A presentation summarising the process of developing an entry-level phenotype for case ascertainment in genetic studies of neuropathic pain. The presentation was made at the 5th International Congress on Neuropathic Pain, Nice, France, 2015.

1. NEUROPATHIC PAIN PHENOTYPING BY INTERNATIONAL CONSENSUS
Peter Kamerman (for the NeuroPPIC Group)
University of the Witwatersrand, South Africa
NeuroPPIC
5th International Congress of Neuropathic Pain, Nice, France, 2015

2. Houle et al., 2010
Genotype to phenotype
Genotype-phenotype-environment interaction

3. Slide courtesy of Blair Smith (University of Dundee, UK)
Genetic association studies
Population-based genetic studies of (neuropathic) pain
SCIENTIFIC
Understanding pain mechanisms and vulnerability
Discovering new genes, or testing candidates from animal
studies
CLINICAL
Understand G:E interactions
Targeted prevention and prognosis
New taxonomies of pain
New drug targets
Targeting existing treatments based on likely response

4. Lanktree et al., 2010
Genetic association studies
Major procedural confounders
Measurement error
Study heterogeneity

5. Lanktree et al., 2010
Genetic association studies
Major procedural confounders
Measurement error
Study heterogeneity
‘Genetic science’ ‘Phenotyping science’

6. Lanktree et al., 2010
Genetic association studies
Major procedural confounders
Measurement error
Study heterogeneity
‘Genetic science’ ‘Phenotyping science’

7. Phenotyping for neuropathic pain

8. Phenotyping for neuropathic pain
Where do we start?
“No whole-genome association study has been
conducted yet for neuropathic pain. The problems are
formidable:
• How to phenotype patients in a standardized way to
eliminate spurious associations,
• Which controls to use, and
• How large the cohorts need to be to retain sensitivity
but eliminate false positive results….”
Costigan et al, Annu Rev Neurosci, 2009
Slide courtesy of Blair Smith (University of Dundee, UK)

9. Phenotyping for neuropathic pain
Benefits of an agreed phenotype
FACILITATES:
Interpretation
Collaboration / meta-analyses
Reproducibility

10. Phenotyping for neuropathic pain
Characteristics of the ‘ideal’ phenotype
VALID:
Accurate
Precise
FEASIBLE:
Simple to implement
Cost-effective
ETHICAL

11. Phenotyping for neuropathic pain
Characteristics of the ‘ideal’ phenotype
HIGH VALIDITY LOW FEASIBILITY
LOW VALIDITY HIGH FEASIBILITY

12. Phenotyping for neuropathic pain
Characteristics of the ‘ideal’ phenotype
CONSISTENT + CUSTOMIZABLE
Slide courtesy of Blair Smith (University of Dundee, UK)
Entry-level phenotyping
(high feasibility / low validity)
Deep phenotyping
(high validity / low feasibility)
Large / very large sample
Small sample

13. NeuroPPIC
Neuropathic pain phenotyping by international consensus
THREE-STAGE PROCESS:
Systematic review: Identify and compare phenotypes used in
genetic studies of non-cancer neuropathic pain in adults;
Delphi survey: Obtain expert consensus on phenotype components
to determine ‘caseness’;
Consensus meeting: To develop a consensus statement on an
approach to phenotyping to identify an ‘entry level’ phenotype.
van Hecke et al., 2015

14. NeuroPPIC: Systematic review
AIM
To identify and compare phenotypes used in genetic studies of
non-cancer neuropathic pain in adults.
SEARCH (January 1966 to April 2014)
MEDLINE;
EMBASE;
SCOPUS;
Science Direct;
ISI Web of Science;
CINAHL
INCLUSION:
Genetic association,
Non-cancer neuropathic pain states,
Adults
Unique records recovered
3 372
PRISMA flowchart
van Hecke et al., 2015

15. NeuroPPIC: Systematic review
AIM
To identify and compare phenotypes used in genetic studies of
non-cancer neuropathic pain in adults.
EXCLUSION:
Not neuropathic pain;
Unclear pain state;
Cancer-related;
Children
Unique records recovered
3 372
Records excluded
(title / abstract)
3 319
Full-text articles assessed
for eligibility
53
PRISMA flowchart
van Hecke et al., 2015

16. NeuroPPIC: Systematic review
AIM
To identify and compare phenotypes used in genetic studies of
non-cancer neuropathic pain in adults.
EXCLUSION:
Not neuropathic pain;
Unclear pain state;
Cancer-related;
Children
Unique records recovered
3 372
Records excluded
(title / abstract)
3 319
Studies included
21
Full-text articles assessed
for eligibility
53
Records excluded
(full text)
31
PRISMA flowchart
van Hecke et al., 2015

17. NeuroPPIC: Systematic review
Diverse populations groups
Population
Nordic/European African-AmericanAfrican
Hispanic-American Israeli-JewishAsian
van Hecke et al., 2015

18. NeuroPPIC: Systematic review
Diverse causes of neuropathic pain
Disease
Post-herpetic neuralgia Diabetic polyneuropathyDiscogenic sciatica
Persistent post-surgical pain
(lumbar discectomy, inguinal hernia, mastectomy)
HIV polyneuropathyOther aetiologies
Multiple sclerosis
Phantom limb /
Stump pain
van Hecke et al., 2015

19. NeuroPPIC: Systematic review
Diverse control groups
Control
Healthy volunteers National reference cohorts
Diseased
van Hecke et al., 2015

20. NeuroPPIC: Systematic review
Diverse phenotyping methods
Study
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Clinical examination l l l l l l l l l l l l l l l l
Pain rating scale l l l l l l l l l l l l l l
History l l l l l l l l l l l
Radiological imaging l l l l l l l l l l
NeP questionnaire l l l l l l
QST l l l l l
NCS l l
IENFD l l
Inflammatory markers l l
Body chart l
Psychological measures l
van Hecke et al., 2015

21. NeuroPPIC: Systematic review
Two studies with ‘build-in’ replication cohorts
van Hecke et al., 2015

22. NeuroPPIC: Systematic review
Lack of reproducibility
COMT
rs4680
GCH1
rs3783641
rs10483639
rs8007267
KCNS1
rs734784
OPRM1
rs1799971
van Hecke et al., 2015

23. NeuroPPIC: Systematic review
Summary
HIGH HETEROGENEITY
Population studied
Diseases studied
Control groups
Phenotyping methods
LACK OF REPLICATION

24. NeuroPPIC: Delphi survey
NeuroPPIC
van Hecke et al., 2015
AIM
Obtain expert consensus on phenotype components to determine
‘caseness’
ROUND 1
• Invited 28 experts
• 20 (71%) completed Round 1
• 17 (85%) agreed to participate in subsequent rounds
ROUND 2
• Results of Round 1 distributed with Round 2 invitations
• 16 (94%) completed Round 2
ROUND 3
• Results of Round 1 & 2 distributed with Round 3 invitations
• 15 (88%) completed Round 3

25. NeuroPPIC: Delphi survey
Diagnostic certainty
Definite Probable Possible
Clinical signs, symptoms,
body chart, history
Probable
Assessments Diagnostic certainty
Most
common
Symptoms,
body chart, history
Possible
Other tests, clinical signs,
symptoms, body chart, history
Definite
Number of responses in Round 3
(percentages shown in blocks)
van Hecke et al., 2015

26. NeuroPPIC: Delphi survey
Summary
Good consensus:
That diagnostic certainty increases as more assessment domains are
used.
Less consensus:
On what the various assessment domains should include
From a list of 14 symptoms consensus was reached on:
o “hot / burning”
o “pain evoked by light touch”
From a list of 12 clinical signs, consensus was reached on:
o “dynamic mechanical allodynia”
o “altered sensitivity to punctate mechanical stimuli”
van Hecke et al., 2015

27. NeuroPPIC: Consensus meeting
AIM
To develop a consensus statement on an approach to phenotyping to
identify an ‘entry level’ phenotype.
CONSENSUS MEETING
Date & venue: 12 to 13 June 2014, Versailles, France
Delegates: 18 experts (neurology, anaesthesiology, pain
medicine, palliative care, primary care, basic neuroscience,
and genetics)
Meeting aims and format
van Hecke et al., 2015

28. NeuroPPIC: Consensus meeting
• The basis of establishing neuropathic pain ‘caseness’ for genetic
studies.
• To provide a framework to:
o Guide study design
o Facilitate unambiguous appraisal of findings
• Allow the addition of more in-depth measures for higher level
phenotyping
Goals of the ‘Entry-level’ phenotype
van Hecke et al., 2015

29. NeuroPPIC: Consensus meeting
Symptom assessment using neuropathic pain screening tools
• The symptom component of at least one validated screening tool
• Screening tools should have been validated in:
o The language and culture of the target population(s)
o The condition(s) under investigation
‘Entry-level’ phenotype – ‘possible neuropathic pain’
van Hecke et al., 2015

30. NeuroPPIC: Consensus meeting
Symptom assessment using neuropathic pain screening tools
Anatomical distribution
• A body chart or checklist
‘Entry-level’ phenotype – ‘possible neuropathic pain’
van Hecke et al., 2015

31. NeuroPPIC: Consensus meeting
Symptom assessment using neuropathic pain screening tools
Anatomical distribution
History
• Pain duration
• Pain intensity over the last 24 hours
• The presence of any previously diagnosed chronic pain syndromes
• Demographic information
‘Entry-level’ phenotype – ‘possible neuropathic pain’
van Hecke et al., 2015

32. NeuroPPIC
Conclusion
• The field is characterized by high levels of heterogeneity
• Heterogeneity reduces:
o Interpretation
o Collaboration / meta-analyses
o Reproducibility
• NeuroPPIC sought to reduce the heterogeneity

33. NeuroPPIC
Conclusion
CONSISTENT + CUSTOMIZABLE
Entry-level phenotyping
(high feasibility / low validity)
Deep phenotyping
(high validity / low feasibility)
NeuroPPIC phenotype
• Symptoms
• Distribution
• History
Large / very large sample
Small sample

34. NeuroPPIC
Conclusion
CONSISTENT + CUSTOMIZABLE
Entry-level phenotyping
(high feasibility / low validity)
Deep phenotyping
(high validity / low feasibility)
NeuroPPIC phenotype
• Symptoms
• Distribution
• History
Large / very large sample
Small sample
Add-on:
• What is feasible
• What is required

35. NeuroPPIC Group:
• Blair H Smith (UK) [Chair]*
• Oliver van Hecke (UK)*
• Nadine Attal (France)
• Ralf Baron (Germany)
• Gyda Bjornsdottir (Iceland)
• David L Bennett (UK)
• Michael I Bennett (UK)
• Didier Bouhassira (France)
• Luda Diatchenko (Canada)
• Roy Freeman (USA)
• Rainer Freynhagen (Germany)
• Maija Haanpää (Finalnd)
• Troels S Jensen (Denmark)
• Srinivasa N Raja (USA)
• Andrew SC Rice (UK)
• Ze’ev Seltzer (Canada)
• Thorgeir E. Thorgeirsson (Iceland)
• David Yarnitsky (Israel)
Acknowledgements
Funding:
• Neuropathic Pain Special
Interest Group (NeuPSIG),
International Association for
the Study of Pain
Special thanks to:
• Harriet Wordsworth (UK)
• Delphi survey respondents