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Journal Pre-proof
“Hydroxychloroquine in patients with COVID-19: A Systematic
Review and meta-
analysis.”
Awadhesh Kumar Singh, Akriti Singh, Ritu Singh, Anoop Misra
PII: S1871-4021(20)30136-3
DOI: https://doi.org/10.1016/j.dsx.2020.05.017
Reference: DSX 1672
To appear in: Diabetes & Metabolic Syndrome: Clinical
Research & Reviews
Received Date: 6 May 2020
Revised Date: 7 May 2020
Accepted Date: 7 May 2020
Please cite this article as: Singh AK, Singh A, Singh R, Misra
A, “Hydroxychloroquine in patients
with COVID-19: A Systematic Review and meta-analysis.”,
Diabetes & Metabolic Syndrome: Clinical
4. Diabetes &
Endocrinology, G.D Hospital & Diabetes Institute, Kolkata,
West Bengal, India.
Akriti Singh: MBBS, Medical Resident, College of Medicine
and JNM Hospital,
Kalyani, Nadia, West Bengal, India.
Ritu Singh: M.D, Senior Consultant, Gynaecology & Obstetrics,
G.D Hospital &
Diabetes Institute, Kolkata, West Bengal, India.
Anoop Misra: M.D, Director, Fortis C-DOC Hospital for
Diabetes and Allied
Sciences, New Delhi, India.
Highlights:
• The role of hydroxychloroquine in the treatment of COVID-19
is not fully
known.
• While initial studies with hydroxychloroquine showed some
ray of hope,
recent studies that have emerged found either no benefit or a
possible harm
in COVID-19.
5. • This meta-analysis showed no benefit on viral clearance,
although a
significant increase in death was observed with
hydroxychloroquine in
patients with COVID-19, compared to the control.
Abstract:
Backgrounds and Aims
The role of hydroxychloroquine (HCQ) in the treatment of
COVID-19 is not fully
known. We studied the efficacy of HCQ compared to the control
in COVID-19
subjects on a. viral clearance measured by reverse transcriptase
polymerase chain
reaction (RT-PCR) and, b. death due to all cause.
Methods
PubMed, Scopus, Cochrane and MedRxiv database were
searched using the
specific keywords up to April 30, 2020. Studies that met our
objectives were
assessed for the risk of bias applying various tools as indicated.
6. Three studies each
that reported the outcome of viral clearance by RT-PCR and
death due to all cause,
were meta-analyzed by applying inverse variance-weighted
averages of
logarithmic risk ratio (RR) using a random effects model.
Heterogeneity and
publication bias were assessed using the I2 statistic and funnel
plots, respectively.
Results
Meta-analysis of 3 studies (n=210) on viral clearance assessed
by RT-PCR showed
no benefit (RR, 1.05; 95% CI, 0.79 to 1.38; p=0.74), although
with a moderate
heterogeneity (I2=61.7%, p=0.07). While meta-analysis of 3
studies (n=474)
showed a significant increase in death with HCQ, compared to
the control (RR,
2.17; 95% 1.32 to 3.57; p=0.002), without any heterogeneity
(I2=0.0%, p=0.43).
Conclusions:
No benefit on viral clearance but a significant increase in
mortality was observed
7. with HCQ compared to control in patients with COVID-19.
Keywords: Hydroxychloroquine, COVID-19, viral clearance,
outcomes, death
1. Introduction:
Scientist and physicians are working at heightened pace to
research the treatment
of coronavirus infection (COVID-19). Several potential
candidate drugs have been
tried in COVID-19. From these list of candidate drugs, two anti-
malarial drugs
came into limelight for following reasons. Initial studies found
both chloroquine
(CQ) and its derivative hydroxychloroquine (HCQ) inhibits
SARS-CoV-2
effectively in vitro [1-3]. This led clinicians to believe that both
drugs may have
good potential in the treatment of COVID-19.
First report of human trial came from China. A commentary by
Gao et al [4]
referring to 15 Chinese trials (whose complete results are still
not available),
claimed benefit with CQ in inhibiting the exacerbation of
8. pneumonia, improving
lung imaging findings, promoting a virus-negative conversion,
and shortening the
disease in more than 100 patients. One study from these 15
Chinese trials,
conducted by Chen et al [5] later showed data of 62 patients and
found that HCQ
significantly improved the clinical recovery (fever and cough)
and pneumonia
assessed by chest CT scan, compared to the control. However, a
close look into
this randomized control trial (RCT) found that the endpoints
specified in the
published protocol differed from those reported. First, the trial
was originally
supposed to report the results from two different dosage of HCQ
on clinical and
radiological outcome, although only the report of higher dose
HCQ was reported
finally. Second, the trial was stopped prematurely [6]. Another
study from France,
a non-randomized trial of HCQ (n=36) by Gautret et al [7] also
reported a
significant effect of HCQ and HCQ plus azithromycin (AZ) in
9. lowering viral load
and viral clearance compared to control as measured by reverse-
transcriptase
polymerase chain reaction (RT-PCR). However, this study was
widely criticized
due to the poor trial design, unreliable conclusions, no clinical
endpoints,
assessments made on day 6 despite a planned 10 days trial,
different value of Cycle
threshold for RT-PCR, and derivation of results after excluding
six patients from
the HCQ arm [8]. The publishing journal’s society also
subsequently declared that
the trial by Gautret and Colleagues did “not meet the Society’s
expected standard”
[9].
Nevertheless, based on these limited observational and
anecdotal evidence, several
guidelines across the world allowed both these drugs in the
treatment of COVID-
19 [10]. Interestingly, Indian Council of Medical research
hurriedly issued a
10. guideline and additionally recommended the use of CQ and
HCQ as a prophylactic
agent in the close contacts including the health care workers
[11]. Surprisingly,
based on these emerging developments, US President while
addressing the nation
on pandemic claimed CQ and HCQ as a “game changer” in the
treatment of
COVID-19. The consequence of this announcement resulted in
FDA issuing an
Emergency Use Authorization (EUA) to use both the drugs in
the treatment of
COVID-19 on March 28, 2020. Historically, this new EUA
represents the second
time when FDA has ever used any emergency authority to
permit use of a
medication for an unapproved indication. Earlier, an
investigational neuraminidase
inhibitor, peramivir was given similar EUA by FDA during the
2009-2010 for
severely ill patients with H1N1 influenza. Although later an
RCT failed to show
any benefit of peramivir in severely ill hospitalized patients
with influenza,
11. compared to the placebo. Nonetheless, peramivir is approved
only for
uncomplicated influenza since 2014.
Since several newer studies of HCQ on COVID-19 have recently
become
available, we aimed to study its effect on COVID-19 on two
important objective
outcomes. These two important outcomes include – a. viral
clearance by RT-PCR
negativity and, b. death due to all cause. In addition, we have
also compiled the
results from all the studies that have studied the efficacy and
safety of HCQ in
COVID-19, including non-controlled trials.
2. Methods:
This study was conducted in accordance with the Preferred
Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) [12].
However, this study has
not been registered in the International Prospective Register of
12. Systematic Reviews
(PROSPERO).
2.1 Search strategy and Inclusion criteria:
Three authors (AKS, AS and RS) systematically searched the
PubMed, Scopus,
Cochrane library and MedRxiv data base up to April 30, 2020.
The key terms
searched were ‘‘Hydroxychloroquine’’ OR ‘‘HCQ’’ (All Fields)
OR “viral
clearance” OR “death” OR “clinical recovery” AND COVID-19
OR SARS-CoV-
2. We retrieved all the studies conducted with
hydroxychloroquine in patients with
COVID-19 that was compared to control and explicitly reported
at least one
outcome of interest which include viral clearance by
transcriptase polymerase
chain reaction (RT-PCR) and or death due to all cause.
We excluded case reports, preclinical studies, studies that did
not report outcomes
with HCQ in COVID-19, and studies that did not compare the
outcomes with HCQ
13. compare to placebo or control. The studies that met our
predefined inclusion
criteria were screened by three authors (AKS, RS and AS), and
the studies that
entirely fulfilled our inclusion criteria were retrieved with their
supplementary
appendix for further review. Any ambiguity during study
selection was resolved
by mutual discussion and consensus. One study whose full text
was available in
Chinese (abstract in English) was translated to English by
Google translator and
one study was retrieved through hand search. A detailed
PRISMA flow-diagram
for the search strategy is included in figure 1.
2.2 Assessment of bias and Statistical Analysis:
Four reviewers (AKS, AS, RS and AM) independently assessed
the studies for risk
of bias ascertained through Jadad checklist, ROBINS-I tool and
Newcastle-Ottawa
scale for randomized, non-randomized and observational
studies, wherever
14. appropriate [13-15] and any disagreements were resolved
through mutual
discussion and consensus. Scoring of these studies on risk of
bias tools have been
outlined in supplementary table 1. A detailed PRISMA checklist
has been
appended in supplementary table 2.
Comprehensive meta-analysis (CMA) software Version 3,
Biostat Inc. Englewood,
NJ, USA was used to calculate all the statistical analyses. Seven
studies were
retrieved that reported any outcome with HCQ compared to the
control in COVID-
19. Three studies each reported for viral clearance measure by
RT-PCR and the
outcome of death due to any cause. We meta-analyzed the
pooled data of primary
outcomes of 3 trials that reported the rate of PCR negativity,
and 3 trials that
reported the difference in mortality between HCQ and control
arm. Since one RCT
by Chen et al reported resorption of pneumonia on chest
computed tomography
(CT) as a primary outcome but neither reported RT-PCR
15. negativity, nor the
mortality outcome, thus we did not include this study in the
meta-analysis,
however the outcome of this study shall be discussed.
Estimates from all the eligible studies have been combined by
applying inverse
variance-weighted averages of logarithmic risk ratio (RR),
using random-effects
analysis. Heterogeneity was measured using Higgins I² and
Cochrane Q statistic
[16]. Heterogeneity was considered as low (I2 <25%) or
moderate (25-50%) or high
(>50%). All the p reported here are two-sided and a p value of <
0.05 is considered
to be statistically significant. We also evaluated the potential
publication bias by
applying funnel plots using the “trim and fill” adjustment, rank
correlation test and
the Egger’s test.
3. Results:
The overview of results including the risk of bias from all the 7
studies that
16. compared HCQ to the control in COVID-19 have been
summarized in table 1 [5, 7,
17-21]. The meta-data that was used in this metanalysis has
been also represented
in table 2. Table 3 summarizes the safety and efficacy of all the
10 trials conducted
with HCQ in COVID-19, to date [5, 7, 17-24]. One RCT by
Chen et al [5] that is
not included in this meta-analysis found “any improvement” in
pneumonia were
significantly higher in HCQ arm, compared to the control (80.6
vs. 54.8%,
p=0.048). Moreover, significant improvement in chest CT (more
than 50%
absorption of pneumonia) was increasingly observed in HCQ
arm, compared to the
control (61.3 vs. 16.1%, p=not reported).
Nevertheless, the meta-analysis of 3 studies (n=210) that
reported the rate of PCR
negativity (figure 2) found no benefit with HCQ, compared to
the control (RR,
1.05; 95% CI, 0.79 to 1.38; p=0.74), although with a moderate
heterogeneity
17. (I2=61.7%, p=0.07). After the adjustment of publication bias,
the Trim and Fill
imputed the RR of 0.99 with 95% CI 0.69 to 1.42
(supplementary figure SF1).
However, the meta-analysis of 3 trials (n=474) that reported the
mortality outcome,
showed a significant (2-fold) increase in death in HCQ arm
(figure 3), compared to
the control (RR, 2.17; 95% 1.32 to 3.57; p=0.002), without any
heterogeneity
(I2=0.0%, p=0.43) and publication bias (supplementary figure
SF2).
4. Discussion:
To our knowledge, this would be the most updated meta-
analysis to report the
effect of HCQ on viral clearance and mortality outcome,
compared to the placebo
that included 6 studies. Additionally, we have also analyzed the
results from all the
10 studies available that have studied the efficacy and safety of
HCQ in patients
with COVID-19 (table 3).
18. A recent meta-analysis published by Sarma et al [25] have
showed no difference in
viral clearance and composite of death or clinical worsening
with HCQ, while a
significant improvement in radiological progression was
observed, compared to the
control. However, the meta-analysis by Sarma et al seems to
have overlooked the
raw data and mistakenly included the wrong denominators. For
example – they
included number of patients for HCQ plus azithromycin (n=20)
in their analysis,
rather than HCQ alone (n=14), for the denominator for viral
clearance. Similarly,
the number of patients included for the composite of death or
clinical worsening in
HCQ arm was also overlooked and mistakenly reported in
denominator (n=20),
rather than the actual number (n=26). We believe that these
differences could have
changed the outcomes.
We do acknowledge a number of limitations in our analysis that
include lesser
number of patients overall, lack of individual patient data,
19. combining the results of
RCT with other non-randomized studies and the inclusion of
pre-print version of
some of the unpublished studies. Moreover, outcomes are not
adjusted for multiple
confounding factors and no sensitivity analysis were made.
Besides, this
metanalysis was not registered at PROSPERO.
While this meta-analysis found no benefit of HCQ in the
treatment of COVID-19
on viral clearance and there was a 2-fold increase in death
compared to the control
arm, this could have been skewed by the one larger study that
have shown a
significant harm with HCQ, even when other smaller studies
found no significant
difference. For example, the study by Magagnoli et al (n=368)
[21] found that
there was no difference in the requirement of mechanical
ventilator (MV) and
death in patients who were on MV. However, the risk of death
from any cause was
20. higher in the HCQ group (adjusted hazard ratio 2.61, 1.10-6.17,
p=0.03), compared
to the control. Since this study contributed more than 84% of
weight in this pooled
meta-analysis of 3 studies, the signal of significant death
appears to emerge.
Moreover, relatively elderly patients (mean age 68 year) and
more sick (moderate
to severe COVID-19) patients were studied in Magagnoli et al
study, compared to
all other studies. Therefore, the purported benefit of HCQ in
early or mild
COVID-19 as observed in studies by Chen et al [5] and Gautret
et al [7] cannot be
entirely ruled out, from the result of this meta-analysis. It is
also possible that
HCQ may have some benefit in early and mild COVID-19 but
possibly harmful in
moderate to severe COVID-19.
Nevertheless, none of these studies attributed the harm of HCQ
directly linked to
the cardiac side effect. However, a recent double-blind RCT,
Cloro-Covid-19
conducted by Borba et al [26] hinted of high lethality with the
21. higher dosage of
chloroquine (CQ). Higher dose of CQ was associated with 39%
death, compared to
15% death in lower dose arm. Fatality rate with high dose of CQ
was as high as
60% in patients with underlying heart disease. QTc prolongation
was significant in
19% of cases on high dose CQ compared to 11% in low dose CQ
arm. Although no
signals of torsade de pointes were noted in this trial, it is
believed that increase in
mortality in this trial could be attributed to the combination of
CQ with
azithromycin (AZ) and oseltamivir or lopinavir/ritonavir, all of
which can prolong
QTc interval [27]. Similarly, emerging studies from France and
USA have
increasingly cautioned for QTc prolongation with both HCQ and
HCQ plus AZ.
While Bessière et al [28] reported (n=40) a prolonged QTc in
93% of the patients
receiving either HCQ or HCQ plus AZ; Mercuro et al [29]
reported QTc
22. prolongation (n=90) in 20% of patients treated with HCQ alone
or HCQ plus AZ.
These findings underscores the safety of HCQ in the light of
negligible benefit
observed in some of these studies.
Despite several limitations of this meta-analysis, we feel this
finding would instill
some degree of skepticism and shall help in curbing the
exuberant use of over
enthusiastically claimed “magical” drug. Hopefully, large
randomized controlled
trial such as DISCOVERY (EudraCT 2020-000936-23) and
RECOVERY (UK),
that is currently studying the effect of HCQ in COVID-19 and
comparing it with
other anti-viral drugs will finally decide its fate. Meanwhile, we
believe that any
prudent clinician would follow a pragmatic approach and shall
apply these drugs
only after assessing the potential risk versus uncertain benefit.
5. Conclusions:
While no benefit on viral clearance demonstrated by HCQ
23. compared to the control
in patients with COVID-19, a significant 2-fold increase in
mortality with the HCQ
warrants its use if at all, with an extreme caution, until the
results from larger
randomized controlled trials are available.
Funding: Not funded
Conflict of interest: Nothing to declare
Ethical permission: Not required as this analysis do not involve
patients directly.
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Table 1: Studies of HCQ compared to placebo in patients with
COVID-19
Study Types
of
studies
Country Age
(mean,
years)
N Case Control Severity of
COVID-19
HCQ
dose/day X
Days
33. (NCT04261517)
RCT China NR 30 15 15 Mild/
moderate
400 mg/d X
5D
Viral load by
RT-PCR + vs.
– at day 7
NR No NR
Tang18
et al.*
(ChiCTR
2000029868)
RCT China 46 150 75 75 Mild/
Moderate
(84%)
1200 mg/d X
3D, followed
by 800 mg/d
X 2 wks.
(mild
/moderate
cases) or 3
wks. (severe
cases)
Viral load by
RT-PCR + vs.
– at day 28
34. Clinical
symptoms,
normalization
of laboratory
parameters and
chest radiology
No No. However,
reduction in
CRP and
symptoms
noted in HCQ
arm in post-
hoc analysis
Gautret7
et al.**
nRCT France 45.1 36 20# 16 Mild/
moderate
600 mg/d X
10D
Viral load by
RT-PCR + vs.
– at day 6
Improvement in
symptoms,
mortality
Yes NR
35. Barbosa19
et al.**
qRCT USA 62.7 63 32 31 Mild/
moderate
800 mg/d X
1-2D
followed by
200-400 mg
OD X 3-4D
Need to
escalate
respiratory
support and
rate of
intubation at
day 5
Change in
lymphocyte
count, NLR,
and mortality
No, rather
harm in
HCQ arm
No, direction
towards harm
Mahevas20 et
al.***
Retro France 60 181 84 97 Pneumonia
36. requiring
O2 Rx
600 mg/d X
7D
ICU transfer or
death from any
cause at day 7
All-cause
mortality at day
7,
Occurrence of
ARDS within 7
day
No No
Magagnoli21 Retro USA 68 368 210## 158 Mild/ NR Need for
MV Death in No benefit. No
et al.*** moderate and death from
any cause
patients on MV Risk of death
due to any
cause was
higher in
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et al
37. POS France 58.7 11 11 0 Fever and
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39. HOLMES INSTITUTE
FACULTY OF
HIGHER EDUCATION
Assessment Details and Submission Guidelines
Trimester T1 2020
Unit Code HI5004
Unit Title Marketing Management
Assessment Type Individual Assignment
This is strictly required to be your own original work.
Plagiarism will be penalised.
Students are required to apply the theories and knowledge
derived from the unit
materials, demonstrate critical analysis and provide a
considered and
comprehensive evaluation. Students must use correct in-text
citation conventions.
Assessment Title Tutorial Question Assignment 1
Purpose of
40. the assessment
and linkage to
ULO.
Student is required to answer 5 questions come from the
recorded tutorial
questions every week from week 3 to week 6
The following Unit Learning Outcomes is applicable to this
assessment:
- Student will be able to, integrate theoretical and practical
knowledge of
Marketing Management
- Research the tools for gathering marketing information and
utilise the tools
to assess markets
- Evaluate consumer behavior and its effect on business
performance
- Conduct and apply marketing research to enhance decision
making
including segmentation and targeting and positioning
Weight 25%
Total Marks 50 Marks
Word limit The word limited is provided in each question
Due Date Week 8 - 22/5/2020 Friday 11:59 PM
[Late submission penalties accrue at the rate of -5% per day]
41. Submission
Guidelines
• All work must be submitted on Blackboard by the due date
along with a
completed Assignment Cover Page.
• The assignment must be in MS Word format, 1.5 spacing, 12-
pt Arial font and
2 cm margins on all four sides of your page with appropriate
section headings
and page numbers.
• Reference sources must be cited in the text of the report, and
listed
appropriately at the end in a reference list, all using Harvard
referencing style.
Page 2 of 3
Assignment Specifications
Purpose:
This individual assignment is an opportunity for students to
demonstrate their understanding of
marketing management
Details
42. Answer All FIVE (5) of the following questions. The questions
come from the recorded tutorial
questions from week 3 to week 6.
Question 1 Week 3: Tutorial 2 (10 marks)
The firm's success depends not only on how well each
department performs its work, but also
on how well the various departmental activities are coordinated
to conduct core business
processes. List and briefly describe in 300 words the four core
business processes. Use an
example for each process to illustrate your discussion
Question 2 Week 4: Tutorial 3 (10 marks)
Explain what is qualitative research and why it might be useful
to marketers. What are its
major drawbacks? Answer this question in 300 words
Question 3 Week 5: Tutorial 4 (10 marks)
https://www.youtube.com/watch?v=7oUqt-WbFkY
“Consumers have become part-time marketers”. Use the
information from the video and
discuss to this statement in 300 words.
43. - The discussion must contain the information from video
- You must support your discussion by referring to 3 additional
academic sources from
ProQuest (ensure that you reference them correctly)
Question 4 Week 5: Tutorial 4 (10 marks)
The family is the most important consumer buying organization
in society, and family
members constitute the most influential primary reference
group. Name two family
categorizations and discuss the impact of each of the categories
on buying behavior. Answer
this question in 300 words
Question 5 Week 6: Tutorial 5 (10 marks)
https://www.youtube.com/watch?v=tF9r9LrOb70
Watch the video and answer all 3 questions in a total of 300
words.
1. How can Tesla implement a marketing campaign with limited
budget? (4 marks)
2. Who is the target customer of Tesla? (3marks)
https://www.youtube.com/watch?v=7oUqt-WbFkY
https://www.youtube.com/watch?v=tF9r9LrOb70
44. Page 3 of 3
3. What is the future of Tesla? (3 marks)
Consequences of bullying victimization in childhood and
adolescence: A systematic review and meta-analysis
Sophie E Moore, Rosana E Norman, Shuichi Suetani, Hannah J
Thomas, Peter D Sly, James G Scott
Sophie E Moore, Peter D Sly, Child Health Research Centre,
the University of Queensland, South Brisbane, QLD 4101,
Australia
Rosana E Norman, Institute of Health and Biomedical Innova-
tion, Queensland University of Technology, Kelvin Grove, QLD
4059, Australia
Rosana E Norman, School of Public Health and Social Work,
Queensland University of Technology, Kelvin Grove, QLD
4059,
Australia
Shuichi Suetani, Queensland Centre for Mental Health
Research, the Park Centre for Mental Health, Wacol, QLD 4076,
Australia
Shuichi Suetani, Faculty of Medicine, the University of
Queensland, Herston, QLD 4029, Australia
45. Hannah J Thomas, James G Scott, the University of Queensland
Centre for Clinical Research, the University of Queensland,
Herston, QLD 4029, Australia
James G Scott, Metro North Mental Health, Royal Brisbane and
Women’s Hospital, Herston, QLD 4029, Australia
Author contributions: Norman RE and Scott JG designed
the study, supervised the systematic review and meta-analysis
and supervised the writing of the manuscript; Moore SE and
Suetani S conducted the systematic review; Moore SE
conducted
the meta-analysis and wrote the first draft of the manuscript;
Thomas HJ drafted sections of the manuscript related to
bullying
measurement and supervised the manuscript content; all authors
contributed to and approved the final manuscript.
Conflict-of-interest statement: The authors have no conflicts of
interest to declare.
Data sharing statement: No additional data is available.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by
external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0)
license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
46. Manuscript source: Invited manuscript
Correspondence to: James G Scott, Associate Professor,
the University of Queensland Centre for Clinical Research, the
University of Queensland, Bowen Bridge Rd, Herston, QLD
4029, Australia. [email protected]
Telephone: +61-73-6368111
Fax: +61-73-6361166
Received: September 13, 2016
Peer-review started: September 14, 2016
First decision: October 21, 2016
Revised: December 4, 2016
Accepted: December 27, 2016
Article in press: December 28, 2016
Published online: March 22, 2017
Abstract
AIM
To identify health and psychosocial problems associated
with bullying victimization and conduct a meta-analysis
summarizing the causal evidence.
METHODS
A systematic review was conducted using PubMed,
EMBASE, ERIC and PsycINFO electronic databases up
to 28 February 2015. The study included published
longitudinal and cross-sectional articles that examined
health and psychosocial consequences of bullying
victimization. All meta-analyses were based on quality-
effects models. Evidence for causality was assessed
using Bradford Hill criteria and the grading system
developed by the World Cancer Research Fund.
RESULTS
Out of 317 articles assessed for eligibility, 165 satisfied
47. the predetermined inclusion criteria for meta-analysis.
META-ANALYSIS
60 March 22, 2017|Volume 7|Issue 1|WJP|www.wjgnet.com
Submit a Manuscript: http://www.wjgnet.com/esps/
DOI: 10.5498/wjp.v7.i1.60
World J Psychiatr 2017 March 22; 7(1): 60-76
ISSN 2220-3206 (online)
World Journal of
PsychiatryW J P
Statistically significant associations were observed
between bullying victimization and a wide range
of adverse health and psychosocial problems. The
evidence was strongest for causal associations between
bullying victimization and mental health problems such
as depression, anxiety, poor general health and suicidal
ideation and behaviours. Probable causal associations
existed between bullying victimization and tobacco and
illicit drug use.
CONCLUSION
Strong evidence exists for a causal relationship between
bullying victimization, mental health problems and
substance use. Evidence also exists for associations
between bullying victimization and other adverse health
and psychosocial problems, however, there is insufficient
evidence to conclude causality. The strong evidence
49. children and adolescents has enduring effects which
may persist into adulthood[2-4]. Bullying victimization is
most commonly defined as exposure to negative actions
repeatedly and over time from one or more people, and
involves a power imbalance between the perpetrator(s)
and the victim[5]. Traditional bullying includes physical
contact (pushing, hitting) as well as verbal harassment
(name calling, verbal taunting), rumour spreading,
intentionally excluding a person from a group, and
obscene gestures. In recent years cyberbullying has
emerged as a significant public health problem[5-8].
The estimated prevalence of bullying victimization
is wide-ranging, with 10% and 35% of adolescents
experiencing recurrent bullying victimization[9-16].
While contextual and cultural differences influence
prevalence estimates[17], this variation is most frequently
explained by differences in measurement strategy[18-20].
As a result, researchers continue to call for greater
consensus in the definition and measurement of bullying
behaviours[17,21,22]. Cook et al[17] examined the variability
in prevalence of bullying victimization in a meta-analysis,
and more recently Modecki et al[20] synthesised studies
measuring both traditional bullying and cyberbullying.
Mean prevalence was 36% for traditional bullying
victimization and 15% for cyberbullying victimization[20].
There was significant overlap between bullying victimi-
zation in traditional and online settings[20]. A meta-
analysis by Kowalski et al[23] showed that the strongest
predictor of cyber-victimization was traditional bullying
victimization.
Many studies have examined adverse health and
psychosocial problems associated with bullying victimi-
zation. Those most commonly reported are mental
50. health problems, specifically depression, anxiety, self-
harm, and suicidal behaviour[2,14,24-28]. Over the past
two decades researchers have conducted a number of
systematic reviews to examine the relationship between
bullying victimization and ill mental health.
The first systematic investigation by Hawker and
Boulton[1] was a meta-analysis of cross-sectional
studies of peer victimization published between 1978
and 1997. The authors reported victimization was
significantly associated with depression, loneliness,
reduced self-esteem and self-concept, as well as anxiety.
To understand the temporal sequence between peer
victimization and mental health problems, Reijntjes
and colleagues conducted a pair of meta-analyses of
longitudinal studies to examine internalizing (depres-
sion, anxiety, withdrawal, loneliness, and somatic
complaints) and externalizing behaviours (aggression
and delinquency) and peer victimization[29,30]. They
examined two prospective paths: (1) peer victimization
at baseline and changes in internalizing and externalizing
problems at a second time point; and (2) internalizing
and externalizing problems at baseline and changes in
peer victimization at follow-up. The two meta-analyses
demonstrated internalizing and externalizing behaviours
are both antecedents and consequences of bullying
victimization[29,30].
Another meta-analytic review on bullying victimi-
Moore SE et al . Consequences of bullying victimization
61WJP|www.wjgnet.com March 22, 2017|Volume 7|Issue 1|
51. zation and depression by Ttofi et al[31] found those
children who were bullied at school were twice as likely
to develop depression compared to those who had
not been bullied. In addition, another meta-analytic
review found those children involved in any bullying
behaviour were more likely to develop psychosomatic
problems[32]. Finally, three systematic reviews have
shown an association between bullying victimization
and increased risk of adolescent suicidal ideation and
behaviours[33-35].
In contrast to mental health, there is mixed evi-
dence for the relationship between bullying victimi-
zation and substance use. Some studies report that
bullying victimization is associated with a reduced risk
of engaging in harmful alcohol use in later life[16,28],
whereas others suggest that being bullied may result in
an increased probability of later harmful alcohol use[36,37].
Similarly, some studies have shown an association
between being bullied and later illicit drug use and
smoking[36-39], whereas others have found no association
at all[2,14,24,40].
The association between bullying victimization and
psychosocial problems, such as academic achievement
and school functioning/connectedness and criminal
behaviour has also been examined. A meta-analysis by
Nakamoto and Schwartz[41] found a small but significant
negative association between bullying victimization
and academic achievement. However, Kowalski et al[23]
found no significant relationship between cyberbullying
victimization and academic achievement. Another
study found those exposed to bullying victimization in
adolescence were at increased risk of involvement in
criminal behaviour such as carrying a weapon[40].
52. There are now a large number of studies examining
associations between bullying victimization and a wide
range of adverse health and psychosocial problems.
However, many of these have not been systematically
examined and many existing systematic reviews did not
include cyberbullying. Furthermore, although associa-
tions exist, it is unclear if there is a causal relationship.
It is plausible that there are common factors that
predispose individuals to being bullied in childhood but
independently also increase the risk of adverse health
and other psychosocial problems. Rigorous appraisal
is required to consider both the possibility of a causal
association but also other plausible explanations for any
significant associations. Given the variation between
studies, this study aimed to investigate adverse
outcomes of both traditional and cyber bullying victimi-
zation and conduct a meta-analysis to summarize each
association. Furthermore, we critically evaluated whe-
ther sufficient evidence existed to establish a causal
relationship between bullying victimization and each of
the adverse health and psychosocial problems. This is
the first study to complete a summary of the evidence
for all adverse health and psychosocial problems that
are potentially a consequence of traditional and cyber
bullying victimization.
MATERIALS AND METHODS
This study followed the recommendations from the
PRISMA 2009 revision[42] and the guidelines outlined
by the Meta-analysis of Observational Studies in
Epidemiology[43] (Supplementary material S1). Methods
and inclusion and exclusion criteria were specified in
advance in the review protocol (Supplementary material
S2).
Inclusion and exclusion criteria
53. This systematic review and meta-analysis included
studies meeting the following inclusion criteria: (1)
reported original, empirical research published in a
peer reviewed journal; (2) examined the relationship
between exposure to bullying victimization as a child
or adolescent and one or more consequences of the
bullying exposure; and (3) is a population based
study. This study did not examine a particular type of
bullying victimization therefore all direct and indirect
forms of bullying including cyberbullying were included.
Included studies reported odds ratios (ORs) and
confidence intervals (CIs) comparing those exposed to
bullying victimization and those not exposed to bullying
victimization or, alternatively, provided information from
which effect sizes (ORs and CIs) could be calculated
between those exposed to bullying victimization and an
outcome.
Search strategy
Four electronic databases (PsycINFO, ERIC, EMBASE
and PubMed) were used to search for literature on the
adverse correlates of bullying victimization as either a
child or adolescent from inception up to 28 February
2015. The search was not restricted to the English
language nor by any other means. The searches of the
databases were conducted using the terms: “bullying”,
“bullied”, “harassment”, “intimidation”, “victimization”
along with “child” and “adolescent”. As this study
aimed to examine all correlates that were potentially a
consequence of bullying victimization, the search terms
used in conjunction with those above were broader
terms such as “outcome” “harm” “consequence” and
“risk”. In addition, reference lists of selected studies
were screened for any other relevant study and articles
in languages other than English were translated
(Supplementary material S2).
54. Data collection and quality assessment
The full text of articles that met all inclusion criteria
were retrieved and examined. Data extracted using a
data extraction template included publication details,
country where study was conducted, methodological
characteristics such as sample size and study design,
exposure and outcome measures, type of bullying and
frequency (Supplementary material S2). Each study
was then subjected to a quality assessment in order
for the reviewers to rate the quality of each study.
62WJP|www.wjgnet.com March 22, 2017|Volume 7|Issue 1|
Moore SE et al . Consequences of bullying victimization
classification criteria), severity of the bullying (frequent
- at least once a month, vs sometimes - less than once
a month), age of bullying victimization (before 13 years
of age vs after 13 years of age), and type of study
(prospective vs cross-sectional).
RESULTS
A total of 8231 articles were primarily identified by
the search, of which 3270 were duplicates. Titles
and abstracts for the 4961 remaining unduplicated
references were reviewed and 15 additional articles were
found from reference lists. From reviewing the title and
abstracts a further 4659 articles were excluded. This left
317 articles meeting the following criteria: (1) original
research extracted from a peer reviewed journal; and
(2) examined the bullying victimization as a child or
adolescent and one or more outcomes. Of the 317
articles reviewed, a further 152 articles were excluded
55. as they did not use a population based sample or did
not report enough information to calculate an effect
size. The remaining 165 articles provided evidence of
an effect size for bullying victimization and an outcome
(Figure 1) - either odds ratio with confidence intervals
or provided data which enabled the calculation of effect
sizes. The majority (n = 142) were from high income
regions. There were far fewer studies (n = 22) from
Two reviewers independently reviewed the included
articles and completed the quality assessment and any
disagreements were resolved by a third reviewer. The
quality assessment tool was based on the Newcastle-
Ottawa Scale for assessing the quality of observational
studies[44] as used by Norman et al[45] (Supplementary
material S2).
Statistical analysis
Following the method used by Norman et al[45], MetaXL
version 2.1[46], an add-in for Microsoft Excel was used
in this study to conduct the meta-analysis. ORs were
chosen as the summary measure. Heterogeneity was
assessed using the Cochran’s Q and I 2 statistics[47].
This meta-analysis used a quality effects model[48], a
modified version of the fixed-effects inverse variance
model that additionally allows greater weight to be
given to studies of higher quality vs studies of lesser
quality. The quality effects model avoids the limitation
in random-effects models of returning to equal weight-
ing irrespective of sample size if heterogeneity is
large[47,48]. Furthermore, in order to address the effects
of important study characteristics and explore hetero-
geneity this study conducted subgroup analyses,
dependent on data availability, for sex of participants in
the sample, geographic location and income level (high
income vs low-to-middle income as per the World Bank
56. 63WJP|www.wjgnet.com March 22, 2017|Volume 7|Issue 1|
Records identified through
database searching
(n = 8231)
Additional records
identified through other
sources (n = 15)
Records after duplicates removed
(n = 4961)
Records screened
(n = 4976)
Full-text articles
assessed for eligibility
(n = 317)
Id
en
ti
fic
at
io
n
S
cr
57. ee
ni
ng
E
lig
ib
ili
ty
In
cl
ud
ed
Studies included in
qualitative synthesis
(n = 165)
Studies included in quantitative
synthesis (meta-analysis)
(n = 165)
Prospective cohort (n = 57)
Cross-sectional (n = 108)
Records excluded
(n = 4659)
Full-text articles excluded,
with reasons (n = 152)
58. n = 120 (not enough
information to calculate
effect size)
n = 32 (did not use
population based
samples)
PRISMA 2009 Flow Diagram
Figure 1 PRISMA flow diagram showing process of study
selection for inclusion in systematic review and meta-analyses.
Moore SE et al . Consequences of bullying victimization
low- and middle-income countries, and only one study
utilized cross-national samples from different income-
level countries. Of the articles included, 57 had a
prospective cohort design and the remaining 108 were
cross-sectional. The majority of studies measured self-
reported bullying victimization. Some were from samples
collected from a state or regions where as others were
nationally representative (Supplementary material S3).
Bullying victimization in children and adolescents and
mental health
Bullying victimization in children and adolescents was
associated with a wide range of adverse mental health
outcomes (Table 1) including poor mental health (OR =
1.60; 95%CI: 1.42-1.81), syndromes such as depression
and anxiety, and symptoms and behaviours such as
psychotic symptoms, suicidal ideation and attempts.
Specifically, those exposed to bullying victimization had
an increased risk of depression (OR = 2.21; 95%CI:
59. 1.34-3.65). This association remained significant for all
the sub-group analyses including prospective studies,
age bullying occurred, sex and severity of the bullying.
A dose response existed between being “sometimes
bullied” and “frequently bullied” and depression (OR
= 1.78; 95%CI: 1.39-2.28 and OR = 3.26; 95%CI:
2.45-4.34 respectively). In comparing high- and low-
to-middle income countries, there was no significant
difference in the odds of developing depression. Those
exposed to bullying victimization were significantly
more likely to experience anxiety (OR = 1.77; 95%CI:
1.34-2.33) and exposure to bullying victimization was
associated with a wide range of anxiety spectrum
disorders such as social phobia and post-traumatic stress
disorder. This association remained after conducting
subgroup analyses including study type, sex and severity
of the bullying; however, the association between
bullying victimization and anxiety was not significant in
children under 13 years (Table 1).
Bullying victimization was also associated with non-
suicidal self-injury (OR = 1.75; 95%CI: 1.40-2.19)
and increased risk of suicidal ideation (OR = 1.77;
95%CI: 1.56-2.02) and the association remained
significant for all subgroup analyses (Table 1). A dose
response existed between being “sometimes bullied”
and “frequently bullied” and suicide ideation (OR = 1.53;
95%CI: 1.28-1.82 and OR = 2.59; 95%CI: 2.06-3.25
respectively). Bullying victimization was associated with
an increase in suicide attempts (OR = 2.13; 95%CI:
1.66-2.73). Subgroup analysis showed both males and
females were approximately three times more likely
to attempt suicide if they were bullied (OR = 2.93;
95%CI: 1.65-5.18 and OR = 2.89; 95%CI: 1.52-5.49
respectively). There was nearly a fourfold increase
in suicide attempts for individuals who experienced
60. frequent bullying victimization (OR = 3.77; 95%CI:
2.55-5.58) (Table 1). When comparing high income
countries to those with low and middle income, the
odds of bullying victims developing suicidal ideation or
attempting suicide were similar.
Although bullying victimization in children and
adolescents was associated with the pooling of all be-
havioural problems (OR = 1.37; 95%CI: 1.18-1.59),
this association was not significant in prospective cohort
studies and no dose-response was observed. Diagnoses
of disruptive behavioural disorders were not associated
with bullying victimization in children and adolescents
(Table 1).
Bullying victimization in children and adolescents and
substance use
Table 2 presents the associations between bullying
victimization and substance use. When all studies were
pooled together there was a significant association
between bullying victimization and alcohol use (OR =
1.26; 95%CI: 1.00-1.58). A subgroup analysis showed
a significant association between bullying victimization
and the risk of tobacco use for prospective studies (OR =
1.62; 95%CI: 1.31-1.99). Furthermore, a dose response
was present with frequent bullying victimization being
associated with tobacco use (OR = 3.19; 95%CI:
1.19-8.58), whereas no significant association was
found with those who were “sometimes bullied” (Table 2).
Bullying victimization was associated with an
increased risk of illicit drug use (OR = 1.41; 95%CI:
1.10-1.81). Subgroup analysis revealed that the
association between bullying victimization and increased
risk of using illicit drugs was significant in both cross-
61. sectional (OR = 2.43; 95%CI: 1.42-4.15) and
prospective studies (OR = 1.27; 95%CI: 1.12-1.44).
A subgroup analysis also revealed bullying victims in
low-to-middle income countries are at an increased
risk of illicit drug use (OR = 4.05; 95%CI: 2.18-7.55)
compared with bullying victims in high income countries
(OR = 1.31; 95%CI: 1.15-1.48). No significant
association was found in a sub group analysis examining
cannabis and bullying victimization in children and
adolescence (Table 2).
Bullying victimization in children and adolescents and
other health outcomes
Table 3 presents the association between bullying
victimization and other health outcomes. Bullying
victimization was associated with increased risk of
somatic symptoms, the most common being stomach
ache (OR = 1.76; 95%CI: 1.53-2.03), sleeping
difficulties (OR = 1.73; 95%CI: 1.46-2.05), headaches
(OR = 1.64; 95%CI: 1.38-1.94), dizziness (OR = 1.64;
95%CI: 1.38-1.95), and back pain (OR = 1.67; 95%CI:
1.43-1.95). Bullying victimization was also associated
with an increased risk of being overweight and obese (OR
= 1.68; 95%CI: 1.21-2.33 and OR = 1.78; 95%CI:
1.42-2.21, respectively). These associations were
significant for cross-sectional studies only and there was
no dose response.
When all studies were pooled, bullying victimization in
children and adolescents was associated with increased
64WJP|www.wjgnet.com March 22, 2017|Volume 7|Issue 1|
Moore SE et al . Consequences of bullying victimization
62. 65WJP|www.wjgnet.com March 22, 2017|Volume 7|Issue 1|
Data points Pooled OR 95%CI
lower bound
95%CI
upper bound
Cochran’s
Q
I ²
(%)
Test for
heterogeneity
(P value)
Poor mental health
Pooling all 39 1.6 1.42 1.81 303.79 87.49 < 0.01
Study type
Retrospective/cross-sectional 25 1.8 1.44 2.25 211.78
88.67 < 0.01
Prospective cohort 14 1.39 1.29 1.49 22.12 41.24 0.05
Sex
Male 3 2.49 1.86 3.32 0.44 0 0.8
Female 3 2.38 1.41 4 6.95 71.22 0.03
Twins 3 1.41 1.27 1.56 2.5 20.09 0.29
Severity of bullying
Sometimes 8 1.5 1.27 1.76 47.68 85.23 < 0.01
Frequent 8 1.52 1.18 1.95 51.4 86.38 < 0.01
Anxiety
Pooling all 58 1.77 1.34 2.33 3816.23 98.51 < 0.01
Anxiety 32 1.56 1.39 1.75 434.61 92.87 < 0.01
63. Social phobia 8 2.48 1.59 3.86 11.01 36.41 0.14
Generalised anxiety disorder 2 2.83 1.38 5.84 0.11
0 0.74
PTSD 12 6.41 1.93 21.22 497.11 97.79 < 0.01
Specific phobia 1 2.4 1 5.6 - - -
Separation anxiety disorder 1 4.6 2 10.6 - - -
Panic disorder 1 3.1 1.5 6.5 - - -
Agoraphobia 1 4.6 1.7 12.5 - - -
Study type
Retrospective/cross-sectional 39 2.02 1.21 3.38 3697.48
98.97 < 0.01
Prospective cohort 19 1.29 1.06 1.55 84.03 78.58 < 0.01
Age of bullying
Less than 13 yr 13 1.4 0.58 3.41 123.12 90.25 < 0.01
Older than 13 yr 45 1.81 1.29 2.56 3688.82 98.81 <
0.01
Sex
Male 16 1.84 1.3 2.59 112.23 86.63 < 0.01
Female 15 2.46 1.74 3.48 124.39 88.74 < 0.01
Severity of bullying
Sometimes 7 1.46 1.06 2 43.41 86.18 < 0.01
Frequent 25 2.47 1.94 3.14 122.47 80.4 < 0.01
Geographic location and income level
Low-to-middle income 22 2.41 1.75 3.32 175.97 88.07 <
0.01
High income 36 1.67 1.24 2.25 3441.17 98.98 < 0.01
Depression
Pooling all 92 2.21 1.34 3.65 14525.32 99.37 < 0.01
Major depressive disorder 2 2.27 0.68 7.57 2.07 51.63
0.15
Study type
Retrospective/cross-sectional 63 1.95 1.24 3.07 2594.97
97.61 < 0.01
Prospective cohort 29 3.03 1.31 6.98 4583.05 99.39 <
0.01
Age of bullying
64. Less than 13 yr 36 2.11 1.63 2.72 544.9 93.58 < 0.01
Older than 13 yr 56 2.29 1.24 4.23 13806.72 99.6 <
0.01
Sex
Male 27 2.07 1.48 2.89 443.84 94.14 < 0.01
Female 21 2.13 1.18 3.86 313.5 93.62 < 0.01
Severity of bullying
Sometimes 15 1.78 1.39 2.28 78.61 82.19 < 0.01
Frequent 28 3.26 2.45 4.34 224.43 87.97 < 0.01
Geographic location and income level
Low-to-middle income 13 2.53 1.75 3.68 143.98 91.67 <
0.01
High income 79 2.15 1.26 3.68 14351.72 99.46 < 0.01
Psychotic symptoms
Specific psychiatric symptoms 6 2.07 1.49 2.87 20.57
75.69 < 0.01
Non-clinical psychotic experiences 9 2.68 2.03 3.54 15.1
47.03 0.06
Psychotic symptoms 5 2.73 1.97 3.77 10.86 63.16
0.03
Personality disorders
Anti-social personality disorder 2 0.58 0.15 2.28 2.53
60.48 0.11
Borderline personality disorder 3 2.2 1.4 3.46 4.8
58.31 0.09
Eating disorders
Bulimia nervosa 1 3 1.4 6.2 - - -
Anorexia nervosa 1 0.004 0 251 - - -
Table 1 Associations between bullying victimization in
children and adolescents and mental health outcomes
Moore SE et al . Consequences of bullying victimization
65. 66WJP|www.wjgnet.com March 22, 2017|Volume 7|Issue 1|
Non-suicidal self injury
Pooling all 30 1.75 1.4 2.19 749.02 96.13 < 0.01
Study type
Retrospective/cross-sectional 21 1.55 1.09 2.22 721.15
97.23 < 0.01
Prospective cohort 9 1.65 1.34 2.02 19.39 58.75 0.01
Sex
Male 6 4.86 3.35 7.07 13.56 63.12 0.02
Female 4 2.7 2 3.65 8.92 66.37 0.03
Twins 2 2.57 1.79 3.7 0.12 0 0.73
Severity of bullying
Sometimes 6 1.57 1.09 2.25 34.04 85.31 < …
See corresponding editorial on page 497.
Meta-analysis of prospective cohort studies evaluating the
association
of saturated fat with cardiovascular disease1–5
Patty W Siri-Tarino, Qi Sun, Frank B Hu, and Ronald M Krauss
ABSTRACT
Background: A reduction in dietary saturated fat has generally
been thought to improve cardiovascular health.
Objective: The objective of this meta-analysis was to summarize
the evidence related to the association of dietary saturated fat
with
risk of coronary heart disease (CHD), stroke, and cardiovascular
disease (CVD; CHD inclusive of stroke) in prospective
epidemio-
logic studies.
Design: Twenty-one studies identified by searching MEDLINE
66. and
EMBASE databases and secondary referencing qualified for
inclu-
sion in this study. A random-effects model was used to derive
composite relative risk estimates for CHD, stroke, and CVD.
Results: During 5–23 y of follow-up of 347,747 subjects,
11,006
developed CHD or stroke. Intake of saturated fat was not
associated
with an increased risk of CHD, stroke, or CVD. The pooled
relative
risk estimates that compared extreme quantiles of saturated fat
in-
take were 1.07 (95% CI: 0.96, 1.19; P = 0.22) for CHD, 0.81
(95%
CI: 0.62, 1.05; P = 0.11) for stroke, and 1.00 (95% CI: 0.89,
1.11;
P = 0.95) for CVD. Consideration of age, sex, and study quality
did
not change the results.
Conclusions: A meta-analysis of prospective epidemiologic
studies
showed that there is no significant evidence for concluding that
dietary saturated fat is associated with an increased risk of CHD
or CVD. More data are needed to elucidate whether CVD risks
are
likely to be influenced by the specific nutrients used to replace
saturated fat. Am J Clin Nutr 2010;91:535–46.
INTRODUCTION
Early animal studies showed that high dietary saturated fat and
cholesterol intakes led to increased plasma cholesterol concen-
trations as well as atherosclerotic lesions (1). These findings
were
supported by associations in humans in which dietary saturated
67. fat correlated with coronary heart disease (CHD) risk (2, 3).
More
recent epidemiologic studies have shown positive (4–10),
inverse
(11, 12), or no (4, 13–18) associations of dietary saturated fat
with
CVD morbidity and/or mortality.
A limited number of randomized clinical interventions have
been conducted that have evaluated the effects of saturated fat
on
risk of CVD.Whereas some studies have shown beneficial
effects
of reduced dietary saturated fat (19–21), others have shown no
effects of such diets on CVD risk (22, 23). The studies that
showed beneficial effects of diets reduced in saturated fat
replaced saturated fat with polyunsaturated fat, with the impli-
cation that the CVD benefit observed could have been due to an
increase in polyunsaturated fat or in the ratio of polyunsaturated
fat to saturated fat (P:S), a hypothesis supported by a recent
pooling analysis conducted by Jakobsen et al (24).
The goal of this study was to conduct a meta-analysis of well-
designed prospective epidemiologic studies to estimate the risk
of
CHD and stroke and a composite risk score for both CHD and
stroke, or total cardiovascular disease (CVD), that was
associated
with increased dietary intakes of saturated fat. Large
prospective
cohort studies can provide statistical power to adjust for cova-
riates, thereby enabling the evaluation of the effects of a
specific
nutrient on disease risk. However, such studies have caveats,
including a reliance on nutritional assessment methods whose
68. validity and reliability may vary (25), the assumption that diets
remain similar over the long term (26) and variable adjustment
for covariates by different investigators. Nonetheless, a
summary
evaluation of the epidemiologic evidence to date provides im-
portant information as to the basis for relating dietary saturated
fat to CVD risk.
SUBJECTS AND METHODS
Study selection
Two investigators (QS and PS-T) independently conducted
a systematic literature search of the MEDLINE
(http://www.ncbi.
nlm.nih.gov/pubmed/) and EMBASE (http://www.embase.com)
databases through 17 September 2009 by using the following
search terms: (“saturated fat” or “dietary fat”) and (“coronary”
or
“cardiovascular” or “stroke”) and (“cohort” or “follow up”).
1 From the Children’s Hospital Oakland Research Institute,
Oakland, CA
(PWS-T and RMK), and the Departments of Nutrition (QS and
FBH) and
Epidemiology (FBH), Harvard School of Public Health, Boston,
MA.
2 PWS-T and QS contributed equally to this work.
3 The contents of this article are solely the responsibility of the
authors
and do not necessarily represent the official view of the
National Center for
69. Research Resources (http://www.ncrr.nih.gov) or the National
Institutes of
Health.
4 Supported by the National Dairy Council (PWS-T and RMK)
and made
possible by grant UL1 RR024131-01 from the National Center
for Research
Resources, a component of the National Institutes of Health
(NIH), and NIH
Roadmap for Medical Research (PWS-T and RMK). QS was
supported by
a Postdoctoral Fellowship from Unilever Corporate Research.
FBH was
supported by NIH grant HL60712.
5 Address correspondence to RM Krauss, Children’s Hospital
Oakland
Research Institute, 5700 Martin Luther King Junior Way,
Oakland, CA
94609. E-mail: [email protected]
Received March 6, 2009. Accepted for publication November
25, 2009.
First published online January 13, 2010; doi:
10.3945/ajcn.2009.27725.
Am J Clin Nutr 2010;91:535–46. Printed in USA. � 2010
American Society for Nutrition 535
70. Studies were eligible if 1) data related to dietary consumption
of
saturated fat were available; 2) the endpoints were nonfatal or
fatal CVD events, but not CVD risk factors; 3) the association
of
saturated fat with CVD was specifically evaluated; 4) the study
design was a prospective cohort study; and 5) study participants
were generally healthy adults at study baseline. The initial
search yielded 661 unique citations, of which 19 studies met the
inclusion criteria and were selected as appropriate for inclusion
in this meta-analysis (Figure 1) (4–6, 8–11, 14–16, 18, 27–34).
All 4 investigators participated in the selection process (PS-T,
QS, FBH, and RMK). Additional reference searches were per-
formed by conducting a hand review of references from re-
trieved articles, and 3 more studies were identified (13, 17, 35).
Of the 22 identified studies, 10 studies provided data
appropriate
to the constraints of this meta-analysis, specifically, relative
risk
(RR) estimates for CVD as a function of saturated fat intake
(10,
14–16, 28, 30–34). Where such data were not provided (n = 12),
data requests were made to investigators. Investigators from 6
of
the studies (4, 5, 8, 18, 29, 35) responded with the requested
data. A data set of the Honolulu Heart Study (9), obtained from
the National Heart, Lung, and Blood Institute (36), was used to
derive the RR estimates for this study. Investigators from 5
studies
either did not respond or could no longer access data sets (6, 11,
13, 17, 27). However, 4 of 5 of these studies provided data for
saturated fat intake as a continuous variable (6, 11, 13, 17). For
these studies, we derived RR estimates (see Statistical analysis)
for categorical saturated fat intake and CHD and/or stroke. The
71. study by Boden-Albala et al (27) was excluded because the RR
estimate published did not correspond to the values given for
the
upper and lower bounds of the CI, ie, using these values to
derive the SE resulted in different estimates, and the authors did
not respond to our attempts to obtain the correct data.
Altogether, this meta-analysis included data from 21 unique
studies, with 16 studies providing risk estimates for CHD and
8 studies providing data for stroke as an endpoint. Data were
de-
rived from347,747participants, ofwhom11,006 developedCVD.
Data extraction
Two authors (PS-T and QS) independently extracted and tab-
ulated data from each study using a standard extraction form.
Discrepancies were resolved via review of the original articles
and
group discussion. From each study, we extracted information on
first author, publication year, disease outcome, country of
origin,
method of outcome ascertainment, sample size, age, sex,
average
study follow-up time, number of cases, dietary
assessmentmethod
and the validity of the method, number of dietary assessments,
covariates adjusted, unit of measurement, RR of CVD
comparing
extreme quantiles of saturated fat intake or per unit of saturated
fat
intake, and corresponding 95% CIs, SEs, or exact P values.
Statistical analysis
RRs and 95% CIs were log transformed to derive corre-
72. sponding SEs for b-coefficients by using Greenland’s formula
(37). Otherwise, we used exact P values to derive SEs where
possible. To minimize the possibility that the association for
saturated fat intake may be influenced by extreme values, we
contacted the authors of studies in which RRs were presented as
per-unit increments of saturated fat intake and requested RRs
comparing extreme quantiles. For studies for which we did not
receive responses, we used the published trend RRs comparing
the 25th and 75th percentiles to estimate RRs comparing high
with low dichotomized saturated fat intakes (38).
Meta-analyses were performed by using STATA 10.0 (Stata-
Corp, College Station TX) and Review Manager 5.0 (The Nordic
Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark; http://www.cc-ims.net/RevMan). P , 0.05 was con-
sidered statistically significant. Random-effects models taking
into account both within-study and between-study variability
were used to estimate pooled RRs for associations of dietary
saturated fat with CHD risk. Relative to fixed-effects models,
random-effects models were more appropriate for the current
study because test statistics showed evidence of heterogeneity
among these studies. When several RRs were given for
subgroup
analyses within a single study, random-effects models were
used
to pool the RRs into one composite estimate.
We used the STATA METAINF module to examine the in-
fluence of an individual study on the pooled estimate of RR by
excluding each study in turn. We used the STATA METAREG
module to examine whether the effect size of these studies
depended on certain characteristics of each study, including
age,
sex, sample size, duration of follow-up, whether disease out-
comes were confirmed by medical record review, and a score
evaluating overall study quality. This quality score was derived
73. from the following information: dietary assessment method
(where 5 points were given for diet records, 4 for validated
FFQs,
3 for FFQs that were not formally validated, 2 for diet history,
and
1 for 24-h recall), number of dietary assessments, and number
of
adjusted established risk factors for CVD. Points were totaled to
construct a composite quality score for each study.
We further conducted secondary analyses to examine age- and
sex-specific effects (ie, age ,60 y compared with �60 y and
FIGURE 1. Study selection process. CHD, coronary heart
disease; CVD,
cardiovascular disease; RR, relative risk. 1Three studies
provided outcome
data for both CHD and stroke.
536 SIRI-TARINO ET AL
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at
a.
META-ANALYSIS OF SATURATED FAT AND CVD 537
male compared with female) of saturated fat on CVD risk.
These
secondary analyses were performed with only those studies that
provided stratified data according to these variables.
To examine the effects of replacing saturated fat with car-
bohydrate or polyunsaturated fat, we performed secondary meta-
analyses with studies that provided pertinent and extractable
125. data.
Because energy from carbohydrate intake was excluded in fully
adjusted models (including adjustments for total energy and
energy from protein and fats other than saturated fat) in 6 of 21
studies, the regression coefficients of saturated fat could be
interpreted as the effects of isocalorically replacing
carbohydrate
intakewith saturated fat (25). Similarly, there were 5 studies (4,
9,
29, 31, 33) in which the regression coefficients of saturated fat
could be interpreted as the effects of isocalorically replacing
polyunsaturated fat intake with saturated fat. Finally, because
consideration for total energy intake has been shown to be rel-
evant in the evaluation of nutrient-disease associations (39), we
also performed a subanalysis of studies (n = 15) that provided
total energy intake data (4, 6, 8–11, 15, 16, 18, 29–31, 33).
Begg
funnel plots were used to assess potential publication bias (40).
RESULTS
The study design characteristics of the 21 studies identified by
database searches and secondary referencing that were included
in this meta-analysis (4–6, 8–11, 13–18, 28–35) are shown in
Table 1. Altogether, there were 16 studies that considered the
association of saturated fat with CHD and 8 studies that evalu-
ated the association of saturated fat with stroke. Dietary as-
sessments included 24-h recalls, food-frequency questionnaires
(FFQs), and multiple daily food records. The duration of
follow-
up ranged from 6 to 23 y, with a mean and median follow-up of
14.3 and 14 y, respectively.
The baseline characteristics of the study participants are
provided in Table 2. The number of subjects in each study
126. ranged from 266 to 85,764. The age of participants ranged from
’30 to 89 y. There were 11 studies conducted exclusively in
men, 2 studies conducted exclusively in women, and 8 studies
that enrolled both men and women. There were 12 studies that
were conducted in North America, 6 in Europe, 2 in Japan, and
1 in Israel.
The level of adjustment for covariates varied according to
study (Table 3). Wherever possible, risk estimates from the
most fully adjusted models were used in the estimation of the
pooled RR. Studies that reported positive associations be-
tween saturated fat and CVD risk included the Lipid Research
Clinics Study (6), the Health Professionals Follow-Up Study
(4), the Health and Lifestyle Survey (5), the Strong Heart Study
(10), and studies by Mann et al (32) and Jakobsen et al (8).
Notably, these positive associations were specific to subsets of
the study population, ie, younger versus older (6, 8, 10), women
versus men (5, 8), or for some, but not all, CHD endpoints (4).
TABLE 2
Baseline characteristics of participants of 21 unique prospective
epidemiologic studies of saturated fat intake and risk of
coronary heart disease (CHD) or
stroke1
Study
No. of
subjects Age Sex
Country of
residence Smoker
127. Disease
outcome
Method of
diagnosis
y %
CHD
Shekelle et al, 1981 (17) 1900 40–55 Male USA NR Fatal CHD
DC
McGee et al, 1984 (9)2 8006 45–68 Male USA NR Total CHD
MR and DC
Kushi et al,1985 (13) 1001 30–69 Male USA NR Fatal CHD DC
Posner et al, 1991 (16) 813 45–65 Male USA 41.6 Total CHD
MR
Fehily et al, 1993 (28) 512 45–59 Male UK NR Total CHD DC
Goldbourt et al, 1993 (35)2 97673 �40 Male Israel NR Fatal
CHD MR and DC
Ascherio et al, 1996 (4) 38,463 40–75 Male USA 9.5 Total CHD
MR and DC
Esrey et al, 1996 (6) 4546 30–79 Both Canada 33.9 Fatal CHD
MR
Mann et al, 1997 (32) 10,802 16–79 Both UK 19.5 Fatal CHD
MR
128. Pietinen et al, 1997 (15) 21,930 50–69 Male Finland 100 Total
CHD MR and DC
Boniface and Tefft, 2002 (5) 2676 40–75 Both UK NR Total
CHD DC
Jakobsen et al, 2004 (8) 3686 30–71 Both Denmark NR Total
CHD MR
Leosdottir et al, 2007 (14)2 28,098 45–73 Both Sweden 29.5
Total CHD DC
Oh et al, 2005 (33) 78,778 30–55 Female USA NR Total CHD
MR and DC
Tucker et al, 2005 (18) 2663 34–80 Male USA 21.8 Fatal CHD
MR and DC
Xu et al, 2006 (10) 2938 47–79 Both USA 29.7 Total CHD MR
Stroke
McGee et al, 1984 (9)2 8006 45–68 Male USA NR Total stroke
MR and DC
Goldbourt et al, 1993 (35)2 97673 �40 Male Israel NR Fatal
stroke MR and DC
Gillman et al, 1997 (11) 832 45–65 Male USA NR Ischemic
stroke MR
Iso et al, 2001 (31) 85,764 34–59 Female USA NR Hemorrhagic
stroke MR and DC
He et al, 2003 (29) 38,4633 40–75 Male USA 9.5 Total stroke
MR and DC
129. Iso et al, 2003 (30) 4775 40–69 Both Japan 13.5 Hemorrhagic
stroke MR and DC
Sauvaget et al, 2004 (34) 3731 35–89 Both Japan 26–35
Ischemic stroke DC
Leosdottir et al, 2007 (14)2 28,098 45–73 Both Sweden 29.5
Ischemic stroke DC
1 NR, not reported; MR, medical records; DC, death certificate.
2 These studies provided both CHD and stroke outcome data.
3 These numbers, as provided by the respective investigators,
differ from those used in the original publications.
538 SIRI-TARINO ET AL
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Solve the questions below using the attached file. 12pt font
size, Times new roman, 3 pages limit.
USE THE ATTACHTED ‘ARTICLE #1’ TO ANSWER THE
QUESTIONS BELOW
Q1: Review the study titled “Consequences of bullying
victimization in childhood and adolescence: A systematic
review and meta-analysis” (Article#1 attachment), and answer
the following:
234. A. Briefly describe of;
1. Search strategy
2. Data collection, quality assessment
3. Statistical analysis
B. Discuss the causality criteria as presented in the paper.
235. USE THE ATTACHTED ‘ARTICLE #2’ TO ANSWER THE
QUESTIONS BELOW
Q2: Review the study titled “Meta-analysis of prospective
cohort studies evaluating the association of saturated fat with
cardiovascular disease”.
A. Describe the findings of this study as presented in figure 2.
B. Describe the publication bias as presented in figure 3.
C. Do you agree with the conclusion of the study? Justify your
answer
USE THE ATTACHTED ‘ARTICLE #3’ TO ANSWER THE
236. QUESTIONS BELOW
Q3: Review the study titled “Hydroxychloroquine in patients
with COVID-19: A Systematic Review and metaanalysis”.
A. Briefly describe the search strategy and Inclusion criteria.
B. Describe the study results as presented in figures 2 and 3.
C. What are the limitations of the study?
D. Do you agree with the conclusion of the study? Justify your
answer
