  Damage to this barrier (b) allows allergens to
  penetrate into the subepidermal layer and
  interact with APCs, leading to allergic
  sensitization and, secondarily, to allergic
  manifestations in the host.

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Regulatory issues Very little clinical
evaluation required of genetic tests (esp. for
labs)
Forbes - 12 Gene Tests That Could Change Your
LifeTCF7L2 DeCode Genetics sells a test for
500 via online test provider DNA Direct.
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TCF7H2 and Diabetes 2 reduced beta cell
(insulin) function

• Identified a hot area on 10q1, for diabetes 2,
  within transcription factor 7like 2 gene
  (TCF7L2 formerly TCF4) p value 2.1x10-9
• replicated in Danish cohort (P 4.8x103) US
  cohort (P3.3x109).
• Compared with non-carriers
• OR CC1.00
• CT1.45
• TT 2.41
• Population attributable risk of 21.

From Grant S et al, Nature Genetics 2006
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Forbes - 12 Gene Tests That Could Change Your
LifeTCF7L2 DeCode Genetics sells a test for
500 via online test provider DNA Direct.
with diabetes or Impaired Fasting Glucose by
TCF7L2 genotype aged 65 in InCHIANTI n944
ADA criteria for Impaired fasting glucose
Melzer, 2006
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Evidence requirement for clinical tests
Hogarth S, et al . Food Drug Law J.
200762(4)831-48.
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Policy issues in genetic tests

• Can balanced regulation be crafted?
• economically viable, allowing innovation etc
• Who is responsible for clinical validity (or
  utility)?
• How much clinical evidence should be required?
• How accessible should this data be (for
  systematic review etc)
• A post marketing surveillance system needed?
• off label use
• Special measures for ethnic groups?

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Defying genotype

• Incidence of Diabetes According to Treatment
  Group and Genotype at Variant rs7903146 (TCF7L2)
• Diabetes prevention programme n3548 (Florez et
  al, N Engl J Med. 2006 July 20 355(3) 241250.)

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Conclusions

• Genes and environment are inseparable
• That is how evolution works!
• Explosion of polygenic gene discovery
• Some great hits but also large number of small
  effect markers
• Provide a genetic explanation for
• trait distributions
• human, system, disease heterogeneity
• lack of natural boundaries
• (genetic) Test regulation for clinical validity
  in Europe is non-existent
• CE mark on a test is worthless!

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Tobacco control research at the University of
BathProfits and policy how understanding corpor
ations can inform public health policy
Dr Anna Gilmore University of Bath LSHTM
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Tobacco control research group at Bath

• Core staff
• Linda Bauld
• Anna Gilmore
• Ken Judge
• Gordon Taylor
• Admin/Comms
• Cathy French (UKCTCS Comms Network manager)
• Cathy Flower (Admin)
• Research
• Dr Gary Fooks (NIH)
• Dr Katherine Smith (SFP/CRUK)
• Dr Michelle Sims (DH/HF)
• Rosemary Hiscock (UKCTCS)
• John Chesterman (statistician, GCPH)
• Janet Ferguson (DH/GCPH)
• Eileen Sutton (SF SW)
• TBA
• PhD Students
• Lucy Hackshaw (PhD CRUK)

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Focus
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International grants (AG)
CIHR 18 country (135,000 people) study of
factors influencing tobacco use
Bloomberg tobacco policy in Russia
FP7 11 country study of health well being in
FSU
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UK Focused Grants (joint)
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UK Focused Grants (AG)
Systematic review of snus (HF)
Tax price policies in Europe (FP7)
Evaluation of smokefree in ethnic minorities
(IPCT)
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DH grant

• Evaluating SF legislation using secondary data
• SHS exposure
• Health impacts eg MI
• Smoking prevalence
• Working with SW PHO
• So far examined trends in determinants of SHS
  exposure in children
• Local relevance need to encourage parents to
  make homes smokefree
• Evidence base on how to encourage SF homes is
  lacking in UK

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Geo Mean Cotinine, in children aged 4-15yr,
1996-2007, HSE data
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UK Focused Grants (LB)
DH PORTS trial (proactive telephone cessation
intervention)
NICE systematic reviews
Cessation service evaluation (2 current projects)
GCPH Feasibility study of incentives for
cessation in pregnancy
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Aim

• To establish the UKCTCS as a major national and
  international resource and driver of new
  research, policy and practice approaches to
  reducing the prevalence of smoking and related
  morbidity and mortality through prevention of
  incident smoking, promotion of smoking cessation,
  and the development of more effective harm
  reduction strategies for those currently unable
  to stop smoking.

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People and Universities

• John Britton, Ann McNeill, Tim Coleman, Sarah
  Lewis and others
• Linda Bauld, Anna Gilmore and colleagues
• Paul Aveyard and colleagues
• Amanda Amos and colleagues
• Peter Hajek and colleagues
• Gerard Hastings and the CTCR
• Robert West and the HBU

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• Profits and policy
• how understanding 
• corporations can inform public health policy

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Corporations as a determinant of health

• In high income countries the major causes of
  mortality and morbidity have an industry directly
  pushing the product responsible (eg tobacco,
  alcohol, food industries)
• Corporations also affect health less directly eg
  through the environment built environment
• Corporations should be recognised as a social
  determinant of health (William Wiist AJPH 2006)

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Understand corporations

• Yet not yet a key part of PH practice.
• Most advanced in tobacco control.
• WHY? (1) Tobacco industry documents released
  through litigations in US (whistleblowers)

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2. Because work on the vector pushed by WHO

• WHO Committee of Experts 2000
• Tobacco use is unlike other threats to global
  health. Infectious diseases do not employ
  multinational public relations firms. There are
  no front groups to promote the spread of cholera.
  Mosquitoes have no lobbyists.

WHO Committee of Experts 2009
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WHO (contd)

• WHA resolution 54.18 (2001)
• 1.URGES WHO Member States to be aware of
  affiliations between tobacco industry and members
  of their delegations,
• 2. to be alert to efforts by the tobacco
  industry to continue its subversive practice ..

• Article 5.3 of the Framework Convention on
  Tobacco control
• In setting and implementing their public
  health policies with respect to tobacco control,
  Parties shall act to protect these policies from
  commercial and other vested interests of the
  tobacco industry..

Yet simultaneously urging partnership with
private sector, PPPs at forefront of efforts to
address other global health issues
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Evidence that understanding the industry can
inform/influence policy?

• availability of the tobacco industry documents
  has spawned an entire new area of investigation
  and has had a substantial impact on .. tobacco
  policy-making. (Givel M, Glantz S. AJPH 2004)
• Our limited successes
• Germany Change in way research funded (Gruning,
  Gilmore AJPH)
• Russia significantly changed opinions of key
  politicians (eg head of the Consumer Protection
  Agency recently attempted legal action against
  BAT), legislation currently being drafted
  informed specifically by document work (Gilmore,
  McKee various papers)
• Article 5.3 of Framework Convention on Tobacco
  Control Our work secured change in EU position
  ensured strong guidelines (Smith, Fooks, Collin,
  Gilmore. PLOS Medicine)

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How does understanding the industry help inform
policy

• Tell you
• How they lobby influence policy
• Where the industry are going/what next dangers
  are
• What works in tobacco control SCREAM TEST
• How the industry will respond
• Also
• Evidence against the industry (support
  legislation litigation)
• Delegitimise the industry reduces their
  influence

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Example 1 Impact assessment

• Work funded by SFP/CRUK
• Smith KE, Fooks G, Collin J, Weishaar H, Mandal
  S, Gilmore A. "Working the system" How British
  American Tobacco secured changes to the European
  Union Treaty and fundamentally reshaped
  policymaking'. PLOS Medicine (under review)
• Smith KE, Fooks G, Gilmore A et al . Is the
  increasing policy use of Impact Assessment in
  Europe likely to support or undermine efforts to
  achieve healthy public policy? JECH (submitted)

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IA in the EU

• Plays a key role in policy development all
  major policy developments must have IA
• Seen as providing a transparent and unbiased
  assessment of impacts
• The form of IA used is claimed to provide
  comprehensive (integrated) assessment of
  impacts, yet critiqued for emphasis on business
  impacts and failure to assess health impacts
• HOW WHY?

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BAT secured changes to the EU Treaty (Treaty of
Amsterdam, 1997)
BAT Shaping the Regulatory Environment
Advertising and Public Smoking. Unknown date
http//bat.library.ucsf.edu//tid/xnz82a99
Accessed on 23 May 2008.
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The multifaceted lobbying approach
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Why?

• From late 1980s BAT recognised that risk
  assessment and a form of IA (BIA) could be
  manipulated to further industry interests
• Specifically, provided a means to prevent the
  introduction of tobacco control policies
  (smokefree legislation advertising controls)

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Why?
3. More generally, felt IA could influence policy
in favour of industry
(IMPACT). Impact Assessments Changing the Way
Business Deals with Government. 95/06/07
http//legacy.library.ucsf.edu/tid/fjf14a99
Accessed on 24 Jul 2008.
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Follow up

• Led to publication of various guidelines on IA
  standards for consultation of interested parties
  by the Commission
• The IA guidelines have been used to challenge PH
  legislation
• The standards for consultation have been used to
  justify consultation with the tobacco industry
  to lobby against Article 5.3 of FCTC
• Preliminary evidence that also influenced system
  of IA in the UK have been working to influence
  interpretation of risk (move away from the
  Precautionary Principle)
• (FPH Conference)

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Example 2 UK strategy Future of the industry

• Ongoing work
• Some based on company annual reports,
  presentations to investors/investment analysts,
  analyst reports, TI journals, media coverage
• NB These are available for all corporations
  therefore much research can be done without the
  documents

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How does understanding the industry help inform
policy?

• Tell you
• How they lobby influence policy
• Where the industry are going/what next dangers
  are
• What works in tobacco control SCREAM TEST
• How the industry will respond
• Also
• Evidence against the industry (support
  legislation litigation)
• Delegitimise the industry reduces their
  influence

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Innovation (Everywhere Annual reports, ppts to
analysts etc)

• Pan Kwan Yuk, Financial Times, 9 May 2009
  (www.ft.com)
• Eileen Khoo, an analyst at Morgan Stanley,
  believes the focus on product innovation will
  take on greater importance in the years ahead ..
  "if you want smokers to continue smoking premium
  brands, you have to give them a reason to stay
  loyal to the brand," she says. "And one of the
  best ways of doing that is through slicker
  packaging and new product features such as
  resealable packs, super-slims and charcoal
  filters."
• Euromonitor International, 2009 Innovation has
  three purposes to justify a premium price, to
  promise a different experience and to suggest a
  reduced risk experience

 
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How does understanding the industry help inform
policy?

• Tell you
• How they lobby influence policy
• Where the industry are going/what next dangers
  are
• What works in tobacco control SCREAM TEST
• How the industry will respond
• Also
• Evidence against the industry (support
  legislation litigation)
• Delegitimise the industry reduces their
  influence

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How will the industry respond to PP?

• Legal challenges
• Trade arguments challenges (including arguments
  that government are expropriating IP claims of
  compensation)
• Challenge the scientific evidence
• Produce their own evidence
• Economic arguments smuggling counterfeiting
  will increase, revenue will fall
• Use RIA/BIA to show not cost effective
• Argue that not a TC measure but anti-industry
  measure

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• Corporations have a major health impact
• Understanding corporations can play a key part in
  developing effective public health policy (eg by
  reducing industry influence, ensuring effective
  policy, providing evidence for policy)
• Imagine if we had an Article 5.3 for every area
  of PH policy!

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Thank you