Heterogeneity An issue in design & analysis for population-
based neuroscience
James B Kirkbride Ph.D.Sir Henry Wellcome Research Fellow
University of Cambridge
Part II Neuroscience Workshop
“Heterogeneity”
“Population-based”
“Heterogeneity”
What if everyone had smoked?
What would we conclude about the relationship between smoking and lung cancer?
0 649
n.s 0 649
What if everyone had smoked?
What would we conclude about the relationship between smoking and lung cancer?
Other factors: alcohol, social class, genetics…
Importance of heterogeneity!!!
Heterogeneity An issue in design & analysis for population-
based neuroscience
James B Kirkbride Ph.D.Sir Henry Wellcome Research Fellow
University of Cambridge
Part II Neuroscience Workshop
What are psychotic disorders?
Population based neuroscience…
• Debilitating set of mental disorders, characterised by:– Positive symptoms
• Seeing or hearing things which aren’t there - hallucinations
• Erroneous beliefs held contrary to normal view of subject - delusions
– Negative symptoms (flat affect, anhedonia)– Affective symptoms – changes in mood
(bipolar disorder, psychotic depression)– Chronic, debilitating socially &
economically
Population based neuroscience…
Positive
Negative
Affective
Population based neuroscience…
How common are psychotic disorders?
Population based neuroscience…
• Prevalence of psychotic symptoms: – Median: 5.3% (IQR: 1.9-14.4%)
Van Os et al. 2009 • Prevalence of psychotic disorders:
– Lifetime prevalence: ~1%Saha et al. 2005; Goldner et al. 2002; Perala et al. 2007; Robins & Regier 1990; Kessler et al. 1994
– Annual prevalence: ~0.4% Kirkbride et al, In Press; Saha et al. 2005
Population based neuroscience…
• Incidence of psychotic disorders: – All psychotic disorders: 31.7 per 100k/pa
Kirkbride et al. PLoS One, 2012– Schizophrenia : 15.2 per 100k/pa
McGrath et al. 2004; Kirkbride et al. PLoS One, 2012
– Affective psychoses: 12.4 per 100k/paKirkbride et al. PLoS One, 2012
– Figures are for guidance only – preclude important heterogeneity along key socio-demographic dimensions
Population based neuroscience…
Kirkbride et al, 2006; Hafner et al 1993
No mind is an island… [Background]Age specific indicence rates of psychoses by sex
0.00
20.00
40.00
60.00
80.00
100.00
120.00
16-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64
Ageband
Rat
e (p
er 1
00,0
00 p
erso
n-ye
ars)
Males
Fem ales
Neighbourhoods & psychotic disorder
Is there an association?
Population based neuroscience…
Schizophrenia
• Highest rates of schizophrenia in inner city tracts
• These tracts tended to be more socially disorganized, socially isolated
• No comparable association with bipolar disorder
• Also observed elsewhere: Mannheim (Germany), Ireland, London, Bristol, Nottingham
Population based neuroscience…
No mind is an island…
(4) < 0 .1
(2) 0 .1 - 0 .2
(18) 0 .2 - 0 .8
(3) 0 .8 - 0 .9
(6) >= 0.9
probability of theta greater than 1.0
2.0km
N
“Don’t people with psychosis end up moving into inner-city
neighbourhoods?”
Population based neuroscience…
“Aren’t these results explained by reverse
causation (social drift)?”
Population based neuroscience…
• Prospectively collected national data on 1.75m Danish people
• Urban birthplace & upbringing associated with increased risk of schizophrenia in later life
• Cannot be explained by social drift• Dose-response relationship
Population based neuroscience…
• Dose-response relationship:
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
2.8
Rural area (baseline)
Provincial town
Provincial city Suburb of Capital
Capital
Adj
uste
d ra
te ra
tio
Urbanicity
Data from Mortensen et al. (1999). Adjusted for age-sex interaction, parental age, family history and season of birth
Population based neuroscience…
Heterogeneity An issue in design & analysis for
population-based neuroscience
James B Kirkbride Ph.D.Sir Henry Wellcome Research Fellow
University of Cambridge
Part II Neuroscience Workshop
“Population-based”
• Population-based studies:– Subjects are collected from the entire
population “at-risk”– Often random selection– Representative sample– Design of study adheres to the principles of
epidemiology:• Minimise chance, bias & confounding• Design may often be case-control or “cohort”
based• Analysis appropriate to design
Population based neuroscience…
• Case-control (ideal)– All cases in a given population of interest
identified – Cases invited to participate in study (sub-
sample)– Cases need to be representative of the total
case group– Controls selected to be representative of
population from which cases come from– i.e. had the case not become unwell they
could have been a control– Control selection random ideally
Population based neuroscience…
• Cohort (ideal)– Representative sample of disease free people
identified– Cohort followed up over time with assessment– Wait to see who develops disease (or not)– Look for differences in assessment between
the two groups– Cohort: prospective – Sample size for psychosis?
Population based neuroscience…
• Population-based neuroscience:– Both approaches can be used for
understanding differences in brain using neuroimaging studies
– Principles of epidemiology central to design & analysis of subjects
– Observational epidemiology may also inform the research question for neuroscience
Population based neuroscience…
What mechanisms might increase psychosis risk
due to exposure to certain environmental
factors?
Population based neuroscience…
How can population heterogeneity inform clinical neuroscience?
(and vice versa)
• Urban living and migrant status appear to increase psychosis risk
• May operate through social stress• i.e. greater social pressures lead to
dopamine dysregulation triggering psychotic symptoms
• If this is true, then you might expect to see neural differences in brains of those living in rural & urban areas (for example)
Population based neuroscience…
No mind is an island… [Mechanisms]
• 32 health German volunteers - students• Given a stress-test (arithmetic based) to
evaluate stress, while under fMRI• Asked about current & past upbringing• Second sample for validation (n=23)
Amygdala signals –ve affect & environmental threat
Perigenual anterior cingulate cortex – region controlling stress, negative affect & amygdala
No mind is an island… [Mechanisms]
• Suggests greater sensitivity to stress in city dwellers
• Amygdala signals –ve affect & environmental threat – important in psychosis symptoms
• Confirms & informs epidemiology• Heterogeneity of exposure critical to detecting
this
No mind is an island… [Mechanisms]
• Next steps• Cases vs. controls? • Migrants vs. non-migrants?• Larger samples?• Interplay with genetic factors?• Measuring (variation in) specific exposures
(beyond urbanicity)
• Heterogeneity provides us with a window on detecting associations between exposure & disorder
• Mental disorders are no exception• To detect risk factors for mental disorders,
heterogeneity in the risk factor (whether genetic or environmental) is important
• This is also true for neuroscientific research• To attribute differences in brain activity to a
proposed factor relies on variation in the factor • fMRI studies need to be designed to take this
heterogeneity into account
Population based neuroscience…
• Peter Jones• Jeremy Coid• ÆSOP study group• ELFEP study group
• Wellcome Trust, UK
Acknowledgements
• Gratitude & thanks to Amber Christian Osterhout, creator of the Gaining Insight campaign, www.gaining-insight.com for allowing me to use her images in this presentation
Population based neuroscience…
“Disease Onset" by Amber Christian Osterhout, creator of the Gaining Insight campaign, www.gaining-insight.com
Population based neuroscience…
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