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Vol. 179, No. 9 DOI: 10.1093/aje/kwu028 Advance Access publication: March 26, 2014
Systematic Reviews and Meta- and Pooled Analyses Alcohol Consumption Over Time and Risk of Death: A Systematic Review and Meta-Analysis
Harindra Jayasekara*, Dallas R. English, Robin Room, and Robert J. MacInnis * Correspondence to Dr. Harindra Jayasekara, Level 3, 207 Bouverie Street, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria 3010, Australia (e-mail: [email protected]).
The results from the few cohort studies that have measured usual alcohol consumption over time have not been summarized. We therefore conducted a systematic review and meta-analysis to quantify mortality risk. Pertinent studies were identified by searching the Medline, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, and Scopus databases through August 2012 using broad search criteria. Studies reporting relative mortality risks for quantitatively defined categories of alcohol consumption over time were eligible. Nine cohort studies published during 1991–2010 (comprising 62,950 participants and 10,490 deaths) met the inclusion criteria. For men, there was weak evidence of lower mortality risk with low levels of alcohol intake over time but higher mortality risk for those with intakes over 40 g/day compared with abstainers using a random-effects model (P for nonlinearity = 0.02). The pooled relative risks were 0.90 (95% confidence interval: 0.81, 0.99) for 1–29 g/day, 1.19 (95% confidence interval: 0.89, 1.58) for 30–59 g/day, and 1.52 (95% confidence interval: 0.78, 2.98) for 60 or more g/day compared with abstention. There was moderate between-study heterogeneity but no evidence of publication bias. Studies including women were extremely scarce. Our findings include a curvilinear association between drinking over time and mortality risk for men overall and widespread disparity in methods used to capture exposure and report results. alcohol consumption over time; meta-analysis; mortality; systematic review
Abbreviations: CI, confidence interval; RR, relative risk.
In 1926, Raymond Pearl first showed that drinking alcohol in moderation was associated with greater longevity than abstaining or drinking heavily (1). In recent times, much attention has been focused on the J-shaped curve for the association between alcohol and ischemic heart disease, and hence, mortality risk (2–4). On the other hand, a large proportion of global deaths are attributable to heavier alcohol intake, which is a major avoidable risk factor for chronic disease (5). The quality of the epidemiologic evidence relating to a protective effect of low-dose alcohol consumption has been challenged. Some consider that the choice of reference group might explain the protective association (6, 7). Whereas Pearl used estimates of the decedent’s lifetime drinking patterns reported by relatives as the alcohol measure (1), most cohort studies have measured alcohol consumption only at baseline
(typically for the past year), although consumption is likely to vary over life (8, 9), and misclassification of intake has the potential to change the magnitude and direction of the dose-response relationship. Consumption over a prolonged period of time is believed to correlate more closely with biological processes that have a chronic effect on health compared with current drinking, which correlates more with acute alcohol effects (10). Results of the few cohort studies that have measured alcohol intake over time and its association with death have not been systematically reviewed. We conducted a systematic review of the literature and a meta-analysis of data from cohort studies that measured usual alcohol consumption over time collected either as repeated measures or as recall of alcohol intake before baseline and the risk of death from all causes. We performed a dose-response meta-analysis to estimate the shape of the 1049
Am J Epidemiol. 2014;179(9):1049–1059
Downloaded from http://aje.oxfordjournals.org/ at Anadolu University on May 2, 2014
Initially submitted October 2, 2013; accepted for publication January 29, 2014.
1050 Jayasekara et al.
association between alcohol consumption and risk of death from all causes. METHODS Literature search and selection
Case definition
We defined death from all causes as the outcome of interest and accepted outcomes based on death indices, registry data, medical records, and reports.
Information from the identified studies was extracted by H.J. with assistance from R.J.M. We abstracted the following information from each study included in the analysis by using a standard pro forma: title; authors; year of publication; study name; study design; country; region; ethnicity; age; sex; sample size; percent lost to follow-up; exposure and follow-up times; exposure assessment and the comparability of reference categories; end points; measures of association; steps taken to minimize bias; and covariates included in the multivariable analysis. We extracted the maximally adjusted relative risks with corresponding 95% confidence intervals for each category of alcohol consumption. If results were reported for 2 multivariable models, we extracted relative risks from the models that did not adjust for possible intermediaries in the causal pathway (e.g., hypercholesterolemia). For studies in which nondrinkers were not the reference category, we recalculated relative risks and confidence intervals for categories of drinkers, making nondrinkers the reference category. We contacted the authors whenever additional information or clarifications were necessary. For the dose-response meta-analysis, the median alcohol consumption in grams per day for each category of average intake was assigned to each corresponding relative risk. When studies defined alcohol intake over time by comparing intakes at baseline and follow-up (e.g., abstainer-to-moderate), we derived an average median intake based on the intake categories at the 2 time points. To calculate the median consumption for each intake category, we first converted the upper and lower boundaries into grams per day of alcohol from milliliters or standard drinks per day by considering the type of alcohol and the size of a standard drink in the study’s country of origin (12). Because the shapes of the alcohol intake distributions are similar across countries (13), we derived the median age- and sex-specific consumption values for each category from Australian National Health Survey data (14). For pooled analyses of comparable categories of alcohol consumption over time, we extracted relative risks under 5 broadly defined categories: nondrinkers (average intake over time 0 g/day) and intakes of less than 1 g/day, 1–29 g/day, 30–59 g/day, and 60 or more g/day. We mapped the intake categories of individual studies into these categories using their calculated median age- and sex-specific consumption values. Statistical analysis
A 2-stage random-effects meta-analysis was used to examine a potential nonlinear relationship between alcohol and allcause mortality risk (15). Alcohol consumption was modeled using restricted cubic splines with 3 knots at fixed percentiles (10%, 50%, and 90%) of the distribution (16). Restricted cubic spline models were initially computed for each study, taking into account the within-study correlation; then, a random-effects meta-analysis was performed using the regression coefficients and the variance-covariance matrix from each individual study (17, 18). Nonlinearity of the doseresponse curve was assessed by testing the null hypothesis that the coefficient of the second spline was equal to 0. In a Am J Epidemiol. 2014;179(9):1049–1059
Downloaded from http://aje.oxfordjournals.org/ at Anadolu University on May 2, 2014
We systematically searched the following electronic databases for potentially relevant original papers published through August 2012: Medline, Web of Science (science citation index expanded, social sciences citation index, and arts and humanities citation index), Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, and Scopus. We used broad search criteria because alcohol consumption over time has not been measured uniformly. We used the following keywords and subject headings to identify relevant articles in electronic databases: (alcohol* OR ethanol) AND (lifetime drinking OR lifetime consumption OR lifetime intake OR cumulative drinking OR cumulative consumption OR cumulative intake OR drinking over time OR consumption over time OR intake over time OR change* in drinking OR change* in consumption OR change* in intake OR drinking pattern) AND (mortality OR death* OR coronary heart disease OR coronary artery disease OR coronary disease OR ischemic heart disease OR ischemic heart disease OR cardiovascular disease OR myocardial infarction OR sudden cardiac death OR angina pectoris OR coronary death) AND (case OR retrospective OR cohort OR prospective OR longitudinal OR follow OR ratio* OR risk*). No language restrictions were imposed. We did not include informally published written material, such as reports, in our search. When an article was not available electronically or otherwise, we contacted the authors to obtain a copy. Standard criteria for analysis and reporting the results were followed (11). Eligible articles included original publications (excluding letters, editorials, conference abstracts, reviews, and commentaries) of cohort studies reporting hazard ratios, relative risks, or odds ratios (referred to herein using the general term, “relative risk”) and their 95% confidence intervals or information allowing us to compute the standard error of the relative risk of the association between alcohol consumption over time (measured as an individual’s alcohol consumption history for different periods of life or as repeated assessments of an individual’s alcohol consumption over time) and the risk of death. We excluded studies that characterized alcohol exposure qualitatively using such terms as “problem drinkers.” If multiple publications from the same study cohort were available, the 1 with the most comprehensive data on alcohol consumption was included. One author (H.J.) performed the search and excluded studies at the first exclusion pass on the basis of titles and abstracts. The studies for our meta-analysis were identified from the remaining articles that reported any assessment of alcohol consumption over time and mortality risk.
Data extraction
Alcohol Intake Over Time and Mortality Risk 1051
separate analysis, we calculated pooled relative risks for comparable categories of alcohol intake over time using DerSimonian-Laird random effects models (19). We used nondrinking as the reference category for both analyses. The inconsistencies across studies and their impact on the analysis were quantified by the I 2 statistic (20). Publication bias was assessed through visual inspection of funnel plots (21) and by using Egger’s regression test (22). All statistical analyses were performed using Stata, version 12.1, software (StataCorp LP, College Station, Texas). P values of less than 0.05 were considered statistically significant. RESULTS Characteristics of studies
Association between alcohol intake over time and mortality risk in men
Using relative risks reported by Lazarus et al. (23), Goldberg et al. (24), Fillmore et al. (25), Emberson et al. (28), Beulens et al. (29), and Britton et al. (33), we observed a nonlinear association between average alcohol consumption over time and mortality risk (P for nonlinearity = 0.02), characterized by little evidence for an inverse association at low levels of intake but higher mortality risk at intakes over
Electronic database search (limit = human) Medline (2,681 articles) Web of Science (2,720 articles) CINAHL Plus (53 articles) Scopus (17 articles)
52 Full-text articles reviewed after excluding others on the basis of title or abstract with minimal uncertainty
43 Articles excluded: 40 did not examine an association between alcohol consumption over time and all-cause mortality risk 1 did not report relative risks using average alcohol intake over time 1 duplicate analysis of the same cohort
9 Unique articles selected for the meta-analysis
1 insufficient data
Figure 1. Flow diagram describing selection of studies for inclusion in a meta-analysis of alcohol consumption measured over time and mortality risk, 1966–2012. A manual search added 1 additional article to the electronic search. CINAHL, Cumulative Index to Nursing and Allied Health Literature.
Am J Epidemiol. 2014;179(9):1049–1059
Downloaded from http://aje.oxfordjournals.org/ at Anadolu University on May 2, 2014
The numbers of articles identified in each database using the search strategy are given in Figure 1. Fifty-two full-text articles were selected after excluding the others on the basis of their titles or abstracts. Of these, 40 were excluded because they did not report a measure of association between alcohol consumption over time and all-cause mortality risk (Web Appendix available at http://aje.oxfordjournals.org/). This left 12 articles that fulfilled the eligibility criteria (23–34). The article by Wannamethee et al. (34) was excluded because Emberson et al. (28) reported more comprehensive data from the same study cohort. King et al. (31) did not report estimates that could be included in a meta-analysis; attempts to obtain further information from the authors were unsuccessful. Paganini-Hill et al. (30) reported estimates for variation in intake but not for average intake over time. Thus, the meta-analysis included 9 independent cohort studies published between 1991 and 2010 (Table 1). These studies included 10,490 deaths and 62,950 study participants. Five
studies were conducted in Europe and 4 in the United States. Friesema et al. (32) measured lifetime alcohol consumption retrospectively for different periods of life, whereas others (23–29, 33) assessed current intake more than once over time. Four studies reported separate relative risks for men and women (23, 25, 26, 32), 1 reported combined relative risk for both sexes (27), and 4 included men only (24, 28, 29, 33). Beulens et al. (29) studied men with hypertension. The relative risks and their 95% confidence intervals for categories of alcohol intake from each study are given in Table 2. Lazarus et al. (23) and Fillmore et al. (25) defined alcohol intake over time by comparing intakes at baseline and follow-up assessment (e.g., abstainer-to-moderate) and included both stable and varying drinkers in their model. Goldberg et al. (24) reported relative risks for stable and varying (e.g., abstainer-to-light/moderate) drinkers separately using consistent abstainers as the reference category. Gronbaek et al. (27), Emberson et al. (28), Beulens et al. (29), and Britton et al. (33) used intake categories defined solely by average intake over time. Wellmann et al. (26) and Friesema et al. (32) included both stable and varying drinkers in their models, as well as categories of stable drinkers by the level of intake.
First Author, Year (Reference No.)
Location
Study Period
Study Design
Sample Size
Age Range at Baseline, years
Majority ≥20
Lazarus, 1991 (23)a
United States
1965–1974 Cohort
1,845 Men and 2,225 women
Goldberg, 1994 (24)a
United States
1965–1974 Cohort
4,020 Middle-aged 51–64 and 1,111 elderly (Middle-aged) and 65–75 (elderly)
Fillmore, 2003 (25)a
United States
1971–1984 Cohort
3,449 Men and 6,084 women
Wellmann, 2004 (26)a Germany
1984–1988 Cohort
Gronbaek, 2004 (27)a
1981–1995 Cohort
Exposure Time Assessed, years
Period of Outcome Ascertainment, years
No. of Deaths
Loss to Follow-up, %
11
6
≥14
25–74
≥11
10
893 Men and 874 7 women
Age, ethnicity, marital status, employment status, educational achievement, smoking status, body mass index,b physical activity, hypertension, sleep, and serious illness
1,345 Men and 1,365 women
35–64
3
14
159 Men and 84 women
5.3 for Men and 6.3 for women
Age, smoking, physical activity, partner status, education, body mass index, total cholesterol, and hypertension
14,654 Men and women
25–98
5
10.5
3,187 Men and women
0.7
Age, sex, smoking habits, educational level, body mass index, and diseases requiring hospitalization
Emberson, 2005 (28)a United Kingdom 1978–2000 Cohort
6,544 Men
40–59
20
20
1,552
0
Light-to-moderate
1.00
0.66, 1.51
0.85
0.48, 1.51
>0–18.1/≥18.2
Moderate-to-moderate
1.01
0.72, 1.44
0.88
0.51, 1.55
≥18.2/≥18.2
>0–18.1/>0–18.1
Moderate-to-light
1.31
0.86, 2.00
1.15
0.65, 2.05
≥18.2/>0–18.1
Light and moderate-to-none
1.46
1.00, 2.13
1.47
0.99, 2.17
>0/0
Never-to-never
1.0
Referent
1.0
Referent
Former-to-former
0.8
0.6, 1.1
1.7
1.2, 2.4
Fillmore, 2003 (25) 0
Drinker-to-abstainer
1.3
0.9, 1.5
1.1
0.9, 1.3
>0/0
Abstainer-to-moderate
0.9
0.6, 1.4
1.3
0.8, 2.1
0/>0–24.1
Moderate-to-moderate
1.0
0.8, 1.3
1.1
0.9, 1.3
>0–24.1/>0–24.1
Heavy-to-moderate
0.8
0.5, 1.2
1.1
0.7, 1.8
≥24.2/>0–24.1
Abstainer-to-moderate/heavy
0.9
0.6, 1.3
1.2
0.8, 1.9
0–24.1/≥24.2
Heavy-to-heavy
2.3
1.6, 3.2
0.9
0.6, 1.5
≥24.2/≥24.2
0
Wellmann, 2004 (26) Intake over time Nondrinker
1.00
Referent
1.00
Referent
Quitter
0.64
0.32, 1.27
0.69
0.36, 1.35
>0/0
Starter
0.57
0.25, 1.29
0.54
0.23, 1.30
0/>0
Constant drinker, g/day 0.1–19.9
0.60
0.33, 1.10
0.71
0.40, 1.26
0.1–19.9
20.0–39.9
0.48
0.26, 0.88
0.94
0.49, 1.81
20.0–39.9
40.0–79.9
0.64
0.36, 1.12
40.0–79.9
≥80.0
0.53
0.25, 1.12
≥80.0
1.00
Referent
Emberson, 2005 (28) “Usual” exposure over timee,f,g Occasional
60
Beulens, 2007 (29) Average intake over time, g/day 0
1.00
Referent
0.1–4.9
0.96
0.79, 1.16
0 0.1–4.9
5.0–9.9
0.98
0.78, 1.22
5.0–9.9
10.0–14.9
0.98
0.79, 1.21
10.0–14.9
15.0–29.9
0.90
0.72, 1.13
15.0–29.9
30.0–49.9
0.96
0.75, 1.23
30.0–49.9
≥50.0
0.92
0.63, 1.34
≥50.0
Table continues
Am J Epidemiol. 2014;179(9):1049–1059
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Intake over timeb
Alcohol Intake Over Time and Mortality Risk 1055
Table 2. Continued Intake Categorya by Study (First Author, Year, (Reference No.))
RR
95% CI
RR
Men
95% CI Women
Intake Derived for Meta-Analysis Using g/day for Men
Britton, 2010 (33) Average intake over time, units/week 0
1.00
Referent
0
1–7
0.74
0.49, 1.12
1–8
8–14
0.60
0.38, 0.93
9–16 17–24
15–21
0.64
0.39, 1.03
22–28
0.72
0.42, 1.23
25–32
29–35
0.93
0.54, 1.60
33–40
≥36
1.52
0.85, 2.72
≥41
Friesema, 2008 (32) Intake over time 1.00
Referent
1.00
Referent
Occasional
1.38
0.43, 4.41
0.40
0.17, 0.95
0–11.8
Moderate
1.10
0.77, 1.58
0.78
0.47, 1.29
11.9–31.5
Heavy
1.31
0.95, 1.80
1.08
0.69, 1.69
≥31.6
Abstainer-to-light-moderate
0.91
0.63, 1.31
0.76
0.44, 1.31
0/>0–31.5
Light/moderate-to-heavy
1.02
0.76, 1.35
0.84
0.59, 1.20
>0–31.5/≥31.6
Heavy/abstainer-to-light/moderate
1.53
1.11, 2.10
0.85
0.54, 1.33
≥31.6/0–31.5
Intake for drinkers with varying pattern over timec
Men and Women Combined
Gronbaek, 2004 (27) Intake for drinkers with stable pattern over timed Light
1.00
Referent
Nondrinker
1.29
1.13, 1.48
1.7–11.9 22.3
a When intake category is defined by alcohol intakes at baseline and follow-up, it is indicated by the construction “baseline intake-to-follow-up intake.” b Reported as drinks/month. c Reported as mL/day. d Reported as drinks/week. e Reported as drinks/day. f Intakes derived at baseline and 4 follow-up assessments were categorized as nondrinker; occasional drinker (1–2 times/ month or on special occasions); light drinker (1–2 drinks/day) or “weekend only” drinker (1–6 drinks/day)); moderate drinker (3–6 drinks/day or “weekend only” drinker (>6 drinks/day)); or heavy drinker (>6 drinks every day). Using a 5-point scale from 0 (nondrinker) to 4 (heavy drinker), we calculated average intake over time as the average numeric value for all 5 assessments and categories as none (6 Drinks/day
2.3
0.88
0.72, 1.61 3–6 Drinks/day
1.42
Not reported Never-to-never 1.00
b,g
Not reported 1.00
1.00
Vol. 179, No. 9 DOI: 10.1093/aje/kwu028 Advance Access publication: March 26, 2014
Systematic Reviews and Meta- and Pooled Analyses Alcohol Consumption Over Time and Risk of Death: A Systematic Review and Meta-Analysis
Harindra Jayasekara*, Dallas R. English, Robin Room, and Robert J. MacInnis * Correspondence to Dr. Harindra Jayasekara, Level 3, 207 Bouverie Street, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria 3010, Australia (e-mail: [email protected]).
The results from the few cohort studies that have measured usual alcohol consumption over time have not been summarized. We therefore conducted a systematic review and meta-analysis to quantify mortality risk. Pertinent studies were identified by searching the Medline, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, and Scopus databases through August 2012 using broad search criteria. Studies reporting relative mortality risks for quantitatively defined categories of alcohol consumption over time were eligible. Nine cohort studies published during 1991–2010 (comprising 62,950 participants and 10,490 deaths) met the inclusion criteria. For men, there was weak evidence of lower mortality risk with low levels of alcohol intake over time but higher mortality risk for those with intakes over 40 g/day compared with abstainers using a random-effects model (P for nonlinearity = 0.02). The pooled relative risks were 0.90 (95% confidence interval: 0.81, 0.99) for 1–29 g/day, 1.19 (95% confidence interval: 0.89, 1.58) for 30–59 g/day, and 1.52 (95% confidence interval: 0.78, 2.98) for 60 or more g/day compared with abstention. There was moderate between-study heterogeneity but no evidence of publication bias. Studies including women were extremely scarce. Our findings include a curvilinear association between drinking over time and mortality risk for men overall and widespread disparity in methods used to capture exposure and report results. alcohol consumption over time; meta-analysis; mortality; systematic review
Abbreviations: CI, confidence interval; RR, relative risk.
In 1926, Raymond Pearl first showed that drinking alcohol in moderation was associated with greater longevity than abstaining or drinking heavily (1). In recent times, much attention has been focused on the J-shaped curve for the association between alcohol and ischemic heart disease, and hence, mortality risk (2–4). On the other hand, a large proportion of global deaths are attributable to heavier alcohol intake, which is a major avoidable risk factor for chronic disease (5). The quality of the epidemiologic evidence relating to a protective effect of low-dose alcohol consumption has been challenged. Some consider that the choice of reference group might explain the protective association (6, 7). Whereas Pearl used estimates of the decedent’s lifetime drinking patterns reported by relatives as the alcohol measure (1), most cohort studies have measured alcohol consumption only at baseline
(typically for the past year), although consumption is likely to vary over life (8, 9), and misclassification of intake has the potential to change the magnitude and direction of the dose-response relationship. Consumption over a prolonged period of time is believed to correlate more closely with biological processes that have a chronic effect on health compared with current drinking, which correlates more with acute alcohol effects (10). Results of the few cohort studies that have measured alcohol intake over time and its association with death have not been systematically reviewed. We conducted a systematic review of the literature and a meta-analysis of data from cohort studies that measured usual alcohol consumption over time collected either as repeated measures or as recall of alcohol intake before baseline and the risk of death from all causes. We performed a dose-response meta-analysis to estimate the shape of the 1049
Am J Epidemiol. 2014;179(9):1049–1059
Downloaded from http://aje.oxfordjournals.org/ at Anadolu University on May 2, 2014
Initially submitted October 2, 2013; accepted for publication January 29, 2014.
1050 Jayasekara et al.
association between alcohol consumption and risk of death from all causes. METHODS Literature search and selection
Case definition
We defined death from all causes as the outcome of interest and accepted outcomes based on death indices, registry data, medical records, and reports.
Information from the identified studies was extracted by H.J. with assistance from R.J.M. We abstracted the following information from each study included in the analysis by using a standard pro forma: title; authors; year of publication; study name; study design; country; region; ethnicity; age; sex; sample size; percent lost to follow-up; exposure and follow-up times; exposure assessment and the comparability of reference categories; end points; measures of association; steps taken to minimize bias; and covariates included in the multivariable analysis. We extracted the maximally adjusted relative risks with corresponding 95% confidence intervals for each category of alcohol consumption. If results were reported for 2 multivariable models, we extracted relative risks from the models that did not adjust for possible intermediaries in the causal pathway (e.g., hypercholesterolemia). For studies in which nondrinkers were not the reference category, we recalculated relative risks and confidence intervals for categories of drinkers, making nondrinkers the reference category. We contacted the authors whenever additional information or clarifications were necessary. For the dose-response meta-analysis, the median alcohol consumption in grams per day for each category of average intake was assigned to each corresponding relative risk. When studies defined alcohol intake over time by comparing intakes at baseline and follow-up (e.g., abstainer-to-moderate), we derived an average median intake based on the intake categories at the 2 time points. To calculate the median consumption for each intake category, we first converted the upper and lower boundaries into grams per day of alcohol from milliliters or standard drinks per day by considering the type of alcohol and the size of a standard drink in the study’s country of origin (12). Because the shapes of the alcohol intake distributions are similar across countries (13), we derived the median age- and sex-specific consumption values for each category from Australian National Health Survey data (14). For pooled analyses of comparable categories of alcohol consumption over time, we extracted relative risks under 5 broadly defined categories: nondrinkers (average intake over time 0 g/day) and intakes of less than 1 g/day, 1–29 g/day, 30–59 g/day, and 60 or more g/day. We mapped the intake categories of individual studies into these categories using their calculated median age- and sex-specific consumption values. Statistical analysis
A 2-stage random-effects meta-analysis was used to examine a potential nonlinear relationship between alcohol and allcause mortality risk (15). Alcohol consumption was modeled using restricted cubic splines with 3 knots at fixed percentiles (10%, 50%, and 90%) of the distribution (16). Restricted cubic spline models were initially computed for each study, taking into account the within-study correlation; then, a random-effects meta-analysis was performed using the regression coefficients and the variance-covariance matrix from each individual study (17, 18). Nonlinearity of the doseresponse curve was assessed by testing the null hypothesis that the coefficient of the second spline was equal to 0. In a Am J Epidemiol. 2014;179(9):1049–1059
Downloaded from http://aje.oxfordjournals.org/ at Anadolu University on May 2, 2014
We systematically searched the following electronic databases for potentially relevant original papers published through August 2012: Medline, Web of Science (science citation index expanded, social sciences citation index, and arts and humanities citation index), Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, and Scopus. We used broad search criteria because alcohol consumption over time has not been measured uniformly. We used the following keywords and subject headings to identify relevant articles in electronic databases: (alcohol* OR ethanol) AND (lifetime drinking OR lifetime consumption OR lifetime intake OR cumulative drinking OR cumulative consumption OR cumulative intake OR drinking over time OR consumption over time OR intake over time OR change* in drinking OR change* in consumption OR change* in intake OR drinking pattern) AND (mortality OR death* OR coronary heart disease OR coronary artery disease OR coronary disease OR ischemic heart disease OR ischemic heart disease OR cardiovascular disease OR myocardial infarction OR sudden cardiac death OR angina pectoris OR coronary death) AND (case OR retrospective OR cohort OR prospective OR longitudinal OR follow OR ratio* OR risk*). No language restrictions were imposed. We did not include informally published written material, such as reports, in our search. When an article was not available electronically or otherwise, we contacted the authors to obtain a copy. Standard criteria for analysis and reporting the results were followed (11). Eligible articles included original publications (excluding letters, editorials, conference abstracts, reviews, and commentaries) of cohort studies reporting hazard ratios, relative risks, or odds ratios (referred to herein using the general term, “relative risk”) and their 95% confidence intervals or information allowing us to compute the standard error of the relative risk of the association between alcohol consumption over time (measured as an individual’s alcohol consumption history for different periods of life or as repeated assessments of an individual’s alcohol consumption over time) and the risk of death. We excluded studies that characterized alcohol exposure qualitatively using such terms as “problem drinkers.” If multiple publications from the same study cohort were available, the 1 with the most comprehensive data on alcohol consumption was included. One author (H.J.) performed the search and excluded studies at the first exclusion pass on the basis of titles and abstracts. The studies for our meta-analysis were identified from the remaining articles that reported any assessment of alcohol consumption over time and mortality risk.
Data extraction
Alcohol Intake Over Time and Mortality Risk 1051
separate analysis, we calculated pooled relative risks for comparable categories of alcohol intake over time using DerSimonian-Laird random effects models (19). We used nondrinking as the reference category for both analyses. The inconsistencies across studies and their impact on the analysis were quantified by the I 2 statistic (20). Publication bias was assessed through visual inspection of funnel plots (21) and by using Egger’s regression test (22). All statistical analyses were performed using Stata, version 12.1, software (StataCorp LP, College Station, Texas). P values of less than 0.05 were considered statistically significant. RESULTS Characteristics of studies
Association between alcohol intake over time and mortality risk in men
Using relative risks reported by Lazarus et al. (23), Goldberg et al. (24), Fillmore et al. (25), Emberson et al. (28), Beulens et al. (29), and Britton et al. (33), we observed a nonlinear association between average alcohol consumption over time and mortality risk (P for nonlinearity = 0.02), characterized by little evidence for an inverse association at low levels of intake but higher mortality risk at intakes over
Electronic database search (limit = human) Medline (2,681 articles) Web of Science (2,720 articles) CINAHL Plus (53 articles) Scopus (17 articles)
52 Full-text articles reviewed after excluding others on the basis of title or abstract with minimal uncertainty
43 Articles excluded: 40 did not examine an association between alcohol consumption over time and all-cause mortality risk 1 did not report relative risks using average alcohol intake over time 1 duplicate analysis of the same cohort
9 Unique articles selected for the meta-analysis
1 insufficient data
Figure 1. Flow diagram describing selection of studies for inclusion in a meta-analysis of alcohol consumption measured over time and mortality risk, 1966–2012. A manual search added 1 additional article to the electronic search. CINAHL, Cumulative Index to Nursing and Allied Health Literature.
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The numbers of articles identified in each database using the search strategy are given in Figure 1. Fifty-two full-text articles were selected after excluding the others on the basis of their titles or abstracts. Of these, 40 were excluded because they did not report a measure of association between alcohol consumption over time and all-cause mortality risk (Web Appendix available at http://aje.oxfordjournals.org/). This left 12 articles that fulfilled the eligibility criteria (23–34). The article by Wannamethee et al. (34) was excluded because Emberson et al. (28) reported more comprehensive data from the same study cohort. King et al. (31) did not report estimates that could be included in a meta-analysis; attempts to obtain further information from the authors were unsuccessful. Paganini-Hill et al. (30) reported estimates for variation in intake but not for average intake over time. Thus, the meta-analysis included 9 independent cohort studies published between 1991 and 2010 (Table 1). These studies included 10,490 deaths and 62,950 study participants. Five
studies were conducted in Europe and 4 in the United States. Friesema et al. (32) measured lifetime alcohol consumption retrospectively for different periods of life, whereas others (23–29, 33) assessed current intake more than once over time. Four studies reported separate relative risks for men and women (23, 25, 26, 32), 1 reported combined relative risk for both sexes (27), and 4 included men only (24, 28, 29, 33). Beulens et al. (29) studied men with hypertension. The relative risks and their 95% confidence intervals for categories of alcohol intake from each study are given in Table 2. Lazarus et al. (23) and Fillmore et al. (25) defined alcohol intake over time by comparing intakes at baseline and follow-up assessment (e.g., abstainer-to-moderate) and included both stable and varying drinkers in their model. Goldberg et al. (24) reported relative risks for stable and varying (e.g., abstainer-to-light/moderate) drinkers separately using consistent abstainers as the reference category. Gronbaek et al. (27), Emberson et al. (28), Beulens et al. (29), and Britton et al. (33) used intake categories defined solely by average intake over time. Wellmann et al. (26) and Friesema et al. (32) included both stable and varying drinkers in their models, as well as categories of stable drinkers by the level of intake.
First Author, Year (Reference No.)
Location
Study Period
Study Design
Sample Size
Age Range at Baseline, years
Majority ≥20
Lazarus, 1991 (23)a
United States
1965–1974 Cohort
1,845 Men and 2,225 women
Goldberg, 1994 (24)a
United States
1965–1974 Cohort
4,020 Middle-aged 51–64 and 1,111 elderly (Middle-aged) and 65–75 (elderly)
Fillmore, 2003 (25)a
United States
1971–1984 Cohort
3,449 Men and 6,084 women
Wellmann, 2004 (26)a Germany
1984–1988 Cohort
Gronbaek, 2004 (27)a
1981–1995 Cohort
Exposure Time Assessed, years
Period of Outcome Ascertainment, years
No. of Deaths
Loss to Follow-up, %
11
6
≥14
25–74
≥11
10
893 Men and 874 7 women
Age, ethnicity, marital status, employment status, educational achievement, smoking status, body mass index,b physical activity, hypertension, sleep, and serious illness
1,345 Men and 1,365 women
35–64
3
14
159 Men and 84 women
5.3 for Men and 6.3 for women
Age, smoking, physical activity, partner status, education, body mass index, total cholesterol, and hypertension
14,654 Men and women
25–98
5
10.5
3,187 Men and women
0.7
Age, sex, smoking habits, educational level, body mass index, and diseases requiring hospitalization
Emberson, 2005 (28)a United Kingdom 1978–2000 Cohort
6,544 Men
40–59
20
20
1,552
0
Light-to-moderate
1.00
0.66, 1.51
0.85
0.48, 1.51
>0–18.1/≥18.2
Moderate-to-moderate
1.01
0.72, 1.44
0.88
0.51, 1.55
≥18.2/≥18.2
>0–18.1/>0–18.1
Moderate-to-light
1.31
0.86, 2.00
1.15
0.65, 2.05
≥18.2/>0–18.1
Light and moderate-to-none
1.46
1.00, 2.13
1.47
0.99, 2.17
>0/0
Never-to-never
1.0
Referent
1.0
Referent
Former-to-former
0.8
0.6, 1.1
1.7
1.2, 2.4
Fillmore, 2003 (25) 0
Drinker-to-abstainer
1.3
0.9, 1.5
1.1
0.9, 1.3
>0/0
Abstainer-to-moderate
0.9
0.6, 1.4
1.3
0.8, 2.1
0/>0–24.1
Moderate-to-moderate
1.0
0.8, 1.3
1.1
0.9, 1.3
>0–24.1/>0–24.1
Heavy-to-moderate
0.8
0.5, 1.2
1.1
0.7, 1.8
≥24.2/>0–24.1
Abstainer-to-moderate/heavy
0.9
0.6, 1.3
1.2
0.8, 1.9
0–24.1/≥24.2
Heavy-to-heavy
2.3
1.6, 3.2
0.9
0.6, 1.5
≥24.2/≥24.2
0
Wellmann, 2004 (26) Intake over time Nondrinker
1.00
Referent
1.00
Referent
Quitter
0.64
0.32, 1.27
0.69
0.36, 1.35
>0/0
Starter
0.57
0.25, 1.29
0.54
0.23, 1.30
0/>0
Constant drinker, g/day 0.1–19.9
0.60
0.33, 1.10
0.71
0.40, 1.26
0.1–19.9
20.0–39.9
0.48
0.26, 0.88
0.94
0.49, 1.81
20.0–39.9
40.0–79.9
0.64
0.36, 1.12
40.0–79.9
≥80.0
0.53
0.25, 1.12
≥80.0
1.00
Referent
Emberson, 2005 (28) “Usual” exposure over timee,f,g Occasional
60
Beulens, 2007 (29) Average intake over time, g/day 0
1.00
Referent
0.1–4.9
0.96
0.79, 1.16
0 0.1–4.9
5.0–9.9
0.98
0.78, 1.22
5.0–9.9
10.0–14.9
0.98
0.79, 1.21
10.0–14.9
15.0–29.9
0.90
0.72, 1.13
15.0–29.9
30.0–49.9
0.96
0.75, 1.23
30.0–49.9
≥50.0
0.92
0.63, 1.34
≥50.0
Table continues
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Intake over timeb
Alcohol Intake Over Time and Mortality Risk 1055
Table 2. Continued Intake Categorya by Study (First Author, Year, (Reference No.))
RR
95% CI
RR
Men
95% CI Women
Intake Derived for Meta-Analysis Using g/day for Men
Britton, 2010 (33) Average intake over time, units/week 0
1.00
Referent
0
1–7
0.74
0.49, 1.12
1–8
8–14
0.60
0.38, 0.93
9–16 17–24
15–21
0.64
0.39, 1.03
22–28
0.72
0.42, 1.23
25–32
29–35
0.93
0.54, 1.60
33–40
≥36
1.52
0.85, 2.72
≥41
Friesema, 2008 (32) Intake over time 1.00
Referent
1.00
Referent
Occasional
1.38
0.43, 4.41
0.40
0.17, 0.95
0–11.8
Moderate
1.10
0.77, 1.58
0.78
0.47, 1.29
11.9–31.5
Heavy
1.31
0.95, 1.80
1.08
0.69, 1.69
≥31.6
Abstainer-to-light-moderate
0.91
0.63, 1.31
0.76
0.44, 1.31
0/>0–31.5
Light/moderate-to-heavy
1.02
0.76, 1.35
0.84
0.59, 1.20
>0–31.5/≥31.6
Heavy/abstainer-to-light/moderate
1.53
1.11, 2.10
0.85
0.54, 1.33
≥31.6/0–31.5
Intake for drinkers with varying pattern over timec
Men and Women Combined
Gronbaek, 2004 (27) Intake for drinkers with stable pattern over timed Light
1.00
Referent
Nondrinker
1.29
1.13, 1.48
1.7–11.9 22.3
a When intake category is defined by alcohol intakes at baseline and follow-up, it is indicated by the construction “baseline intake-to-follow-up intake.” b Reported as drinks/month. c Reported as mL/day. d Reported as drinks/week. e Reported as drinks/day. f Intakes derived at baseline and 4 follow-up assessments were categorized as nondrinker; occasional drinker (1–2 times/ month or on special occasions); light drinker (1–2 drinks/day) or “weekend only” drinker (1–6 drinks/day)); moderate drinker (3–6 drinks/day or “weekend only” drinker (>6 drinks/day)); or heavy drinker (>6 drinks every day). Using a 5-point scale from 0 (nondrinker) to 4 (heavy drinker), we calculated average intake over time as the average numeric value for all 5 assessments and categories as none (6 Drinks/day
2.3
0.88
0.72, 1.61 3–6 Drinks/day
1.42
Not reported Never-to-never 1.00
b,g
Not reported 1.00
1.00
