For peer review only
Prevalence and patterns of congenital heart diseases in Africa: a systematic review and meta-analysis protocol
Journal: BMJ Open
Manuscript ID bmjopen-2016-015633
Article Type: Protocol
Date Submitted by the Author: 19-Dec-2016
Complete List of Authors: Tankeu, Aurel; Faculty of Medecine and Biomedical Sciences, Internal medicine and specialities Bigna, Jean Joel; Centre Pasteur of Cameroon, Epidemiology and Public Health Nansseu, Jobert Richie; Mother and Child Centre, Chantal Biya Foundation, Sickle cell unit Aminde, Leopold; Clinical Research Education, Networking & Consultancy (CRENC), Douala and Nguti District Hospital,
Danwang, Celestin; Faculty of Medecine and Biomedical Sciences, Internal medicine and specialities Mazou, Temgoua Ngou ; Faculty of Medecine and Biomedical Sciences, Internal medicine and specialities Noubiap, Jean Jacques; Edea Regional Hospital, Internal Medicine Unit
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Epidemiology
Keywords: Congenital heart disease < CARDIOLOGY, Africa, Heart defects, cardiac malformation
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on A
pril 20, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2016-015633 on 14 February 2017. D
ownloaded from
For peer review only
1
Prevalence and patterns of congenital heart diseases in Africa: a systematic
review and meta-analysis protocol
Aurel T. Tankeu1, Jean Joel R. Bigna
2,3, Jobert Richie N. Nansseu
4,5, Leopold Ndemnge
Aminde6, Celestin Danwang
7, Temgoua Ngou Mazou
1, Jean Jacques N. Noubiap
8*
1. Department of Internal Medicine and Specialties, Faculty of Medicine and Biomedical
Sciences, Yaoundé, Cameroon
2. Department of Epidemiology and Public Health, Centre Pasteur of Cameroon, Yaoundé,
Cameroon
3. Faculty of Medicine, University of Paris Sud XI, Le Kremlin Bicêtre, France
4. Department of Public Health, Faculty of Medicine and Biomedical Sciences, University of
Yaoundé 1, Yaoundé, Cameroon
5. Sickle Cell Disease Unit, Mother and Child Centre of the Chantal Biya Foundation,
Yaoundé, Cameroon
6. Faculty of Medicine & Biomedical Sciences, School of Public Health, The University of
Queensland, Brisbane, Queensland, Australia
7. Department of Surgery and Specialties, Faculty of Medicine and Biomedical Sciences,
University of Yaoundé 1, Yaoundé, Cameroon
8. Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape
Town, South Africa
E-mail addresses: ATT: [email protected]; JJRB: [email protected]; JRNN:
[email protected]; LNA: [email protected]; CD: [email protected];
TNM: [email protected]; JJNN: [email protected]
*Corresponding author: Dr. Jean Jacques N. Noubiap. Department of Medicine, Groote
Schuur Hospital and University of Cape Town, 7295, Cape Town, South Africa.
Page 1 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
2
Abstract
Introduction
Congenital heart diseases (CHD) are common causes of cardiovascular morbidity and
mortality among young children and adolescents living in Africa. Accurate epidemiological
data are needed in order to evaluate and improve preventive strategies. This review aims to
determine the prevalence of CHD and their main patterns in Africa.
Methods and analysis
This systematic review and meta-analysis will include cross-sectional, case–control and
cohort studies of populations residing inside African countries, which have reported the
prevalence of CHD; confirmed by an echocardiographic examination, and/or describing
different patterns of these abnormalities in Africa. Relevant abstracts published without
language restriction from January 1st, 1986 to December 31
st 2016 will be searched in
PubMed, Exerpta Medica Database and online African journals as well as references of
included articles and relevant reviews. Two review authors will independently screen, select
studies, extract data and assess the risk of bias in each study. The study-specific estimates will
be pooled through a random-effects meta-analysis model to obtain an overall summary
estimate of the prevalence of CHD across studies. Clinical and statistical heterogeneity will be
assessed, and we will pool studies judged to be clinically homogenous. On the other hand,
statistical heterogeneity will be evaluated by the χ2 test on Cochrane’s Q statistic. Funnel-
plots analysis and Egger’s test will be used to detect publication bias. Results will be
presented by geographic region (central, eastern, northern, southern and western Africa).
Ethics and dissemination
Page 2 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
3
The current study will be based on published data, and thus ethical approval is not required.
This systematic review and meta-analysis is expected to serve as a base which could help
estimating and evaluating the burden of these abnormalities on the African continent. The
final report of this study will be published in a peer-reviewed journal.
Review registration number
PROSPERO CRD42016052880.
Funding
None.
Page 3 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
4
Strengths and limitations of the study
• To the best of our knowledge, this will be the first systematic review on the topic of
Congenital heart diseases (CHD) to summarize available data on African continent.
• We will use powerful meta-analysis techniques to derive accurate estimates.
• A major possible limitation of this study could be the limited data with predominance of
hospital-based studies. Indeed, these studies may not reflect the true prevalence of CHD in
the general population, therefore overestimating these threats.
• Another possible limitation may be heterogeneity of studies done on the topic in Africa.
Page 4 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
5
Introduction
Congenital heart disease or congenital heart defect (CHD) is a problem of heart’s structure
and function present at birth, affecting heart or adjacent great blood vessels present either at
the time of birth or detected later in life.1
2 Worldwide, CHD are the main heart diseases
found in children and constitute one of the major causes of infant mortality, particularly in
developing countries.2 3
They also represent the most common of all congenital malformations
accounting for more than 20% of perinatal deaths.4 5
Their estimate prevalence is eight cases
per 1,000 live births across the globe, representing approximately 1.35 million newborns each
year with CHD but these figures vary worldwide.2 For instance, the incidence of CHD in
different studies varies from about 4/1.000 to 50/1.000 live births and despite advances in
detection and treatment, congenital heart diseases accounts for 3% of all infant deaths and
46% of death from congenital malformations in developed countries such as USA.4-6
In
addition, these abnormalities can be life threatening in early childhood, and children born with
severe forms are at approximately 12 times higher risk of mortality in the first year of life.7
Thus, hundreds of thousands of children die each year from CHD, while millions more remain
in desperate need of treatment in the developing world.8 Since mortality and morbidity from
cardiac disease among children in developing countries are gaining recognition, there is a
need of summarized data on CHD in African continent. Africa is thought to have one of the
highest prevalence of heart diseases in children and young adults, including CHD but main
findings include evidence that the CHD burden is underestimated mainly due to the poor
outcome of African children with CHD.7 From a global point of view, the epidemiology of
these abnormalities is still unknown in Africa with few or even no global data on the topic.
Reducing the prevalence of these diseases is urgent and requires a real inventory of the
premises of the problem that would clarify the issue for more effective prevention strategies
Page 5 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
6
and improved management. In this context, we present the protocol for a systematic review
and meta-analysis to assess the prevalence and patterns of CHD in Africa.
Objective
This systematic review and meta-analysis aims to determine the prevalence and of CHD and
their different patterns in Africa.
Review question
This review of studies published in the past 30 years, from 1st January 1986 to 31
st December
2016, should answer the following questions
1. What is the prevalence of CHD among African populations?
2. What are the different patterns of CHD in Africa?
Methods and analysis
Criteria for considering studies for the review
Inclusion criteria
We will include:
1. Cross-sectional, case–control or cohort studies of populations residing in African countries
reporting the prevalence of CHD in African countries or enough data to compute these
estimates.
Page 6 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
7
2. Studies describing the different patterns of CHD on the African continent.
Exclusion criteria
We will not consider:
1. Studies on congenital abnormalities involving the heart but not considered as CHD (Long
QT syndrome, congenital but functionless abnormalities of the heart, cardiomyopathies).
2. Studies conducted among populations of African origin residing outside Africa.
3. Studies in subgroups of participants selected on the basis of cardiac murmurs without
echocardiographic confirmation of CHD (e.g. suspected but non-confirmed CHD).
4. Studies including many pathologies in which it will not be possible to extract data
regarding CHD or studies reporting congenital abnormalities affecting many systems at time.
5. Letters, reviews, commentaries and editorials.
6. Studies lacking key data and/or explicit method description.
7. Duplicates: for studies published in more than one paper, the most comprehensive one
reporting the largest sample size will be considered.
8. Studies whose full data will not be accessible even after request from the authors.
Search strategy for identifying relevant studies
The search strategy will be implemented in two stages:
Bibliographic database searches
A. Relevant abstracts published without language restriction on the prevalence, incidence,
main etiologies and clinical features of CHD in Africa will be identified via searching
Page 7 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
8
PubMed, Exerpta Medica Database, and online African journals. The search will be limited to
studies published between January 1st, 1986 and December 31
st, 2016. Both text words and
medical subject heading terms will be used. Key search terms include: ‘congenital heart
defects’ or ‘congenital heart disease’ as well as the name of every known pattern of these
abnormalities. We will also use individual country names for the 54 African countries as
additional key search terms for more abstracts on the subject. Conference proceedings of the
study period will also be identified through databases and checked. The main search strategy
is shown in Table 1.
B. The abstracts of all eligible papers will be reviewed and full articles will be accessed
through PubMed, Exerpta Medica Database, Google Scholar, HINARI or journals’ websites.
Additionally, references of all relevant articles and reviews will be scrutinized for other
potential data sources, and their full texts will be accessed in a similar way. The authors
whose full text papers will not be accessible by the numerous internet-based sources will be
directly contacted to provide them. In case of no feedback from these authors, the
corresponding studies will be excluded.
Searching for others sources
References of all relevant researches and review articles will be scrutinized for additional
potential data sources, and their full texts will be accessed in a similar way. Those authors
whose full text papers will not be accessible by the numerous internet-based sources will be
directly contacted via email to provide them. In case of no feedback from these authors, the
corresponding studies will be excluded.
Selection of studies for inclusion in the review
Page 8 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
9
Assessment of eligible papers will be independently run by two authors using an assessment
guide to ensure that the selection criteria are reliably applied by all the team. They will screen
the titles and abstracts obtained from the searches and retrieve the full texts of potentially
eligible papers by at least one author. Thereafter, they will independently review the full text
of each potentially eligible study, compare their results and resolve any discrepancy by
discussion and consensus. If a decision is not reached, a third review author will be consulted
for arbitration.
Assessment of methodological quality and reporting of data
The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in
meta-analyses will be used to assess the methodological quality and risk of bias for each study
(see online supplementary appendix S1).9 Risk of bias and quality scores will be presented in
a table.
Data extraction and management
A data extraction sheet will be used to collect information about the author, the country, the
year of publication, the study design, the sample size population, the mean/median age of the
population, the age range, the sex ratio, the prevalence of CHD as well as main patterns when
available. Where prevalence or information for calculating them (eg. sample size, number of
outcomes) are lacking, we will directly contact the corresponding author to request the
information. In case of multinational studies, we will separate the results to show the
prevalence and etiologies within individual countries. Where it will not be possible to
disaggregate the data by country, the study will be presented as one and the countries in which
the study was done will be shown.
Data synthesis and analysis
Page 9 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
10
Data will be analyzed using Stata software version 13 (Stata Corp V.13, Texas, USA). A
meta-analysis will be conducted for data obtained from studies in which CHD has the same
etiologies, Standard errors (SEs) for the study-specific estimates will first be determined from
the point estimate and the appropriate denominators, assuming a binominal distribution. Then,
the study-specific estimates will be pooled through a random-effects meta-analysis model to
obtain an overall summary estimate of the prevalence across studies, after stabilizing the
variance of individual studies using the Freeman-Tukey double arc-sine transformation (to
keep the effect of studies with extremely small or extremely large estimates).10
Heterogeneity
will be evaluated by the χ² test on Cochrane’s Q statistic11
which is quantified by I² values,
assuming that I² values of 25%, 50% and 75% represent low, medium and high heterogeneity
respectively.12
Where substantial heterogeneity will be detected, a subgroup analysis will be
performed to detect its possible sources using the following grouping variables: type of CHD,
consequences on cardiac hemodynamic, study setting (hospital vs community-based), age of
diagnosis, geographical area (central, eastern, northern, southern and western Africa), and
study quality. Difference between groups will be detected if p value < 0.05. Inter-rater
agreement for study inclusion will be assessed using Cohen’s κappa coefficient.13
Funnel
plots analysis and Egger’s test14
will be done to detect publication bias. Publication bias will
be confirmed if p value on Egger’s test < 0.10. Results will be presented by geographic region
(central, eastern, northern, southern and western Africa).
Presentation and reporting of results
The study selection process will be summarized using a flow diagram. Reasons for studies’
exclusion will be described. The report will follow the PRISMA (Preferred Reporting Items
for systematic review and Meta-analysis) Guidelines {Citation}. Tables and forest plots will
Page 10 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
11
serve to summarize quantitative data where appropriate. We will examine prevalence and
etiologies by region, setting (hospital or community) and time period depending on the data
available. We plan to report on quality scores and risk of bias for each eligible study. This
may be tabulated and accompanied by narrative summaries.
Conclusion
CHD represent the second major cause of CVD morbidity and mortality among young
Africans. Their management is limited in Africa in an inadequate socio-economic
environment with insufficient technical platform and human resources. Moreover, the global
burden of these conditions is unknown on the continent. Therefore, it becomes urgent to
provide summarized recent and reliable data in order to help estimating the prevalence as well
as etiologies in Africa in other to highlight the importance of these abnormalities and the need
to reinforce of effective preventives strategies based on systematic screening of cardiac
abnormalities in the perinatal period. We hope that this review will help sensitizing health
care providers on the problem represented by CHD in Africa, assist and support the
implementation of new policies, practices and researches by providing insights into the
current situation and the true impact of CHD on African continent as well as shortcomings
that can guide future research around this topic.
Protocol and registration
The protocol for this review has been published in the PROSPERO International Prospective
Register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO), registration number:
PROSPERO CRD42016052880
Page 11 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
12
Authors’ Contributions
ATT and JJNN conceived and designed the protocol. ATT drafted the manuscript. JJRB,
JRNN, LNA, CD, TNM and JJNN critically revised the manuscript for methodological and
intellectual content. JJNN is the guarantor of the review. All authors approved the final
version of this manuscript.
Competing interests
None.
Funding
This research received no specific grant from any funding agency in the public, commercial or
not-for-profit sectors.
Data sharing statement
No additional data are available.
References
1. Tantchou Tchoumi JC, Butera G, Giamberti A, et al. Occurrence and pattern of
congenital heart diseases in a rural area of sub-Saharan Africa. Cardiovasc J Afr.
2011;22(2):63–6.
2. Chelo D, Nguefack F, Menanga AP, et al. Spectrum of heart diseases in children: an
echocardiographic study of 1,666 subjects in a pediatric hospital, Yaounde, Cameroon.
Cardiovasc Diagn Ther. 2016;6(1):10–9.
3. Kouame BD, N’guetta-Brou IA, Kouame GSY, et al. Epidemiology of congenital
abnormalities in West Africa: Results of a descriptive study in teaching hospitals in
Abidjan: Cote d’Ivoire. Afr J Paediatr Surg. 2015;12(1):51–5.
Page 12 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
13
4. Sadowski SL. Congenital cardiac disease in the newborn infant: past, present, and future.
Crit Care Nurs Clin North Am. 2009;21(1):37–48.
5. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol.
2002;39(12):1890–900.
6. Chinawa JM, Eze JC, Obi I, et al. Synopsis of congenital cardiac disease among children
attending University of Nigeria Teaching Hospital Ituku Ozalla, Enugu. BMC Res
Notes. 2013;6:475.
7. Otaigbe BE, Tabansi PN. Congenital heart disease in the Niger Delta region of Nigeria:
a four-year prospective echocardiographic analysis. Cardiovasc J Afr. 2014;25(6):265–8.
8. Massoure PL, Roche NC, Lamblin G, et al. Cardiovascular disease in children in
Djibouti: a single-centre study. Pan Afr Med J. 2013;14:141.
9. Turner L, Boutron I, Hróbjartsson A, et al. The evolution of assessing bias in Cochrane
systematic reviews of interventions: celebrating methodological contributions of the
Cochrane Collaboration. Syst Rev. 2013;2:79.
10. Miller JJ. The Inverse of the Freeman – Tukey Double Arcsine Transformation. Am
Stat. 1978;32(4):138–138.
11. Cochran GW. The Combination of Estimates from Different Experiments. Biometrics
1954;10(1):101-29.
12. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing
heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods.
2006;11(2):193–206.
13. McHugh ML. Interrater reliability: the kappa statistic. Biochem Medica. 2012
15;22(3):276–82.
14. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a
simple, graphical test. Bmj 1997;315(7109):629-34.
Page 13 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
14
Table 1: Search strategy for PubMed
Search Search terms
#1 congenital heart OR heart defects OR heart murmur OR fallot OR ventricular
defect OR atrial defect OR septal defect OR great vessels transposition OR
foramen ovale OR single ventricle OR persistent ductus arteriosus OR dorv
OR avsd OR ASD OR VSD OR BAV OR d-tga OR aorta coarctation OR
hypoplastic heart OR total anomalous pulmonary venous connection OR
truncus arteriosus OR ebstein s abnormality OR tricuspid atresia OR cyanotic
heart OR non cyanotic heart OR mitral stenosis[tw] OR mitral
incompetence[tw] OR tricuspid incompetence[MeSH terms] OR tricuspid
stenosis[tw] OR pulmonary stenosis[tw] OR pulmonary incompetence[tw]
OR aortic incompetence[tw] OR aortic stenosis[MeSH terms] OR heart
murmur[tw] OR Atrial septal defect[tw] OR Ventricular septal defect[tw] OR
Pulmonary atresia[tw] OR Aortic atresia[tw] OR echocardiography
abnormalities[tw] OR Fallot tetralogy[tw] OR aorta coarctation[tw] OR
cyanotic cardiac abnormalities[tw] OR atrioventricular septal defects[tw] OR
biscupid aortic valve[tw] OR double outlet right ventricle[tw] OR patent
ductus arteriosus[tw] OR single ventricle[tw] OR great arteries
transposition[tw] OR hypoplastic heart[tw] OR tricuspid atresia[tw] OR
Ebstein abnormality[tw] OR truncus arteriosus[tw] OR total anomalous
pulmonary venous connection[tw]
#2 (Africa* OR Algeria OR Angola OR Benin OR Botswana OR "Burkina Faso"
OR Burundi OR Cameroon OR "Canary Islands" OR "Cape Verde" OR
"Central African Republic" OR Chad OR Comoros OR Congo OR
Page 14 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
15
"Democratic Republic of Congo" OR Djibouti OR Egypt OR "Equatorial
Guinea" OR Eritrea OR Ethiopia OR Gabon OR Gambia OR Ghana OR
Guinea OR "Guinea Bissau" OR "Ivory Coast" OR "Cote d'Ivoire" OR
Jamahiriya OR Kenya OR Lesotho OR Liberia OR Libya OR Madagascar
OR Malawi OR Mali OR Mauritania OR Mauritius OR Mayotte OR Morocco
OR Mozambique OR Namibia OR Niger OR Nigeria OR Principe OR
Reunion OR Rwanda OR "Sao Tome" OR Senegal OR Seychelles OR "Sierra
Leone" OR Somalia OR "South Africa" OR “South Sudan” OR "St Helena"
OR Sudan OR Swaziland OR Tanzania OR Togo OR Tunisia OR Uganda OR
"Western Sahara" OR Zaire OR Zambia OR Zimbabwe OR "Central Africa"
OR "Central African" OR "West Africa" OR "West African" OR "Western
Africa" OR "Western African" OR "East Africa" OR "East African" OR
"Eastern Africa" OR "Eastern African" OR "North Africa" OR "North
African" OR "Northern Africa" OR "Northern African" OR "South African"
OR "Southern Africa" OR "Southern African" OR "sub Saharan Africa" OR
"sub Saharan African" OR "subSaharan Africa" OR "subSaharan African")
NOT ("guinea pig" OR "guinea pigs" OR "aspergillus niger")
#3 #1 AND #2
#4 # 3 Limits: : 1986/01/01 to 2016/12/31
Page 15 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
CASE CONTROL STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and
Exposure categories. A maximum of two stars can be given for Comparability.
Selection
1) Is the case definition adequate?
a) yes, with independent validation ����
b) yes, eg record linkage or based on self reports
c) no description
2) Representativeness of the cases
a) consecutive or obviously representative series of cases ����
b) potential for selection biases or not stated
3) Selection of Controls
a) community controls ����
b) hospital controls
c) no description
4) Definition of Controls
a) no history of disease (endpoint) ����
b) no description of source
Comparability
1) Comparability of cases and controls on the basis of the design or analysis
a) study controls for _______________ (Select the most important factor.) ����
b) study controls for any additional factor ���� (This criteria could be modified to indicate specific
control for a second important factor.)
Exposure
1) Ascertainment of exposure
a) secure record (eg surgical records) ����
b) structured interview where blind to case/control status ����
c) interview not blinded to case/control status
d) written self report or medical record only
e) no description
2) Same method of ascertainment for cases and controls
a) yes ����
b) no
3) Non-Response rate
a) same rate for both groups ����
b) non respondents described
c) rate different and no designation
Page 16 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
COHORT STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and
Outcome categories. A maximum of two stars can be given for Comparability
Selection
1) Representativeness of the exposed cohort
a) truly representative of the average _______________ (describe) in the community ����
b) somewhat representative of the average ______________ in the community ����
c) selected group of users eg nurses, volunteers
d) no description of the derivation of the cohort
2) Selection of the non exposed cohort
a) drawn from the same community as the exposed cohort ����
b) drawn from a different source
c) no description of the derivation of the non exposed cohort
3) Ascertainment of exposure
a) secure record (eg surgical records) ����
b) structured interview ����
c) written self report
d) no description
4) Demonstration that outcome of interest was not present at start of study
a) yes ����
b) no
Comparability
1) Comparability of cohorts on the basis of the design or analysis
a) study controls for _____________ (select the most important factor) ����
b) study controls for any additional factor ���� (This criteria could be modified to indicate specific
control for a second important factor.)
Outcome
1) Assessment of outcome
a) independent blind assessment ����
b) record linkage ����
c) self report
d) no description
2) Was follow-up long enough for outcomes to occur
a) yes (select an adequate follow up period for outcome of interest) ����
b) no
3) Adequacy of follow up of cohorts
a) complete follow up - all subjects accounted for ����
b) subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an
adequate %) follow up, or description provided of those lost) ����
c) follow up rate < ____% (select an adequate %) and no description of those lost
d) no statement
Page 17 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
(adapted for cross-sectional studies)
Selection: (Maximum 3 stars)
1) Representativeness of the sample:
a) Truly representative of the average in the target population. * (all subjects or random sampling)
b) Somewhat representative of the average in the target population. * (non-random sampling)
c) Selected group of users.
d) No description of the sampling strategy.
2) Sample size:
a) Justified and satisfactory. *
b) Not justified.
3) Non-respondents:
a) Comparability between respondents and non-respondents’ characteristics is established, and
the response rate is satisfactory. *
b) The response rate is unsatisfactory, or the comparability between respondents and non-
respondents is unsatisfactory.
c) No description of the response rate or the characteristics of the responders and the non-
responders.
Control of confounders: (Maximum 2 stars)
1) The subjects in different outcome groups are comparable, based on the study design or analysis.
Confounding factors are controlled.
a) The study controls for the most important factor (select one). *
b) The study control for any additional factor. *
Outcome: (Maximum 4 stars)
1) Assessment of the outcome:
a) Independent blind assessment. **
b) Record linkage. *
c) Self report.
d) No description.
2) Statistical test:
a) The statistical test used to analyze the data is clearly described and appropriate, and the
measurement of the association is presented, including confidence intervals and the probability level (p
value). *
b) The statistical test is not appropriate, not described or incomplete.
3) Ascertainment of the outcome measurement:
a) Validated measurement tool.*
b) Non-validated measurement tool, but the tool is available or described.
c) No description of the measurement tool.
Page 18 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to
address in a systematic review protocol
Section and topic Item
No
Checklist item Page #
ADMINISTRATIVE INFORMATION
Title:
Identification 1a Identify the report as a protocol of a systematic review 1
Update 1b If the protocol is for an update of a previous systematic review, identify as such -
Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number 3
Authors:
Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of corresponding author 1
Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 12
Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state
plan for documenting important protocol amendments
-
Support:
Sources 5a Indicate sources of financial or other support for the review 12
Sponsor 5b Provide name for the review funder and/or sponsor 12
Role of sponsor
or funder
5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol 12
INTRODUCTION
Rationale 6 Describe the rationale for the review in the context of what is already known 5-6
Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes
(PICO)
6
METHODS
Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years considered,
language, publication status) to be used as criteria for eligibility for the review
6-7
Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other grey literature
sources) with planned dates of coverage
7-8
Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated 7-8,
Table 1
Study records:
Page 19 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2016-015633 on 14 February 2017. Downloaded from
For peer review only
Data
management
11a Describe the mechanism(s) that will be used to manage records and data throughout the review 8-9
Selection
process
11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review (that is,
screening, eligibility and inclusion in meta-analysis)
8-9
Data collection
process
11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining
and confirming data from investigators
9
Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data assumptions and
simplifications
9
Outcomes and
prioritization
13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale 9
Risk of bias in
individual studies
14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level,
or both; state how this information will be used in data synthesis
9
Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised 10
15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods of combining
data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ)
10
15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) 10
15d If quantitative synthesis is not appropriate, describe the type of summary planned 10
Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies) 10-11
Confidence in
cumulative evidence
17 Describe how the strength of the body of evidence will be assessed (such as GRADE) 10
Page 20 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2016-015633 on 14 February 2017. Downloaded from
For peer review only
Prevalence and patterns of congenital heart diseases in Africa: a systematic review and meta-analysis protocol
Journal: BMJ Open
Manuscript ID bmjopen-2016-015633.R1
Article Type: Protocol
Date Submitted by the Author: 18-Jan-2017
Complete List of Authors: Tankeu, Aurel; Faculty of Medecine and Biomedical Sciences, Internal medicine and specialities Bigna, Jean Joel; Centre Pasteur of Cameroon, Epidemiology and Public Health Nansseu, Jobert Richie; Mother and Child Centre, Chantal Biya Foundation, Sickle cell unit Aminde, Leopold; Clinical Research Education, Networking & Consultancy (CRENC), Douala and Nguti District Hospital,
Danwang, Celestin; Faculty of Medecine and Biomedical Sciences, Internal medicine and specialities Mazou, Temgoua Ngou ; Faculty of Medecine and Biomedical Sciences, Internal medicine and specialities Noubiap, Jean Jacques; Edea Regional Hospital, Internal Medicine Unit
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Epidemiology
Keywords: Congenital heart disease < CARDIOLOGY, Africa, Heart defects, cardiac malformation
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on A
pril 20, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2016-015633 on 14 February 2017. D
ownloaded from
For peer review only
1
Prevalence and patterns of congenital heart diseases in Africa: a systematic
review and meta-analysis protocol
Aurel T. Tankeu1, Jean Joel R. Bigna
2,3, Jobert Richie N. Nansseu
4,5, Leopold Ndemnge
Aminde6, Celestin Danwang
7, Temgoua Ngou Mazou
1, Jean Jacques N. Noubiap
8*
1. Department of Internal Medicine and Specialties, Faculty of Medicine and Biomedical
Sciences, Yaoundé, Cameroon
2. Department of Epidemiology and Public Health, Centre Pasteur of Cameroon, Yaoundé,
Cameroon
3. Faculty of Medicine, University of Paris Sud XI, Le Kremlin Bicêtre, France
4. Department of Public Health, Faculty of Medicine and Biomedical Sciences, University of
Yaoundé 1, Yaoundé, Cameroon
5. Sickle Cell Disease Unit, Mother and Child Centre of the Chantal Biya Foundation,
Yaoundé, Cameroon
6. Faculty of Medicine & Biomedical Sciences, School of Public Health, The University of
Queensland, Brisbane, Queensland, Australia
7. Department of Surgery and Specialties, Faculty of Medicine and Biomedical Sciences,
University of Yaoundé 1, Yaoundé, Cameroon
8. Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape
Town, South Africa
E-mail addresses: ATT: [email protected]; JJRB: [email protected]; JRNN:
[email protected]; LNA: [email protected]; CD: [email protected];
TNM: [email protected]; JJNN: [email protected]
*Corresponding author: Dr. Jean Jacques N. Noubiap. Department of Medicine, Groote
Schuur Hospital and University of Cape Town, 7295, Cape Town, South Africa.
Page 1 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
2
Abstract
Introduction
Congenital heart diseases (CHD) are common causes of cardiovascular morbidity and
mortality among young children and adolescents living in Africa. Accurate epidemiological
data are needed in order to evaluate and improve preventive strategies. This review aims to
determine the prevalence of CHD and their main patterns in Africa.
Methods and analysis
This systematic review and meta-analysis will include cross-sectional, case–control and
cohort studies of populations residing inside African countries, which have reported the
prevalence of CHD; confirmed by an echocardiographic examination, and/or describing
different patterns of these abnormalities in Africa. Relevant abstracts published without
language restriction from January 1st, 1986 to December 31
st 2016 will be searched in
PubMed, Exerpta Medica Database and online African journals as well as references of
included articles and relevant reviews. Two review authors will independently screen, select
studies, extract data and assess the risk of bias in each study. The study-specific estimates will
be pooled through a random-effects meta-analysis model to obtain an overall summary
estimate of the prevalence of CHD across studies. Clinical and statistical heterogeneity will be
assessed, and we will pool studies judged to be clinically homogenous. On the other hand,
statistical heterogeneity will be evaluated by the χ2 test on Cochrane’s Q statistic. Funnel-
plots analysis and Egger’s test will be used to detect publication bias. Results will be
presented by geographic region (central, eastern, northern, southern and western Africa).
Ethics and dissemination
Page 2 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
3
The current study will be based on published data, and thus ethical approval is not required.
This systematic review and meta-analysis is expected to serve as a base which could help
estimating and evaluating the burden of these abnormalities on the African continent. The
final report of this study will be published in a peer-reviewed journal.
Review registration number
PROSPERO CRD42016052880.
Funding
None.
Page 3 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
4
Strengths and limitations of the study
• To the best of our knowledge, this will be the first systematic review on the topic of
Congenital heart diseases (CHD) to summarize available data on African continent.
• We will use powerful meta-analysis techniques to derive accurate estimates.
• A major possible limitation of this study could be the limited data with predominance of
hospital-based studies. Indeed, these studies may not reflect the true prevalence of CHD in
the general population, therefore overestimating these estimates.
• Another possible limitation may be heterogeneity of studies done on the topic in Africa.
Page 4 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
5
Introduction
Congenital heart disease or congenital heart defect (CHD) is a problem of the heart’s structure
and function present at birth, affecting heart or adjacent great blood vessels detected either at
the time of birth or detected later in life.1
2 Worldwide, CHD are the main heart diseases
found in children and constitute one of the major causes of infant mortality, particularly in
developing countries.2 3
They also represent the most common of all congenital malformations
accounting for more than 20% of perinatal deaths.4 5
Their estimate prevalence is eight cases
per 1,000 live births across the globe, representing approximately 1.35 million newborns each
year with CHD but these figures vary worldwide.2 For instance, the incidence of CHD in
different studies varies from about 4/1.000 to 50/1.000 live births and despite advances in
detection and treatment, congenital heart diseases accounts for 3% of all infant deaths and
46% of death from congenital malformations in developed countries such as USA.4-6
In
addition, these abnormalities can be life threatening in early childhood, and children born with
severe forms are at approximately 12 times higher risk of mortality in the first year of life.7
Thus, hundreds of thousands of children die each year from CHD, while millions more remain
in desperate need of treatment in the developing world.8 Since mortality and morbidity from
cardiac disease among children in developing countries are gaining recognition, there is a
need of summarized data on CHD in African continent. Africa is thought to have one of the
highest prevalence of heart diseases in children and young adults, including CHD but main
findings include evidence that the CHD burden is underestimated mainly due to the poor
outcome of African children with CHD.7 From a global point of view, the epidemiology of
these abnormalities is still unknown in Africa with few data on the topic. Reducing the
prevalence of these diseases is urgent and requires a real inventory of the premises of the
problem that would clarify the issue for more effective prevention strategies and improved
Page 5 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
6
management. In this context, we present the protocol for a systematic review and meta-
analysis to assess the prevalence and patterns of CHD in Africa.
Objective
This systematic review and meta-analysis aims to determine the prevalence of CHD and their
different patterns in Africa.
Review question
This review of studies published in the past 30 years, from 1st January 1986 to 31
st December
2016, should answer the following questions
1. What is the prevalence of CHD among African populations?
2. What are the different patterns of CHD in Africa?
Methods and analysis
Criteria for considering studies for the review
Inclusion criteria
We will include:
1. Cross-sectional, case–control or cohort studies of populations residing in African countries
reporting the prevalence of CHD in African countries or enough data to compute these
estimates, regardless of stillbirth.
Page 6 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
7
2. Studies describing the different patterns of CHD on the African continent.
Exclusion criteria
We will not consider:
1. Studies on congenital abnormalities involving the heart but not considered as CHD (Long
QT syndrome, congenital but functionless abnormalities of the heart, cardiomyopathies).
2. Studies conducted among populations of African origin residing outside Africa.
3. Studies in subgroups of participants selected on the basis of cardiac murmurs without
echocardiographic confirmation of CHD (e.g. suspected but non-confirmed CHD).
4. Studies including many pathologies in which it will not be possible to extract data
regarding CHD or studies reporting congenital abnormalities affecting many systems at time.
5. Letters, reviews, commentaries and editorials.
6. Studies lacking key data and/or explicit method description.
7. Duplicates: for studies published in more than one paper, the most comprehensive one
reporting the largest sample size will be considered.
8. Studies whose full data will not be accessible even after request from the authors.
Search strategy for identifying relevant studies
The search strategy will be implemented in two stages:
Bibliographic database searches
A. Relevant abstracts published without language restriction on the prevalence, incidence,
main etiologies and clinical features of CHD in Africa will be identified via searching
Page 7 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
8
PubMed, Exerpta Medica Database, and online African journals. The search will be limited to
studies published between January 1st, 1986 and December 31
st, 2016. Both text words and
medical subject heading terms will be used. Key search terms include: ‘congenital heart
defects’ or ‘congenital heart disease’ as well as the name of every known pattern of these
abnormalities. We will also use individual country names for the 54 African countries as
additional key search terms for more abstracts on the subject. Conference proceedings and
studies from grey literature of the study period will also be identified through databases and
checked. The main search strategy is shown in Table 1.
B. The abstracts of all eligible papers will be reviewed and full articles will be accessed
through PubMed, Exerpta Medica Database, Google Scholar, HINARI or journals’ websites.
Additionally, references of all relevant articles and reviews will be scrutinized for other
potential data sources, and their full texts will be accessed in a similar way. The authors
whose full text papers will not be accessible by the numerous internet-based sources will be
directly contacted to provide them. In case of no feedback from these authors, the
corresponding studies will be excluded.
Searching for others sources
References of all relevant researches and review articles will be scrutinized for additional
potential data sources, and their full texts will be accessed in a similar way. Those authors
whose full text papers will not be accessible by the numerous internet-based sources will be
directly contacted via email to provide them. In case of no feedback from these authors, the
corresponding studies will be excluded.
Selection of studies for inclusion in the review
Page 8 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
9
Assessment of eligible papers will be independently run by two authors using an assessment
guide to ensure that the selection criteria are reliably applied by all the team. They will screen
the titles and abstracts obtained from the searches and retrieve the full texts of potentially
eligible papers by at least one author. Thereafter, they will independently review the full text
of each potentially eligible study, compare their results and resolve any discrepancy by
discussion and consensus. If a decision is not reached, a third review author will be consulted
for arbitration.
Assessment of methodological quality and reporting of data
The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in
meta-analyses will be used to assess the methodological quality and risk of bias for each study
(see online supplementary appendix S1).9 Risk of bias and quality scores will be presented in
a table.
Data extraction and management
A data extraction sheet will be used to collect information about the author, the country, the
year of publication, the study design, the sample size population, the mean/median age of the
population, the age range, the sex ratio, the prevalence of CHD as well as main patterns when
available. Where prevalence or information for calculating them (eg. sample size, number of
outcomes) are lacking, we will directly contact the corresponding author to request the
information. In case of multinational studies, we will separate the results to show the
prevalence and etiologies within individual countries. Where it will not be possible to
disaggregate the data by country, the study will be presented as one and the countries in which
the study was done will be shown.
Data synthesis and analysis
Page 9 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
10
Data will be analyzed using Stata software version 13 (Stata Corp V.13, Texas, USA). A
meta-analysis will be conducted for data obtained from studies in which CHD has the same
etiologies, Standard errors (SEs) for the study-specific estimates will first be determined from
the point estimate and the appropriate denominators, assuming a binominal distribution. Then,
the study-specific estimates will be pooled through a random-effects meta-analysis model to
obtain an overall summary estimate of the prevalence across studies, after stabilizing the
variance of individual studies using the Freeman-Tukey double arc-sine transformation (to
keep the effect of studies with extremely small or extremely large estimates).10
Heterogeneity
will be evaluated by the χ² test on Cochrane’s Q statistic11
which is quantified by I² values,
assuming that I² values of 25%, 50% and 75% represent low, medium and high heterogeneity
respectively.12
Where substantial heterogeneity will be detected, a subgroup analysis will be
performed to detect its possible sources using the following grouping variables: type of CHD,
consequences on cardiac hemodynamic, study setting (hospital vs community-based), age of
diagnosis, geographical area (central, eastern, northern, southern and western Africa), and
study quality. Difference between groups will be detected if p value < 0.05. Inter-rater
agreement for study inclusion will be assessed using Cohen’s κappa coefficient.13
Funnel
plots analysis and Egger’s test14
will be done to detect publication bias. Publication bias will
be confirmed if p value on Egger’s test < 0.10. Results will be presented by geographic region
(central, eastern, northern, southern and western Africa).
Presentation and reporting of results
The study selection process will be summarized using a flow diagram. Reasons for studies’
exclusion will be described. The report will follow the PRISMA (Preferred Reporting Items
for systematic review and Meta-analysis) Guidelines.15
Tables and forest plots will serve to
Page 10 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
11
summarize quantitative data where appropriate. We will examine prevalence and etiologies by
region, setting (hospital or community) and time period depending on the data available. We
plan to report on quality scores and risk of bias for each eligible study. This may be tabulated
and accompanied by narrative summaries.
Conclusion
CHD represent the second major cause of CVD morbidity and mortality among young
Africans. Their management is limited in Africa in an inadequate socio-economic
environment with insufficient technical platform and human resources. Moreover, the global
burden of these conditions is unknown on the continent. Therefore, it becomes urgent to
provide summarized recent and reliable data in order to help estimating the prevalence as well
as etiologies in Africa in other to highlight the importance of these abnormalities and the need
to reinforce of effective preventives strategies based on systematic screening of cardiac
abnormalities in the perinatal period. We hope that this review will help sensitizing health
care providers on the problem represented by CHD in Africa, assist and support the
implementation of new policies, practices and researches by providing insights into the
current situation and the true impact of CHD on African continent as well as shortcomings
that can guide future research around this topic.
Protocol and registration
The protocol for this review has been published in the PROSPERO International Prospective
Register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO), registration number:
PROSPERO CRD42016052880
Page 11 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
12
Authors’ Contributions
ATT and JJNN conceived and designed the protocol. ATT drafted the manuscript. JJRB,
JRNN, LNA, CD, TNM and JJNN critically revised the manuscript for methodological and
intellectual content. JJNN is the guarantor of the review. All authors approved the final
version of this manuscript.
Competing interests
None.
Funding
This research received no specific grant from any funding agency in the public, commercial or
not-for-profit sectors.
Data sharing statement
No additional data are available.
References
1. Tantchou Tchoumi JC, Butera G, Giamberti A, et al. Occurrence and pattern of
congenital heart diseases in a rural area of sub-Saharan Africa. Cardiovasc J Afr.
2011;22(2):63–6.
2. Chelo D, Nguefack F, Menanga AP, et al. Spectrum of heart diseases in children: an
echocardiographic study of 1,666 subjects in a pediatric hospital, Yaounde, Cameroon.
Cardiovasc Diagn Ther. 2016;6(1):10–9.
3. Kouame BD, N’guetta-Brou IA, Kouame GSY, et al. Epidemiology of congenital
abnormalities in West Africa: Results of a descriptive study in teaching hospitals in
Abidjan: Cote d’Ivoire. Afr J Paediatr Surg. 2015;12(1):51–5.
Page 12 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
13
4. Sadowski SL. Congenital cardiac disease in the newborn infant: past, present, and future.
Crit Care Nurs Clin North Am. 2009;21(1):37–48.
5. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol.
2002;39(12):1890–900.
6. Chinawa JM, Eze JC, Obi I, et al. Synopsis of congenital cardiac disease among children
attending University of Nigeria Teaching Hospital Ituku Ozalla, Enugu. BMC Res
Notes. 2013;6:475.
7. Otaigbe BE, Tabansi PN. Congenital heart disease in the Niger Delta region of Nigeria:
a four-year prospective echocardiographic analysis. Cardiovasc J Afr. 2014;25(6):265–8.
8. Massoure PL, Roche NC, Lamblin G, et al. Cardiovascular disease in children in
Djibouti: a single-centre study. Pan Afr Med J. 2013;14:141.
9. Turner L, Boutron I, Hróbjartsson A, et al. The evolution of assessing bias in Cochrane
systematic reviews of interventions: celebrating methodological contributions of the
Cochrane Collaboration. Syst Rev. 2013;2:79.
10. Miller JJ. The Inverse of the Freeman – Tukey Double Arcsine Transformation. Am
Stat. 1978;32(4):138–138.
11. Cochran GW. The Combination of Estimates from Different Experiments. Biometrics
1954;10(1):101-29.
12. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing
heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods.
2006;11(2):193–206.
13. McHugh ML. Interrater reliability: the kappa statistic. Biochem Medica. 2012
15;22(3):276–82.
14. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a
simple, graphical test. Bmj 1997;315(7109):629-34.
15. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and
meta-analyses: the PRISMA statement. Journal of clinical epidemiology
2009;62(10):1006-12.
Page 13 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
14
Table 1: Search strategy for PubMed
Search Search terms
#1 congenital heart OR heart defects OR heart murmur OR fallot OR ventricular
defect OR atrial defect OR septal defect OR great vessels transposition OR
foramen ovale OR single ventricle OR persistent ductus arteriosus OR dorv
OR avsd OR ASD OR VSD OR BAV OR d-tga OR aorta coarctation OR
hypoplastic heart OR total anomalous pulmonary venous connection OR
truncus arteriosus OR ebstein s abnormality OR tricuspid atresia OR cyanotic
heart OR non cyanotic heart OR mitral stenosis[tw] OR mitral
incompetence[tw] OR tricuspid incompetence[MeSH terms] OR tricuspid
stenosis[tw] OR pulmonary stenosis[tw] OR pulmonary incompetence[tw]
OR aortic incompetence[tw] OR aortic stenosis[MeSH terms] OR heart
murmur[tw] OR Atrial septal defect[tw] OR Ventricular septal defect[tw] OR
Pulmonary atresia[tw] OR Aortic atresia[tw] OR echocardiography
abnormalities[tw] OR Fallot tetralogy[tw] OR aorta coarctation[tw] OR
cyanotic cardiac abnormalities[tw] OR atrioventricular septal defects[tw] OR
biscupid aortic valve[tw] OR double outlet right ventricle[tw] OR patent
ductus arteriosus[tw] OR single ventricle[tw] OR great arteries
transposition[tw] OR hypoplastic heart[tw] OR tricuspid atresia[tw] OR
Ebstein abnormality[tw] OR truncus arteriosus[tw] OR total anomalous
pulmonary venous connection[tw]
#2 (Africa* OR Algeria OR Angola OR Benin OR Botswana OR "Burkina Faso"
OR Burundi OR Cameroon OR "Canary Islands" OR "Cape Verde" OR
"Central African Republic" OR Chad OR Comoros OR Congo OR
Page 14 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
15
"Democratic Republic of Congo" OR Djibouti OR Egypt OR "Equatorial
Guinea" OR Eritrea OR Ethiopia OR Gabon OR Gambia OR Ghana OR
Guinea OR "Guinea Bissau" OR "Ivory Coast" OR "Cote d'Ivoire" OR
Jamahiriya OR Kenya OR Lesotho OR Liberia OR Libya OR Madagascar
OR Malawi OR Mali OR Mauritania OR Mauritius OR Mayotte OR Morocco
OR Mozambique OR Namibia OR Niger OR Nigeria OR Principe OR
Reunion OR Rwanda OR "Sao Tome" OR Senegal OR Seychelles OR "Sierra
Leone" OR Somalia OR "South Africa" OR “South Sudan” OR "St Helena"
OR Sudan OR Swaziland OR Tanzania OR Togo OR Tunisia OR Uganda OR
"Western Sahara" OR Zaire OR Zambia OR Zimbabwe OR "Central Africa"
OR "Central African" OR "West Africa" OR "West African" OR "Western
Africa" OR "Western African" OR "East Africa" OR "East African" OR
"Eastern Africa" OR "Eastern African" OR "North Africa" OR "North
African" OR "Northern Africa" OR "Northern African" OR "South African"
OR "Southern Africa" OR "Southern African" OR "sub Saharan Africa" OR
"sub Saharan African" OR "subSaharan Africa" OR "subSaharan African")
NOT ("guinea pig" OR "guinea pigs" OR "aspergillus niger")
#3 #1 AND #2
#4 # 3 Limits: : 1986/01/01 to 2016/12/31
Page 15 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
CASE CONTROL STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and
Exposure categories. A maximum of two stars can be given for Comparability.
Selection
1) Is the case definition adequate?
a) yes, with independent validation
b) yes, eg record linkage or based on self reports
c) no description
2) Representativeness of the cases
a) consecutive or obviously representative series of cases
b) potential for selection biases or not stated
3) Selection of Controls
a) community controls
b) hospital controls
c) no description
4) Definition of Controls
a) no history of disease (endpoint)
b) no description of source
Comparability
1) Comparability of cases and controls on the basis of the design or analysis
a) study controls for _______________ (Select the most important factor.)
b) study controls for any additional factor (This criteria could be modified to indicate specific
control for a second important factor.)
Exposure
1) Ascertainment of exposure
a) secure record (eg surgical records)
b) structured interview where blind to case/control status
c) interview not blinded to case/control status
d) written self report or medical record only
e) no description
2) Same method of ascertainment for cases and controls
a) yes
b) no
3) Non-Response rate
a) same rate for both groups
b) non respondents described
c) rate different and no designation
Page 16 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
COHORT STUDIES
Note: A study can be awarded a maximum of one star for each numbered item within the Selection and
Outcome categories. A maximum of two stars can be given for Comparability
Selection
1) Representativeness of the exposed cohort
a) truly representative of the average _______________ (describe) in the community
b) somewhat representative of the average ______________ in the community
c) selected group of users eg nurses, volunteers
d) no description of the derivation of the cohort
2) Selection of the non exposed cohort
a) drawn from the same community as the exposed cohort
b) drawn from a different source
c) no description of the derivation of the non exposed cohort
3) Ascertainment of exposure
a) secure record (eg surgical records)
b) structured interview
c) written self report
d) no description
4) Demonstration that outcome of interest was not present at start of study
a) yes
b) no
Comparability
1) Comparability of cohorts on the basis of the design or analysis
a) study controls for _____________ (select the most important factor)
b) study controls for any additional factor (This criteria could be modified to indicate specific
control for a second important factor.)
Outcome
1) Assessment of outcome
a) independent blind assessment
b) record linkage
c) self report
d) no description
2) Was follow-up long enough for outcomes to occur
a) yes (select an adequate follow up period for outcome of interest)
b) no
3) Adequacy of follow up of cohorts
a) complete follow up - all subjects accounted for
b) subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an
adequate %) follow up, or description provided of those lost)
c) follow up rate < ____% (select an adequate %) and no description of those lost
d) no statement
Page 17 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE
(adapted for cross-sectional studies)
Selection: (Maximum 3 stars)
1) Representativeness of the sample:
a) Truly representative of the average in the target population. * (all subjects or random sampling)
b) Somewhat representative of the average in the target population. * (non-random sampling)
c) Selected group of users.
d) No description of the sampling strategy.
2) Sample size:
a) Justified and satisfactory. *
b) Not justified.
3) Non-respondents:
a) Comparability between respondents and non-respondents’ characteristics is established, and
the response rate is satisfactory. *
b) The response rate is unsatisfactory, or the comparability between respondents and non-
respondents is unsatisfactory.
c) No description of the response rate or the characteristics of the responders and the non-
responders.
Control of confounders: (Maximum 2 stars)
1) The subjects in different outcome groups are comparable, based on the study design or analysis.
Confounding factors are controlled.
a) The study controls for the most important factor (select one). *
b) The study control for any additional factor. *
Outcome: (Maximum 4 stars)
1) Assessment of the outcome:
a) Independent blind assessment. **
b) Record linkage. *
c) Self report.
d) No description.
2) Statistical test:
a) The statistical test used to analyze the data is clearly described and appropriate, and the
measurement of the association is presented, including confidence intervals and the probability level (p
value). *
b) The statistical test is not appropriate, not described or incomplete.
3) Ascertainment of the outcome measurement:
a) Validated measurement tool.*
b) Non-validated measurement tool, but the tool is available or described.
c) No description of the measurement tool.
Page 18 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to
address in a systematic review protocol
Section and topic Item
No
Checklist item Page #
ADMINISTRATIVE INFORMATION
Title:
Identification 1a Identify the report as a protocol of a systematic review 1
Update 1b If the protocol is for an update of a previous systematic review, identify as such -
Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number 3
Authors:
Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of corresponding author 1
Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 12
Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state
plan for documenting important protocol amendments
-
Support:
Sources 5a Indicate sources of financial or other support for the review 12
Sponsor 5b Provide name for the review funder and/or sponsor 12
Role of sponsor
or funder
5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol 12
INTRODUCTION
Rationale 6 Describe the rationale for the review in the context of what is already known 5-6
Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes
(PICO)
6
METHODS
Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years considered,
language, publication status) to be used as criteria for eligibility for the review
6-7
Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other grey literature
sources) with planned dates of coverage
7-8
Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated 7-8,
Table 1
Study records:
Page 19 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from
For peer review only
Data
management
11a Describe the mechanism(s) that will be used to manage records and data throughout the review 8-9
Selection
process
11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review (that is,
screening, eligibility and inclusion in meta-analysis)
8-9
Data collection
process
11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining
and confirming data from investigators
9
Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data assumptions and
simplifications
9
Outcomes and
prioritization
13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale 9
Risk of bias in
individual studies
14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level,
or both; state how this information will be used in data synthesis
9
Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised 10
15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods of combining
data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ)
10
15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) 10
15d If quantitative synthesis is not appropriate, describe the type of summary planned 10
Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies) 10-11
Confidence in
cumulative evidence
17 Describe how the strength of the body of evidence will be assessed (such as GRADE) 10
Page 20 of 20
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 20, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2016-015633 on 14 F
ebruary 2017. Dow
nloaded from