HEALTH EVIDENCE NETWORK SYNTHESIS REPORT

The relationship between psychosocial risk factors and

health outcomes of chronic diseases: a review of the
evidence for cancer and cardiovascular diseases
Hynek Pikhart | Jitka Pikhartova
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 Health Evidence Network synthesis report

The relationship between psychosocial risk factors

and health outcomes of chronic diseases: a review of
the evidence for cancer and cardiovascular diseases

Hynek Pikhart | Jitka Pikhartova

Abstract
This report summarizes the best available evidence for a link between psychosocial factors
and cardiovascular and cancer morbidity and mortality in Europe. A total of 1822 Medline and
PubMed articles published in English since January 2000 were searched, identifying 37 systematic
reviews and meta-analyses. Among the psychosocial factors repeatedly identified as related to
chronic diseases, in and outside work, were high job demand, low autonomy, low control or high
effort–reward imbalance, interpersonal conflicts, and low social support or low trust. The evidence
suggests that multiple adverse psychosocial factors are independently associated with a range of
adverse chronic diseases throughout adulthood. In addition, the social gradient in health observed
throughout adulthood may partly operate through psychosocial factors on the pathway between
socioeconomic characteristics and health. Psychosocial factors, therefore, might become part of
complex total risk-reducing interventions focusing on multiple risk factors.

Keywords
CANCER, CHRONIC DISEASE, CARDIOVASCULAR DISEASES, EVIDENCE-BASED HEALTH CARE,
PSYCHOSOCIAL FACTORS, SOCIAL DETERMINANTS OF HEALTH

Suggested citation
Pikhart H, Pikhartova J. The relationship between psychosocial risk factors and health outcomes
of chronic diseases. A review of the evidence for cancer and cardiovascular diseases. Copenhagen:
WHO Regional Office for Europe; 2015 (Health Evidence Network (HEN) synthesis report).

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ISSN 2227-4316
ISBN 978 92 890 5083 8

© World Health Organization 2015

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Design and layout: Paprika, Agence de Communication

CONTENTS

Abbreviations............................................................................................................ iv

Contributors................................................................................................................v

Summary.................................................................................................................... vi

Glossary.................................................................................................................... viii

1. Introduction ............................................................................................................ 1

1.1. Background...........................................................................................................................1
1.2. Methodology...................................................................................................................... 3

2. Results.................................................................................................................... 12
2.1. Psychosocial factors and CVDs................................................................................12
2.2. Psychosocial factors and cancer............................................................................ 14

3. Discussion.............................................................................................................. 15
3.1. Linkages with CVDs and cancer............................................................................ 15
3.2. Strengths and limitations of the review............................................................ 16
3.3. Policy options and implications for research, scientific knowledge,
policy and practice.........................................................................................................17

4. Conclusions........................................................................................................... 19

References.................................................................................................................20

Annex 1. P
 RISMA guidelines for systematic reviews.........................................26

Annex 2. Search strategy.........................................................................................29

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

ABBREVIATIONS
CVD cardiovascular disease
IPD-Work Individual-Participant-Data Meta-analysis in Working Populations
NCD noncommunicable disease

iv
CONTRIBUTORS
This report has been produced with the financial assistance of the European Union.
The views expressed herein can in no way be taken to reflect the official opinion
of the European Union.

Authors
Hynek Pikhart
Senior Lecturer, Research Department of Epidemiology and Public Health, University
College London, London, United Kingdom

Jitka Pikhartova
Research Fellow, School of Health Sciences and Social Care, Brunel University,
London, United Kingdom

External peer reviewers

Stephen Bunker
Clinical Research Consultant, Melbourne, Australia

Tom C. Russ
Member, Alzheimer Scotland Dementia Research Centre
Associate Member, Centre for Cognitive Ageing & Cognitive Epidemiology,
Edinburgh, United Kingdom
Alzheimer Scotland Clinical Research Fellow, Scottish Dementia Clinical Research
Network, NHS Scotland, Perth, United Kingdom

HEN editorial team

Claudia Stein, Executive Editor and Director
Tim Nguyen, Series Editor
Ryoko Takahashi, Managing Editor

The HEN editorial team is part of the Division of Information, Evidence, Research
and Innovation, at the WHO Regional Office for Europe. HEN synthesis reports
are commissioned works that are subjected to international peer review, and the
contents are the responsibility of the authors. They do not necessarily reflect the
official policies of the Regional Office.

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

SUMMARY
The issue
The European Region with its 53 Member States is the WHO region with the
highest mortality rate from noncommunicable diseases (NCDs) for adults aged
15–59 years (1). A relatively small group of health conditions is responsible for
a large part of the disease burden in Europe. Preliminary assessments indicate
that chronic diseases (or NCDs) are the leading cause of mortality and morbidity
in Europe, accounting for 86% of total premature deaths (2). In order to better
understand the main NCDs, it is essential to identify and discuss their risk factors.
Among others, psychosocial factors have been proposed as risk factors for NCDs.
Despite substantial research, it remains unclear whether psychosocial factors are
causally linked with NCDs and whether any interventions focusing on modifying
psychosocial factors are effective (in terms of modification of the risk) and might
be included in chronic disease prevention and management.

The synthesis question

The objective of this report is to synthesize research findings from systematic
reviews and meta-analyses to address the following question:

What is the evidence for a link between psychosocial factors and morbidity and
mortality for chronic diseases?
Based on evidence from the reviews, the report also addresses the issue of
whether psychosocial factors might be included in chronic disease prevention
and management in Europe.

Type of evidence used in the review

The evidence comes from 37 systematic reviews and meta-analyses focusing on the
role of psychosocial factors at work and outside work in morbidity and mortality
from cardiovascular diseases (CVDs) and cancer, including high job demand,
low autonomy, low control or high effort–reward imbalance, interpersonal conflicts,
low social support, low trust, mastery, depression, anger and hostility.

vi
Results
• The role of psychosocial factors in development of cardiovascular-related
outcomes has been investigated much more extensively than cancer outcomes.
• Only eight identified papers meeting the eligibility criteria include results for
cancer outcomes.
• Most studies, particularly for cardiovascular outcomes, focused on work-related
psychosocial factors, and in particular the role of job demands, job control and
their combination in a job strain model.
• Most psychosocial factors appear to influence cardiovascular outcomes, however,
the evidence for an association between psychosocial factors and cancer is
weaker than for cardiovascular outcomes.
• There does not seem to be one particular group of reviewed psychosocial factors
that would have more importance on development of cardiovascular outcomes
or cancer than any other group of factors.
Consistency of findings in most reviews related to social support, social isolation
or various measures of stress at work supports the hypothesis that psychosocial
factors are causal risk factors for CVDs and cancer.

Policy considerations
There is only limited evidence related to intervention studies focusing on the role
of psychosocial factors in development of CVDs or cancer. However, evidence from
observational studies supports the relationship between psychosocial factors and
CVDs and, in limited way, with cancer. Although based on results from a relatively
low population, attributable risk of psychosocial factors might become part of
complex total risk-reducing interventions focusing on multiple risk factors rather
than being the focus of single factor interventions.

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

GLOSSARY
Psychosocial factors
Psychosocial factors mean a combination of psychological and social. These are
social, cultural or environmental influences affecting health and behaviours of
individuals. Although psychosocial factors include acute and chronic stressors,
this review focuses on chronic factors. Examples of psychosocial factors used in
this review include social support, social networks, social integration, loneliness,
social capital, bereavement, social disruption, work environment, psychological
distress, depression, anger and hostility. Psychosocial work environment includes
high workload, job demands, strict and tight deadlines, lack of control over work,
and imbalance between efforts at work and relevant rewards or job satisfaction.

Noncommunicable diseases
In line with WHO definition, NCDs are those diseases that are not passed from
person to person. In general, they are of long duration and slow progression.
The four main groups of NCDs are CVDs, cancers, chronic respiratory
diseases and diabetes mellitus. This review focuses only on the first two,
CVDs and cancers, as these are responsible for the majority of chronic disease
events. For example, it has been estimated that CVDs account globally for
17.3 million deaths annually, followed by cancers (7.6 million), respiratory diseases
(4.2 million) and diabetes (1.3 million) (3). These four groups of NCDs thus account
for around 80% of all NCD deaths (3). It has been estimated that CVDs alone led to
151 million disability-adjusted life years in 2008 (representing 10% of all disability-
adjusted life years in that year) (4). In addition, there were about 12.9 million new
cancer cases in 2009 alone and it is projected that this number will further rise to
almost 17 million by 2020 (5).

viii
1. INTRODUCTION

1.1. Background
The European Region with its 53 Member States is the WHO region with the highest
mortality rate from NCDs for adults aged 15–59 years (1). A relatively small group
of health conditions is responsible for a large part of the disease burden in Europe.
Preliminary assessments indicate that chronic (or noncommunicable) disease is
responsible for most of the disease and deaths in Europe, accounting for 86% of
total premature deaths. CVDs are the number one killer, causing more than half of
all deaths across the European Region (2). Data from around the world show that
in high-income countries the poor carry a disproportionate amount of the chronic
disease burden (6). It has been reported that chronic diseases have significantly
influenced economic growth in high-income countries and that every 10% increase
in the working age rates of mortality from chronic NCDs decreases economic
growth rates by approximately 0.5% (7). At the Sixty-sixth World Health Assembly,
countries unanimously adopted and supported a resolution (WHA66.10) on NCDs
(8). This marked a major moment for efforts in NCD prevention and control, putting
in place the strong foundations of a global NCD framework, through:

• endorsement of the WHO Global Action Plan for the Prevention and Control
of NCDs 2013–2020 (9);
• adoption of the Global Monitoring Framework on NCDs, including the 9 global
targets and 25 indicators;
• agreement to develop a global coordination mechanism by the end of 2013 to
coordinate activities and promote engagement of all actors in the global NCD
response; and
• adoption of the Mental Health Action Plan at both global and regional level in
Europe.
In addition, all the Member States of the WHO European Region adopted the
Health 2020 policy framework in 2012 (10), which included targets to reduce
inequalities in Europe and enhance the well-being of the European population.
The WHO Regional Office for Europe has launched an initiative to measure
subjective and objective well-being in the European population. The European
Union’s Europe 2020 strategy considers health as a resource for the success of
this strategy (11).

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

Finally, in 2011, the WHO European Region agreed to a European Action Plan for
the Implementation of the European Strategy for the Prevention and Control
of Noncommunicable Diseases (2012–2016), which has a series of priority actions.
The Action Plan included explicit linkage between mental and physical health,
and a concern with seeking population- and individual-level interventions that
could reduce the burden of NCDs.

In order to better understand the main NCDs, it is essential to improve understanding

of, and discuss, their risk factors. In addition to the non-modifiable risk factors
such as gender, ethnicity or age, there is whole range of modifiable risk factors
such as health behaviours, socioeconomic factors or psychosocial factors that are
considered as risk factors for NCDs. A wide range of psychosocial factors have
been suggested as risk factors for CVDs, cancer or respiratory diseases in a large
number of observational studies (3). Being modifiable, psychosocial conditions
are increasingly suggested as a target for interventions. Such interventions are
expected to have a relatively strong impact on an individual’s life-course health
and to achieve higher returns than later interventions. Further research is, however,
required to demonstrate that such interventions will indeed will reduce NCD risk.

In recognition of the importance of psychosocial factors, the WHO Commission

on Social Determinants of Health report Closing the gap in a generation suggested
in 2008 that psychosocial factors should play an important role in actions to reduce
health inequalities within and between countries and regions (12). The recent WHO
Regional Office for Europe review of social determinants and the health divide
reinforces this message, suggesting that adverse psychosocial environment both at
work and outside work is associated with an increase in stress-related conditions
and that unfavourable psychosocial factors can damage health through various
mechanisms (13). There are several potential pathways for the effect of psychosocial
factors on NCD risk. First, psychosocial factors may be linked with NCDs such
as CVDs or cancer through unhealthy behaviours such as lack of exercise and
physical activity, eating fatty foods, excessive alcohol drinking or smoking (14).
Second, psychosocial factors may influence access and use of health care services
and thus indirectly NCD risk. Third, psychosocial distress may be a consequence of
unfavourable social position related to increased NCD risk. Psychosocial distress
may also have a direct effect on NCDs such as coronary heart disease independent
of these other factors (15).

A comprehensive knowledge base detailing which psychosocial factors have the

most profound effects on NCDs is, therefore, a fundamental step in structuring

2
potential interventions. Although a large number of studies exist that have examined
the relationship between specific psychosocial factors operating at different levels
and specific NCDs, only a few studies to date have attempted to systematically
collate and synthesize the overall evidence provided from this considerable,
but widely dispersed, evidence base. The existing reviews usually focus on individual
psychosocial factor or individual health outcome.

The purpose of this report is to respond to the synthesis question and provide
a systematic review of the relevant evidence linking psychosocial factors with
two broad groups of NCDs, CVD and cancers, with a focus on the European
Region. Such a review will enable identification of the important psychosocial
factors operating at various levels, as well as help in evaluation of any important
between-country differences. Identifying the range of such factors will facilitate
more evidence-informed, clinically relevant and cost-effective interventions in the
future. Furthermore, it may help to identify areas that might require more research.

1.2. Methodology
1.2.1. Sources for the review
This report is primarily based on searching scientific literature databases
(Medline and PubMed). In addition, relevant references and bibliographies were
hand searched for additional studies. We developed and followed a standard
protocol for this review according to the PRISMA guidelines for systematic reviews,
which define a process of study identification, screening, eligibility and inclusion
(the PRISMA checklist is given in Annex 1) (16).

1.2.2. Eligibility criteria

Studies were considered eligible for inclusion in this review if they were
published between 1 January 2000 and 20 June 2014. This is because the role
of psychosocial factors has been documented to change over time, and this
review aimed to reflect the current situation. Papers were considered eligible
only if they were themselves reviews or meta-analyses of observational or
interventional studies. This is because psychosocial factors have become the subject
of numerous reviews in recent years (see section 2), and systematic reviews on this
subject form an extensive body of evidence. All included studies were published
in English (although a few non-English studies were identified as they had English
abstracts, these were excluded from the report). Only those papers published in national
or international peer-reviewed journals were considered.
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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

Additionally, reviews were considered only if they included discussion of quantitative

assessments of the associations between psychosocial factors and selected health
outcomes. In studies considering more than one health outcome, studies were
included in this review if they included at least one of the outcomes of this report.
Some studies appear more than once in selected reviews but this will be discussed
in later stages of this report. Across studies, a 5% significance level was accepted
as evidence of statistical significance.

An initial review of titles and abstracts and, subsequently, a full review of all remaining
search results were carried out independently by two reviewers to determine
whether they met the criteria for inclusion in this review. All disagreements were
resolved via discussion between the two reviewers. Where additional information
pertaining to a study was necessary, the respective authors were contacted.

1.2.3. Data extraction

Study identification and data extraction were performed using the search terms
listed in Annex 1. A flow chart shows the stages of data extraction (Fig. 1). In Medline
and PubMed, 1818 potential titles were identified and these were screened based on
title and abstract content. Most of these were excluded as they were not relevant
to the research questions of this report; 83 papers were identified as potential for
inclusion into the review. Among those excluded, in addition to many studies
that were irrelevant for the studied topic, there were some studies focusing on
psychosocial factors affecting various outcomes such as quality of life after a CVD
or cancer event. As the focus of this review was on risk factors for these outcomes,
all such papers were excluded. A full-text article review was performed for these
remaining 83 articles. Of these, 35 were considered as eligible to be included in
the final review. Papers focusing on individual studies were excluded from this
synthesis. Reference lists of these identified papers were further screened and
four papers were identified as possible additions. These were also obtained and
a full-text review performed. Two of these four papers have been classified as
eligible and included in the review. This gave a final number of 37 papers to
be included in the systematic review (17–52). (The full reference list is included;
Table 1 gives a brief description of the included papers.)

4
Fig. 1. Flow diagram for the systematic review (PRISMA template)
Identification

Records identified
Additional articles
through database Records
through search of
searching and screened excluded
relevant references
by title/abstract (n = 1735)
(n = 4)
(n = 1818)
Screening

Full-text articles assessed Full-text articles Full-text articles Full-text articles

for eligibility excluded assessed for eligibility excluded
Eligibility

(n = 83) (n = 48) (n = 4) (n = 2)

Studies included Studies included

in review in review
(n = 35) (n = 2)
Included

Studies included in final review

(n = 37)

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

Table 1. Selected papers

No. Psychosocial Period Paper

Paper Outcome Main findings
studies factor covered type
CVD-related outcomes
Rugulies, 1966– Pooled estimate RR, 1.64
11 Depression CHD R/M
2002 (17) 2000 (95% CI, 1.29–2.08)
Kuper et al., Pooled estimate RR, 1.9 (95%
11 Depression CHD –2007 R/M
2009 (18) CI, 1.5–2.4)
Emotional
Strike &
stress, anger, Acute coronary 1970– Consistent evidence for
Steptoe, R
extreme syndrome 2004 triggering syndrome
2005 (19)
excitement
Proportion of etiologic
5 psychosocial 1966–
CHD R studies reporting a strong or
factors 2001
moderate association
Type A
18 behaviour and 6/18
hostility
Kuper et al.,
2002 (20) 22 Depression 15/22
8 Anxiety 4/8
Psychosocial
13 work 10/13
characteristics
9 Social support 6/9
Job strain related to CVD
in most studies (including
cohort, case–control and
Belkic et al., 1966– cross-sectional studies);
34 Job strain CVDs R
2004 (21) 2001 authors suggested most
studies biased towards
null (underestimating real
association)
Age/sex-adjusted RR
Low job strain: RR, 1.16 (95%
CI 0.94–1.43)
Kivimäki et
14 Work stress CHD –2006 M Organizational injustice: RR,
al., 2006 (22)
1.47 (95% CI 1.12–1.95)
Effort–reward imbalance:
RR, 1.58 (95% CI 0.84–2.97)

6
Table 1. contd

No. Psychosocial Period Paper

Paper Outcome Main findings
studies factor covered type
Work-related
High psychologic
factors
demands,lack of social
(demand–
support, isostrain: moderate
control, social
evidence in men
support
Job strain: inconsistent
Eller et al., at work,
33 IHD –2006 R results in men
2009 (23) effort–reward
Effort–reward imbalance,
imbalance,
injustice, insecurity, long
injustice, job
working hours: not sufficient
insecurity,
evidence in men
long working
No conclusions for women
hours)
Work-related
factors
(demand-
control, social
support
Update to Eller et al. (23)
Pejtersen et at work,
44 IHD -2013 R with 11 additional studies:
al., 2014 (24) effort–reward
similar results
imbalance,
injustice, job
insecurity,
long working
hours)
OR, 1.3 (95% CI, 1.14–1.48)
Babu et al., (OR, 3.17 for case–control
9 Job strain Hypertension -2011 M
2014 (25) studies and 1.24 for cohort
studies)
Work stress: 13/20 cohorts
show association
Demand-control model: 7/13
Backé et al., cohorts
26 Work stress CVD R
2012 (26) Effort–reward imbalance: 3/3
Other models: 3/6
Most results only for men;
results for women less clear
Inconsistent results; may
Szerencsi et
71 Work stress CVD R related to methodology used
al., 2012 (27)
in individual studies
Kivimäki et 1985–
13 Job strain CHD Ma RR, 1.23 (95% CI, 1.10–1.37)
al., 2012 (28) 2006

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

Table 1. contd

No. Psychosocial Period Paper

Paper Outcome Main findings
studies factor covered type
Kivimäki et Coronary artery 1985–
7 Job strain Ma RR, 1.25 (95% CI, 1.06–1.47)
al., 2013 (29) disease 2006
Both models showed a more
Demand–
consistent adverse effect of
control–
74: 64 work stress for men
Gilbert- support (DCS)
DCS, 12 1979– DCS: studies of higher
Ouimet et al., model and Blood pressure R
ERI (2 both 2010 methodological quality
2014 (30) effort–reward
exposures) observed a more consistent
imbalance
effect than those of lesser
(ERI) model
quality
Landsbergis
1985– Association identified,
et al., 2013 29 Job strain Blood pressure R
2012 higher for men than women
(31)
Diabetes: OR, 1.29 (95% CI,
1.11–1.51)
Smoking: OR, 1.14 (95% CI,
1.08–1.20)
Physical inactivity: OR, 1.34
(95% CI, 1.26–1.41)
Nyberg et al.,
8 Job strain CVD risk factors Ma Obesity: OR, 1.12 (95% CI,
2013 (32)
1.04–1.20)
Elevated Framingham risk
score: OR, 1.13 (95% CI,
1.03–1.25)
Raised blood pressure or
blood lipids: no association
1988–
CHD R/M
2012
Steptoe & RR, 1.34-fold (95% CI,
17 Job strain
Kivimäki, 1.18–1.51)
2013 (33)
Loneliness
9 and social RR, 1.51-fold (1.21–1.88)
isolation
Seemed to be risk factor for
Rosenthal, Occupational 1977–
54 Hypertension R elevated blood pressure and
2012 (34) stress 2011
hypertension
10 (work
Hwang &
stress), Work stress, 1985–
Hong, 2012 CVD R Both related to CVD
3 social social support 2009
(35)
support)

8
Table 1. contd

No. Psychosocial Period Paper

Paper Outcome Main findings
studies factor covered type
17 (13 in
Age-adjusted RR, 1.32 (95%
individual
Virtanen et Perceived job CI, 1.09–1.59)
meta- CHD –2012 R/Mb
al., 2013 (36) insecurity Multivariable-adjusted RR,
analysis + 4
1.19 (95% CI, 1.00–1.42)
published)
Functional social support:
3 studies suggesting some
Barth et al., CHD, myocardial 1950– evidence for a negative role
5 Social support R
2010 (37) infarction 2007 Structural social support: 2
studies with low evidence
for a negative role
5/7 studies showed
association
Fortmann &
Nocturnal blood Some preliminary evidence
Gallo, 2013 11 Social support R
pressure dipping for protective effects of
(38)
marriage and social contact
frequency
All cause
Holt-Lunstad 50% increased likelihood of
Social mortality, 1900–
et al., 2010 148 R/M survival for participants with
relationships cause-specific 2007
(39) stronger social relationships
mortality
Tay et al., Social Social relations predictive
CVD
2012 (40) relations of CVD
Chida & Positive
Cardiovascular 1969– Combined HR, 0.71 (95% CI,
Steptoe, 6 psychological M
mortality 2007 0.52–0.98)
2008 (41) well-being
GHQ scores:
1–3: RR, 1.25 (1.08–1.44)
Russ et al., Psychological 1994–
10 CVD M a
4–6: RR, 1.45 (1.23–1.71)
2012 (42) distress 2008
7–12: RR, 1.72 (1.44–2.06)
p < 0.001 for trend
Richardson
Perceived Combined RR, 1.27 (95% CI,
et al., 2012 6 Incident CHD M
stress 1.12–1.45)
(43)
CVD events/
Mastery associated with
Roepke & mortality, other
better cardiometabolic
Grant, 2011 32 Mastery measures of R
health and reduced risk of
(44) cardiometabolic
disease/death
health

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

Table 1. contd

No. Psychosocial Period Paper

Paper Outcome Main findings
studies factor covered type
Chida &
Anger and Combined HR, 1.19 (95% CI,
Steptoe, 25 CHD –2008 M
hostility 1.05–1.35)
2009 (45)
Significant inverse
Koenig, Religion,
19 CVD –2010 R relationship: 12 studies
2012 (46) spirituality
Positive relationship: 1 study
Steptoe &
Emotional Acute coronary 1995–
Kivimäki, 5 R/M RR, 2.48 (1.75–3.51)
stress syndrome 2012
2013 (33)
Acute Higher rate of events in the
Mostofsky et 1966–
9 Anger cardiovascular R/M 2 hours after outbursts of
al., 2014 (47) 2013
events anger
Cancer-related outcomes
Stressful
life events,
death of
spouse, death
of relative Stressful life events: OR, 1.77
or friend, (95% CI, 1.31–2.40)
Duijts et al., personal 1966– Death of spouse: OR, 1.37
27 Breast cancer M
2003 (48) health 2002 (95% CI, 1.10–1.71)
difficulties, Death of relative/friend: OR,
change in 1.35 (95% CI, 1.09–1.68)
marital status,
change in
financial
status
Stress-related
factors (e.g. Incidence, 1.21 (95% CI,
165 as acute 1.09–1.34)
Chida et al., (incidence); life events, 1996– Mortality: 1.29 (95% CI,
Cancer incidence M
2008 (49) 53 work stress, 2007 1.16–1.44)
(mortality) personality, Cancer-specific estimates
coping style, also published
depression)
Santos et al., High intensity 1982–
6 Breast cancer M RR, 1.73 (95% CI, 0.98–3.05)
2009 (50) stress 2007

10
Table 1. contd

No. Psychosocial Period Paper

Paper Outcome Main findings
studies factor covered type
GHQ scores
1–3: RR, 0.95 (95% CI,
0.85–1.07)
Russ et al., Psychological 1994– 4–6: RR, 1.05 (95%
10 Cancer deaths Ma
2012 (42) distress 2008 CI,0.85–1.30)
7–12: RR, 1.29 (95% CI,1.
04–1.61)
p = 0.14 for trend
More religious/spiritual had
a lower risk of cancer in 16
Koenig, 2012 Religion,
29 Cancer -2010 R studies
(46) spirituality
Significantly worse
prognosis in 2 studies
Tay et al., Social Mixed evidence for an
Cancer R
2012 (40) relations association
All cancers:
HR, 0.97 (95% CI, 0.90–1.04)
(no assoication)
Colorectal cancer: HR, 1.16
(95% CI, 0.90–1.48)
Heikkila et
12 Work stress Cancer Ma Lung cancer: HR, 1.17 (95%
al.,2013 (51)
CI, 0.88–1.54)
Breast cancer: HR, 0.97 (95%
CI, 0.82–1.14)
Prostate cancer: HR, 0.86
(95% CI, 0.68–1.09)
Striking life events: pooled
Lin et al., 2013 Stressful life 1995– OR, 1.51 (95% CI, 1.15–1.97)
7 Breast cancer M
(52) events 4/2012 Severe life events: pooled
OR, 2.07 (95% CI, 1.06–4.03)

Notes: CHD: coronary heart disease; CI: confidence interval; GHQ: General Health Questionnaire;
HR: hazard ratio; IHD: ischaemic heart disease; M: meta-analysis; OR: odds ratio; R: review; RR: relative
ratio.
a
Individual participant’s data meta-analysis.
b
Partial individual participant’s data meta-analysis.

11
 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

2. RESULTS

2.1. Psychosocial factors and CVDs

Although this review focuses on the period after 1 January 2000, it is important to
mention the work by Hemingway & Marmot in 1999 (53). Their work is probably the
first extensive systematic review of prospective cohort studies covering a wide range
of psychosocial factors including depression, work stress or social support. It was
updated in 2002 (20) and concluded based on the existing results that there was
evidence for the association between depression, social support and psychosocial
work characteristics and etiology of coronary heart disease.

Following these reviews, a number of other systematic reviews have been conducted
to investigate the adverse effect of a range of psychosocial factors. Among these,
the role of work-related psychosocial factors on CVDs was investigated most
frequently (e.g. 21,22,23,26). The evidence related to the role of work-related
psychosocial factors is not entirely consistent. Most reviews concluded that work-
related psychosocial factors play an important role in development of CVDs. Most of
these reviews also concluded that negative effects of work-related factors were
more consistently identified in men than women (e.g. 22,26). Two reviews (31,34)
published recently have showed that adverse work-related psychosocial factors
may increase the risk of elevated blood pressure. However, they also showed results
that were not entirely consistent. For example, Landsbergis et al. (31) reported that
more than half of published studies found nonsignificant effects.

Most recently, the Individual-Participant-Data Meta-analysis in Working Populations

(IPD-Work) consortium published a series of papers reporting the associations
between work-related psychosocial factors and a range of outcomes, including
coronary heart disease, coronary artery disease or cardiovascular risk factors
(28,29,32,36). The advantage of this collaboration is that it is using original data
and allowing uniform analysis including the same covariates and thus is able to
prepare directly comparable results. This collaboration has brought extensive new
evidence on the association between work-related stress (and other psychosocial
factors, as mentioned below) and CVD-related outcomes; however, it is based on
the same set of cohort studies, all originating from western and northern European
countries (including Finland, Sweden, Denmark, the Netherlands, Belgium, France,
Germany and the United Kingdom). Some of these studies are occupational cohorts
(such as studies from the United Kingdom and France) and do not represent the

12
whole population. No countries from other regions, such as Asia, northern America,
south Europe or eastern Europe, are represented.

The role of other psychosocial factors on risk of CVDs has not been investigated to
the extent seen with work stress. Among these, the most consistent results can be
found for the association between depression and coronary heart disease. While
Hemingway & Marmot (53) reported that depression was associated with coronary
heart disease in 11 out of 11 identified studies, Kuper, Marmot & Hemingway (20)
in the updated review reported the same in 15 out of 22 identified studies. In two
meta-analyses, Rugulies (17) and Kuper et al. (18), respectively, reported 64% and
90% increased risk of coronary heart disease associated with depression.

Social support was studied as one of the psychosocial factors of interest by

Kuper, Marmot & Hemingway (20), who reported its relationship with coronary
heart disease in six out of nine identified studies. Hwang & Hong (35) identified
three studies focusing on the relationship between social support and CVDs and
reported that social support was likely to be related to CVDs. In more detailed
review, Barth, Schneider & von Känel (37) identified three studies suggesting some
evidence for a negative role of low functional support on coronary heart disease
and myocardial infarction, and two studies giving weak evidence of the negative
role of low structural social support on coronary heart disease. In another two
reviews Tay et al. (40) and Steptoe & Kivimäki (33) focused on social relations and
social isolation, respectively, and also concluded that these psychosocial factors
might be related to CVDs and coronary heart disease. Fortmann & Gallo (38)
focused on the role of social support on the nocturnal dip in blood pressure that
had previously been shown as a risk factor for coronary heart disease and found
that five out of seven identified studies showed the association between functional
social support and studied outcome.

Further reviews focused either on more general psychosocial constructs such as

positive psychological well-being (41), psychological distress (42) or perceived stress
(43). Other reviews focused on a range of more specific psychosocial outcomes
such as personal mastery (44), anger and hostility (45,46), religion and spirituality
(46) or emotional stress (33). Most studies in these reviews were longitudinal,
thus allowing assessment of the temporality of the association, but no interventional
research was included. Although the magnitude of identified associations was not
very large in most reviews and meta-analyses, most results showed a negative role
for psychosocial disadvantage in development of CVDs or coronary heart disease.

13
 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

2.2. Psychosocial factors and cancer

Compared with cardiovascular outcomes, fewer systematic reviews and
meta-analyses have been identified for cancer outcomes (either all cancers
combined or site-specific cancers). Duijts et al. (48), Lin et al. (52) and Chida et al.
(49) focused on stressful life events and concluded that stressful events increase
risk of breast cancer (48,52), cancer incidence and cancer mortality (49). In addition
to stressful events, Chida et al. (49) included work stress, personality, coping style
and depression among investigated psychosocial factors and their relationship with
cancer incidence and mortality. Psychosocial distress was investigated also by Russ
et al. (42), who found only weak evidence for its association with cancer mortality.
Heikkilä et al. (51), in a meta-analysis of the association between work stress and
risk of cancer, found no association with all-cancer risk or risk of colorectal, lung,
breast and prostate cancer. Tay et al. (40) found mixed evidence for the association
between social relations and cancer risk. Finally, Santos et al. (50) found only weak
borderline association between high-intensity stress and breast cancer. Results
of cancer reviews suggest that except for stressful life events the evidence for an
association between psychosocial factors and cancer is much weaker than that
for cardiovascular outcomes.

14
3. DISCUSSION

3.1. Linkages with CVDs and cancer

Overall, the results of the analysis of the 37 reviews and meta-analyses published
since the beginning of 2000 provide evidence that psychosocial factors are associated
with these two groups of outcomes: CVDs and cancers. These 37 reviews and
meta-analyses included results from several hundred individual studies originating
in wide range of countries. The role of psychosocial factors in development of
cardiovascular-related outcomes has been investigated much more extensively
than cancer outcomes. Only eight identified papers included results for cancer
outcomes. Most studies, particularly for cardiovascular outcomes, focused on
work-related psychosocial factors, and especially the role of job demands, job control
and their combination in a job strain model. As instruments for measurement of
psychosocial outcomes have been developed relatively recently, and have been
included in cohort studies more commonly only from 1990s, most results of
individual studies have been published after 2000; consequently, many systematic
reviews and meta-analyses have been published in last three or four years and have
added substantial new evidence to the existing knowledge base.

Although a large range of countries are represented in these meta-analyses and

systematic reviews, it is important to note that most reported results originate
from small number of countries, and in particular from the United Kingdom,
the Scandinavian countries, Germany, Belgium, the Netherlands, France and the
United States. Other countries are represented substantially less and there is a very
limited number of studies included in these systematic reviews and meta-analyses
originating from whole regions such as eastern Europe, Asian countries or Latin
America. Almost no results exist for African countries.

Nevertheless, findings in most reviews related to social support, social isolation

or, to some extent, various measures of stress at work support the hypothesis that
psychosocial factors are causal risk factors for CVDs and cancer. In particular, detailed
analysis by the IPD-Work consortium showing that the relationship between job
stress and coronary heart disease remains similar after excluding events from the
first five years after assessing psychosocial measures (28) support arguments of
causality of the association.

15
 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

3.2. Strengths and limitations of the review

This review provides the largest systematic synthesis of existing systematic reviews
and meta-analyses on psychosocial factors and their role on two large groups of
NCD-related outcomes. It has a number of strengths.

1. Inclusion of only contemporary and, therefore, relevant and timely evidence

(only reviews published after 2000 were considered) reduced the possibility of
a cohort effect (although it did not removing it entirely).
2. Inclusion only of reviews published in peer-reviewed journals ensured quality
of the data.
3. A definition of psychosocial factors was used to reflect the full spectrum of
(potential) psychosocial disadvantage.
4. Inclusion of a wide range of health outcomes in these two groups of NCDs
similarly allowed reflection of the spectrum of potential outcomes.

Conversely, there are some limitations in this synthesis.

1. Although evidence comes from a wide range of countries, most of this evidence
is derived primarily from the United States, the United Kingdom and northern
and western European countries.
2. Only English written publications were considered.
3. Only reviews and meta-analyses were considered. Consequently, psychosocial
factors that have not been previously a focus of reviews were omitted. Similarly,
studies that have never been included in reviews were omitted. It is likely that
only a very limited number of such individual studies have been omitted as a
large number of reviews were identified. Nevertheless, it is possible that some
studies not published in English language were omitted because most of the
systematic reviews included in this synthesis also looked only into publications
written in English language.
4. The proportion of studies reporting significant associations between psychosocial
factors and selected outcomes may be an overestimate because of underreporting
of nonsignificant findings (i.e. publication bias).

16
5. Some individual studies appear in several of the systematic reviews and meta-
analyses included in this synthesis, and therefore they artificially strengthen
the evidence showing the association between psychosocial factors and these
two groups of NCDs.
6. Most evidence originates from observational studies while evidence originating
from intervention studies is very limited. The proportion of observation studies
included in the reviews is cross-sectional, thus allowing assessment only of an
association between psychosocial factors and reported health outcomes rather
than evaluating causality.

3.3. Policy options and implications for research,

scientific knowledge, policy and practice
The findings of this study carry important implications for scientific knowledge,
policy and practice: (1) most psychosocial factors identified appear to be associated
with cardiovascular outcomes but less so with cancer outcomes; (2) there does
not seem to be one particular group of psychosocial factors that would have more
importance on development of CVD outcomes or cancer compared with other
factors, although the association with depression and social isolation is more
consistent than with work-related factors; (3) there are some gender differences
repeatedly reported in individual studies and systematic reviews, suggesting that
these psychosocial factors may operate differently in men and women.

There is only limited evidence related to intervention studies focusing on the role
of psychosocial factors in development of CVD or cancer. No systematic reviews
focusing on intervention studies have been identified so far, perhaps with the
exception of that of Schneider et al. (54), who reported results combining two
randomized control trials of long-term effects on mortality of stress reduction using
transcendental meditation. They showed that mortality from CVDs decreased by
30% and cancer mortality by 49% in an intervention group. These large effects
must, however, be considered in the light of small sample size: even when the two
studies were combined the sample size was just 202 subjects. Some individual
intervention studies have been reported in recent years, and focusing a systematic
review on such studies may be one direction of research that should be developed
in the future.

17
 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

The findings from the above-mentioned observational studies might also have
implications for policy and practice, although caution should be exercised because
of the limited results from interventions. We have identified three policy options.

1. The finding that multiple psychosocial factors, operating in different environments

(at work and outside work), affect a range of different, often related, health
outcomes highlights the complex nature of psychosocial disadvantage. It also
indicates the multiplicity of targets that potential interventions could, and should,
consider in order to be maximally effective. Although findings related to work
stress, social support or social isolation may form a basis for interventions,
it must be taken into account that recently published estimates of population
attributable risk are relatively low (28), around 4% for coronary heart disease,
and lower than estimates for smoking or physical activity. Therefore, funders
may decide to focus on behavioural interventions when focusing specifically on
coronary heart disease or cancer. When arguing for psychosocial intervention,
a wider range of health outcomes or general well-being must be considered.
2. Psychosocial interventions on CVDs or cancer have focused mostly on patients
with advanced disease, while primary prevention needs more attention. The Fifth
Joint Task Force of the European Society of Cardiology and Other Societies on
Cardiovascular Disease Prevention recommended in 2012 that psychosocial
factors should be assessed by clinical interview and tailored management
is recommended for individuals with high CVD risk (55). This might be an
important step towards moving interventions from those already ill towards
primary prevention of chronic disease. Psychosocial factors, therefore, might
become part of complex total risk-reducing interventions focusing on multiple
risk factors rather than single risk factor interventions.
3. The Health 2020 policy framework (10) promotes development of national (and
subnational) health policies, preparing comprehensive health and well-being
plans and strategies. Recent evidence related to the role of psychosocial factors
on chronic disease outcomes should inform those developing such strategies and
highlight areas for effective use of resources with the aim of improving health
and well-being across the life-course as well as reducing health inequalities
within the societies.

18
4. CONCLUSIONS
In the largest systematic review of psychosocial factors on CVDs and cancer to
date, we indirectly included several hundred individual, mostly observational,
studies in reported reviews and meta-analyses. As such, this report provides
evidence that psychosocial factors play an important role in explaining CVD
and cancer outcomes (although the evidence of the relationship between
psychosocial factors and cancer is not as strong as for CVDs), and that these
factors act independently as risks for these groups of NCDs. In particular for
CVDs, the evidence for the association with depression and social isolation is
both strong and consistent. These findings suggest that psychosocial factors
may provide multiple opportunities for prevention, intervention and possible
intersectoral approaches to tackle the social inequalities in health observed
in middle and older ages. These findings also support the Health 2020 policy
framework and strategy, which aims to reduce health inequalities and focuses on
actions that would improve health, including improving psychosocial conditions
to reduce stress through measures such as job control, adequate social protection
or improved job security (10).

19
 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

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in the aetiology and prognosis of coronary heart disease. Systematic review
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54. Schneider RH, Alexander CN, Staggers F, Rainforth M, Salerno JW, Hartz A,
et al. Long-term effects of stress reduction on mortality in persons ≥55 years
of age with systemic hypertension. Am J Cardiol. 2005;95(9):1060–4.

55. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M et al.

European guidelines on cardiovascular disease prevention in clinical practice
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Eur Heart J. 2012;33:1635–701.

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 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

Annex 1. PRISMA GUIDELINES FOR

SYSTEMATIC REVIEWS
The PRISMA guidelines for systematic reviews define a process of study identification,
screening, eligibility and inclusion and are outlined in Table A1.

Table A1. PRISMA systematic review reporting checklist

Section/topic No. Checklist item
TITLE
Title 1 Identify the report as a systematic review, meta-analysis,
or both
ABSTRACT
Structured 2 Provide a structured summary including, as applicable:
summary background; objectives; data sources; study eligibility criteria,
participants and interventions; study appraisal and synthesis
methods; results; limitations; conclusions and implications of
key findings; systematic review registration number
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is
already known
Objectives 4 Provide an explicit statement of questions being addressed
with reference to participants, interventions, comparisons,
outcomes and study design (PICOS)
METHODS
Protocol and 5 Indicate if a review protocol exists, if and where it can
registration be accessed (e.g. web address), and, if available, provide
registration information including registration number
Eligibility criteria 6 Specify study characteristics (e.g. PICOS, length of follow-up)
and report characteristics (e.g. years considered, language,
publication status) used as criteria for eligibility, giving
rationale
Information 7 Describe all information sources (e.g. databases with dates
sources of coverage, contact with study authors to identify additional
studies) in the search and date last searched

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Table A1. contd
Section/topic No. Checklist item
Search 8 Present full electronic search strategy for at least one
database, including any limits used, such that it could be
repeated
Study selection 9 State the process for selecting studies (i.e. screening, eligibility,
included in systematic review and, if applicable, included in
the meta-analysis)
Data collection 10 Describe method of data extraction from reports (e.g. piloted
process forms, independently, in duplicate) and any processes for
obtaining and confirming data from investigators
Data items 11 List and define all variables for which data were sought
(e.g. PICOS, funding sources) and any assumptions and
simplifications made
Risk of bias 12 Describe methods used for assessing risk of bias of individual
in individual studies (including specification of whether this was done at
studies the study or outcome level), and how this information is to be
used in any data synthesis
Summary 13 State the principal summary measures (e.g. risk ratio,
measures difference in means)
Synthesis of 14 Describe the methods of handling data and combining results
results of studies, if done, including measures of consistency (e.g. I2)
for each meta-analysis
Risk of bias 15 Specify any assessment of risk of bias that may affect the
across studies cumulative evidence (e.g. publication bias, selective reporting
within studies)
Additional 16 Describe methods of additional analyses (e.g. sensitivity or
analyses subgroup analyses, meta-regression), if done, indicating which
were pre-specified
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility,
and included in the review, with reasons for exclusions at each
stage, ideally with a flow diagram
Study 18 For each study, present characteristics for which data were
characteristics extracted (e.g. study size, PICOS, follow-up period) and
provide the citations
27
 HEALTH EVIDENCE THE RELATIONSHIP BETWEEN PSYCHOSOCIAL RISK FACTORS AND HEALTH
NETWORK SYNTHESIS OUTCOMES OF CHRONIC DISEASES: A REVIEW OF THE EVIDENCE FOR
REPORT CANCER AND CARDIOVASCULAR DISEASES

Table A1. contd

Section/topic No. Checklist item
Risk of bias 19 Present data on risk of bias of each study and, if available,
within studies any outcome-level assessment (see Item 12)
Results of 20 For all outcomes considered (benefits or harms), present,
individual for each study: (a) simple summary data for each intervention
studies group and (b) effect estimates and confidence intervals,
ideally with a forest plot
Synthesis of 21 Present results of each meta-analysis done, including
results confidence intervals and measures of consistency
Risk of bias 22 Present results of any assessment of risk of bias across studies
across studies (see Item 15)
Additional 23 Give results of additional analyses, if done (e.g. sensitivity or
analysis subgroup analyses, meta-regression [see Item 16])
DISCUSSION
Summary of 24 Summarize the main findings including the strength of
evidence evidence for each main outcome; consider their relevance
to key groups (e.g. health care providers, users and
policy-makers)
Limitations 25 Discuss limitations at study and outcome level (e.g. risk of
bias) and at review level (e.g. incomplete retrieval of identified
research, reporting bias)
Conclusions 26 Provide a general interpretation of the results in the context of
other evidence, and implications for future research
FUNDING
Funding 27 Describe sources of funding for the systematic review and
other support (e.g. supply of data); role of funders
for the systematic review

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Annex 2. SEARCH STRATEGY
The present review was based upon a bibliographic search of databases, concluded
on 23 June 2014.

Databases
The PubMed and Medline databases were searched, using keywords as set out in
the search terms below.

Search terms
1. psychosocial OR “psycho-social” OR “PS factor” OR “PS factors” OR stress OR
“job demand” OR “job demands” OR “job strain” OR “work demand” OR “work
demands” OR “job control” OR “perceived control” OR “ERI” OR effort OR
reward OR trust OR “social capital” OR “social support” OR “social network”
OR “social disruption” OR “loneliness” OR bereavement” OR “psychological
work environment” OR “social integration” OR “self esteem” OR “self-esteem”
OR “social esteem” OR happiness
2. “systematic review” OR “metaanalysis” OR “meta-analysis”
3. “chronic disease” OR “NCD” OR “non-communicable disease” OR
“noncommunicable disease” OR “non-communicable mortality” OR
“noncommunicable mortality” OR “cancer” OR “neoplasm” OR “neoplasma”
OR “tumour” OR “malignancy” OR “melanoma” OR “CVD” OR “CHD” OR
“MI” OR “heart attack” OR “stroke” OR “AMI” OR “myocardial infarction” OR
“cardiovascular” OR “coronary heart”
4. “2000/01/01”[Date - Publication] : “3000”[Date - Publication]
5. 1 AND 2 AND 3 AND 4

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