How to have a good idea

5/12/2014
Lessons from studying
premature mortality in Russia
How to have a good idea
David Leon
IEA Course, Vilnius, Lithuania
May 2014
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You always build on what has been done before •
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Treml, V. G. Alcohol in the USSR. Statistical Study. Durham,NC: Duke Press Policy Studies, 1982.
Vikhert, A. M., V. G. Tsiplenkova, and N. M. Cherpachenko. "Alcoholic cardiomyopathy and sudden cardiac death." J.Am.Coll.Cardiol. 8 (1986): 3A‐11A.
Deev, A. D. and R. G. Oganov. "Trends and determinants of cardiovascular mortality in the Soviet Union." International Journal of Epidemiology 18 (1989): S137‐S144.
Feshbach M and A Friendly Ecocide in the USSR New York: Basic books 1992
Feshbach, M. and A. Friendly. Ecocide in the USSR. New York: Basic books, 1992.
Meslé, F., V. Shkolnikov, and J. Vallin. "Mortality by cause in the USSR in 1970‐
1987 : the reconstruction of time series." European Journal of Population 8 (1992): 281‐308.
Eberstadt, N. "Demographic disaster. The Soviet legacy." National Interest
Summer (1994): 53‐57.
Meslé, F. and V. Shkolnikov. "La mortalité en Russie : une crise sanitaire en deux
temps." Revue d'études comparitives Est‐Ouest 4 (1995): 9‐24.
Shkolnikov, V., F. Meslé, and J. Vallin. "La crise sanitaire en Russie. I. Tendances
récentes de l'espérance de vie et des causes de décès de 1970 à 1993 [Health crisis in Russia. I. Recent trends in life expectancy and causes of death from 1970 to 1993]." Population 50 (1995): 907‐44.
Lancet 350 (9075):383‐388, 1997
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Chronology 1999‐2010
• 1999 – Original case‐control study of male deaths in Udmurt cities funded by UNDP (Shkolnikov and Chervyakov, 2000)
y
y ‐ Case‐control • 2003‐5 – Izhevsk Family Study 1
study of working age male mortalty in Izhevsk
with focus on alcohol funded by WT
• 2006‐10 – Izhevsk Family Study 2 – Follow‐up of live men, physical examination and intervention trial to reduce funded by WT
The Izhevsk Studies
Going from routine to individual‐level (micro) data
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5/12/2014
June 2008
The team ....
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Izhevsk Family Study I and II
Focus of research
Key features
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• Association of alcohol with :
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cause‐specific mortality Biomarkers (including of heart damage)
Blood pressure and anthropomentry
Employment and marital status
• Individual‐level determinants of hazardous drinking
• Broader policy context of alcohol and its health effects
• Exploratory trial of intervention to reduce drinking
UK Wellcome Trust
Funder
Udmurt
Government
Izhevsk State Medical Academy
Medical examination team
Forensic Service
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Study team
Subjects, data and biological samples
Izhevsk Technical University
ZAGS
MPIDR
Germany
Interview team
LSHTM
UK
Address Bureau
Blood Transfusion Centre (storage)
Vavilov Institute Human Genetics, Moscow
Interviews with proxy as well as informant Measures of alcohol drinking that are specific to Russia
Sociological expertise in tracing and initial contact Physical examination at home if requested
Use of Blood Transfusion centre for ‐80C
Use of Blood Transfusion centre for 80C sample storage sample storage
(reliable power supply)
Final storage and analysis in Moscow (VIGG and Lytech)
Development of meta‐data website to facilitate data access to bona fide researchers Publication of results in Russian and internationally
Support of local administration ....
Linked anonymised
dataset for analysis
• Case‐control study with 1750 deaths and 2000 live controls, and interviews with proxies = 5000+ interviews 2003‐5 covering socio‐demographic characteristics and behaviours
• Follow‐up of 1500+ of live controls 2008‐9 of whom Follow up of 1500+ of live controls 2008 9 of whom
1050 had health check
• Serum and plasma and buffy coat (and extracted DNA) stored • Analyses completed of liver enzymes, lipids, apo‐
lipoproteins, creatinine, B‐type natriuretic peptide
Lytech laboratory
Moscow
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Case‐control design
• Case (dead men) – control (live men) • Proxy informants (living in same household) • Interviewer administered questionnaire on alcohol consumption and other characteristics l h l
i
d h h
i i
especially for previous year
• For cases data collected within 6‐8 weeks after death
Izhevsk Family Study I
Case‐control studyy
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Cases and controls
• Cases (1750 proxies = 62% response)
–Deaths of working age (25‐54 years) men October 2003 to October 2005
–All deaths notified by city vital statistics bureau ( GS)
(ZAGS) Looking after the team ....
• Controls (1750 proxies= 57% response)
–Live men of working age (25‐54 years)
–Sampled from electoral roll
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• In a cohort study, we estimate “the risk of being diseased, given exposure status”
Selection bias ?
• In a case control study, we estimate
“ ..........................”
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5/12/2014
Using external data (1)
• In a cohort study, we estimate “the risk of being diseased, given exposure status”
• In a case control study, we estimate
“the risk of being exposed, given disease status”
• People with alcohol and drug problems are often treated (and then registered) at a Narcology Dispensary
,
• We sent name, address and date of birth of all subjects (cases and controls) to Izhevsk Narcology Dispensary and asked them to tell us if they could find them
• We did not tell Narcology Dispensary who was case or control (blinding)
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% registered with narcology dispensary by interview outcome and case‐control status
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20
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15
Percen
ntage
Percen
ntage
% registered with narcology dispensary by interview outcome and case‐control status
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5
10
5
0
But Narcology Dispensary only p p
p p
treats a proportion of people with alcohol problems ...
DOES THIS MATTER ?
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Cases
Interviewed
Controls
Cases
Not interviewed
Controls
Interviewed
Not interviewed
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Hazardous drinking and mortality from various
types of circulatory disease
Men aged 25‐54 years, Izhevsk, 2003 ‐ 5
Underlying cause of
death
Misclassification of cause of death ?
Alcoholic
cardiomyopathy
Other cardiomyopathy
Cerebrovascular
disease
Other circulatory
disease
Ischaemic heart
disease
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Number of
deaths
Hazardous drinking
(proxy report)
OR*
(95% CI)
98
15.70
(9.5,25.94)
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3.84
(2.05,7.18)
90
2.05
(1.24,3.40)
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3.43
(1.51,7.81)
219
3.04
(2.17,4.24)
* OR adjusted for age, smoking and education
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Source : Leon, Shkolnikov, McKee, Kiryanov, Andreev, IJE, 2010
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5/12/2014
Misclassification of acute alcohol poisonings ?
Ischaemic heart disease mortality and alcohol
Men aged 25‐54 years, Izhevsk, 2003 ‐ 5
Zaridze et al Int.J.Epidemiol. 38:143‐153, 2009 Cause of death
Hazardous drinking
(proxy report)
Number of
deaths
OR*
(95% CI)
Myocardial infarction
59
1.17
(0.59,2.32)
Other ischaemic heart
disease
160
4.04
(2.79,5.84)
All ischaemic heart
disease
219
3.04
(2.17,4.24)
• Study of deaths in Barnaul, Siberia, 1990‐2004, found many deaths from circulatory disease to have high blood alcohol concentrations at autopsy
blood alcohol concentrations at autopsy
• Notable that deaths from “myocardial infarction” did not have high BAC but deaths from “other IHD” did
• Concluded that many deaths from acute alcohol poisoning were in fact misclassified as deaths due to circulatory disease
* OR adjusted for age, smoking and education
Source : Leon, Shkolnikov, McKee, Kiryanov, Andreev, IJE, 2010
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A Lithuanian perspective ...
“A significant number of alcohol‐attributable deaths in Lithuania were misclassified as coronary deaths, accounting for almost one‐tenth of officially registered deaths from IHD in ages 25–64.”
This was based on assumption that raised concentrations of alcohol in blood or urine at death meant that the death was caused by prior drinking episode .... May not be the case !
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Using external data (2)
• 70% of the cases were subject to forensic autopsy. • In Russia (and other parts of former Soviet Union) blood and urine alcohol
Union), blood and urine alcohol concentrations are routinely measured
• We abstracted this information from autopsy records
Defining a sub‐set of deaths where acute alcohol poisoning unlikely
p
g
y
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Restricted to low blood alcohol concentration (<=2.5g/L) and without zapoi in previous week
Number of
deaths
Cause of death
Hazardous drinking
(proxy report)
OR*
(95% CI)
Myocardial infarction
22
1.05
(0.34,3.27)
Other ischaemic heart
disease
102
3.18
(2.01,5.03)
Alcoholic
cardiomyopathy
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4.29
(2.07,8.89)
Cerebrovascular
disease
11
7.10
(2.02,24.9)
216
3.33
(2.38,4.67)
All circulatory disease
Autopsy rates vary over time and between countries !
Source : Leon, Shkolnikov, McKee, Kiryanov, Andreev, IJE, 2010
* OR adjusted for age, smoking and education
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Trend in autopsy rate United States, 1972–2007
Turning controls into a cohort Source : Hoyert,D.L. NCHS Data Brief No. 67 August 2011
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The issue ….
The solution ….
• Original IFS1 case‐control study showed strong associations of mortality with alcohol drinking behaviour
• Could not completely exclude bias due to • In Izhevsk Family Study 2 we went back to the live (control) men of the original case‐control study
• Some of them had died • Conducted a small‐scale prospective mortality study of the 2000 men
– proxy reporting of cases being influenced by death of man (information bias) – cases and controls not fully comparable (selection bias)
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– Advantage is that proxy information about alcohol (and everything else) given BEFORE man’s death, and selection bias not an issue (almost !)
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Mortality follow‐up studies difficult in Russia
Aims
• To test whether the associations with alcohol drinking behaviours (and other factors) observed in the IFS1 case‐control study (2003‐
5) were also observed in a prospective follow‐
5) were also observed in a prospective follow
up of the originally live control men
• Problems with follow‐up – Data protection legislation meant that ZAGS data on cause of death could no longer be accessed
• Persisting
Persisting problem with follow‐up studies in problem with follow up studies in
Russia (no single source available to researchers)
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Identifying Deaths
• ZAGS : All deaths in our age group notified to study team throughout IFS1 for period October 2003 – 31 March 2009 (except for 2006)
• On attempted recontact of men in IFS2, informants would sometimes tell interviewers that man had died –
would sometimes tell interviewers that man had died and his exact or approximate date of death
• If approximate date of death known, attempt to trace further details through Forensic Service
• Other methods to determine whether men were still alive (telephone contact , visits, address bureau)
Representative ?
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Age‐specific mortality rates in the cohort (2003‐9) and the City of Izhevsk (2008) 40
Kaplan‐Meier cumulative probability of death over follow‐up by proxy reported type of alcohol drinking Age
30‐39
30
39
334
17
1 27
1.27
(0 79 2.05)
(0.79,
2 05)
0 59
0.59
40‐49
827
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1.08
(0.78, 1.50)
1.05
50‐59
695
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1.96
(1.50, 2.56)
2.19
Cumulative p
probability of death
0.3
City of Izhevsk male Number of Number Rate per 100 person of mortality rate in 2008 men at years (95% CI)
deaths
(per 100 population)
baseline
A: Abstains
B: Beverage only (not problematic)
C: Beverage only (problematic)
D: Non‐beverage alcohol drinkers
0.2
D
C
0.1
A
B
0.0
0
1
2
3
4
201
1186
90
103
120
813
59
79
Follow‐up time (years
Number at risk
Source : S. Tomkins et al PLoS ONE 7 (2):e30274, 2012
A: 239
B: 1383
C: 109
D: 140
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236
1376
105
132
232
1365
104
124
Source : S. Tomkins et al PLoS ONE 7 (2):e30274, 2012
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Adjusted* mortality odds ratios by proxy reported drinking behaviour at IFS1 interview (case‐control study 2003‐5)
Drinking behaviour
Direct comparison of cohort and case‐control results
Odds Ratio (95% CI)
Ab t i
Abstains
2 07 (1 18 3 62)
2.07 (1.18, 3.62)
Beverage (not problem)
1.00 [reference]
Beverage (problem)
2.91 (1.56, 5.42)
Non‐beverage alcohol
4.80 (2.93, 7.87)
* Adjusted for education and smoking
Source : S. Tomkins et al PLoS ONE 7 (2):e30274, 2012
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Adjusted* mortality ratios by proxy reported drinking behaviour at IFS1 interview
Drinking behaviour
Cohort HRs
С‐C ORs
Ab t i
Abstains
2 07
2.07
1 25
1.25
Beverage (not problem)
1.00
1.00
Beverage (problem)
2.91
2.93
Non‐beverage alcohol
4.80
8.64
Izhevsk Family Study II
2008‐10
* Adjusted for education and smoking
Source : S. Tomkins et al PLoS ONE 7 (2):e30274, 2012
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A problem with blood pressure
A departure from protocol | c2. have you ever been told by a
|
doctor or nurse that you had
id of |
high blood pressure ?
doctor |
yes
no don't know|
Total
-----------+---------------------------------+---------2 |
105
102
4 |
211
|
49.76
48.34
1.90 |
100.00
-----------+---------------------------------+---------3 |
39
28
0 |
67
|
58.21
41.79
0.00 |
100.00
-----------+---------------------------------+---------4 |
296
371
11 |
678
|
43.66
54.72
1.62 |
100.00
-----------+---------------------------------+---------5 |
63
47
2 |
112
|
56.25
41.96
1.79 |
100.00
-----------+---------------------------------+---------Total |
503
548
17 |
1,068
|
47.10
51.31
1.59 |
100.00
or
A problem of showing too much initiative .....
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5/12/2014
A problem with blood pressure
| c2. have you ever been told by a
|
doctor or nurse that you had
id of |
high blood pressure ?
doctor |
yes
no don't know|
Total
-----------+---------------------------------+---------2 |
105
102
4 |
211
|
49.76
48.34
1.90 |
100.00
-----------+---------------------------------+---------3 |
39
28
0 |
67
|
58.21
41.79
0.00 |
100.00
-----------+---------------------------------+---------4 |
296
371
11 |
678
|
43.66
54.72
1.62 |
100.00
-----------+---------------------------------+---------5 |
63
47
2 |
112
|
56.25
41.96
1.79 |
100.00
-----------+---------------------------------+---------Total |
503
548
17 |
1,068
|
47.10
51.31
1.59 |
100.00
Open data in the Izhevsk Family Studyy
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Meta data for the
Izhevsk Family Study
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Limitations and Challenges
• Restricted to working age men in one urban setting
• Shortage of people with professional training in field research and epidemiological methods Secure long‐term
term sample storage difficult
sample storage difficult
• Secure long
• Export of samples not possible, and few laboratories in Russia able to do all the analyses required to an international standard (eg CDT not possible)
• Very difficult to do mortality follow‐up
http://www.ifsmetadata.info/
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Summary of main results
• Hazardous drinking strongly associated with mortality, including cardiovascular disease, and accounts for 4/10 deaths of working age men in Russia (had impact on Federal alcohol policy)
• Alcohol drinking strongly associated with increased risk of Alcohol drinking strongly associated with increased risk of
hypertension, but with low risk atherogenic lipid profile
• Alcohol drinking positively associated increased levels of BNP – indicates non‐atherogenic cardiac abnormalities
• Hazardous alcohol drinking has negative employment effects • Non‐beverage alcohols widely available throughout Russia and much cheaper source of ethanol than vodka Thank you !
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