An assessment of the impact of Cochrane diagnostic test accuracy reviews for infectious diseases prevalent in low and middle-income countries
An assessment of the impact of Cochrane diagnostic test accuracy reviews for infectious diseases prevalent in low and middle-income countries
Protocol
Student ID: 1866688
09th March 2017
Acknowledgement
I would like to thank my advisor, for their time and insights when discussing the project.
Background and rationale
Correct and prompt diagnosis is a critical step in the care pathway of every patient as it will guide the direction of the management of their condition. The importance of correct diagnosis has been highlighted in autopsy studies showing that 10 20% of cases have a missed or incorrect diagnosis that may have otherwise been lifesaving.(1) Given how critical diagnosis is, the drive to use evidence to inform decisions on which diagnostic test to use is increasing. This is highlighted by the formation of the Cochrane diagnostic test accuracy (DTA) group in 2008,(2) and the World Health Organisations (WHO) current development plan for an Essentials Diagnostics List (EDL).(3) The aim of the Cochrane DTA group is to manage and edit DTA systematic reviews to improve rigor and quality, while the EDL will provide a summary of evidence-based diagnostic recommendations which countries can use to guide decision-making.(2, 3)
In low and middle-income countries (LMICs), the importance of prioritisation and making evidence-based decisions is critical due to budget constraints. The burden of disease is high across this region, and although the prevalence of non-communicable diseases is increasing, communicable diseases still place a large burden on LMIC health systems (Figure 1).(4) In 2016, in countries with a low socio-demographic index (SDI; a summary score based on income, fertility rate and educational level) three of the top five causes of disability-adjusted life years per 100,000 were infectious diseases.(4) In countries with low-middle SDIs, although non-communicable diseases were moving up the list, diarrhoea, lower respiratory infections and other retained the top position (Figure 1).(4)
Figure 1: Ranking of diseases based on number of disability adjusted life years per 100,000 in 2016 in countries with a low, or a low-middle socio-demographic index.(4)
Abbreviations: AIDS: acquired immunodeficiency syndrome; endo: endocrine diseases; inj: injuries; HIV: human immunodeficiency virus; LRI: lower respiratory infection; NTDs: neglected tropical diseases; urog: urogenital
Given the burden of infectious disease in LMICs, the importance of efficient and appropriate use of limited resources is essential in order to ensure the best outcomes for patients. A valuable source of evidence-based information on DTA are Cochrane systematic reviews. To date, the Cochrane DTA group have produced 83 systematic reviews, of which, nine reviews focus on five infectious diseases prevalent in LMICs: malaria, visceral leishmaniasis, tuberculosis (TB), schistosomiasis, and typhoid/paratyphoid (Table 1).(5-13) These reviews are of high quality, being
undertaken to meet Cochrane standards.(14) In addition, Cochrane DTA reviews provide clear conclusions which detail the implications the review has for both clinical practice and research. Given these systematic reviews are freely available and provide accessible, evidence-based recommendations it is important to understand the impact they are having and whether the evidence is translating into positive effects on practice and ultimately patient health.
Table 1: Overview of Cochrane systematic reviews of infectious diseases prevalent in LMICs
Author (Year) Reference Disease Test
Abba (2011) (5) Uncomplicated plasmodium falciparum malaria Rapid diagnostic tests
Abba (2014) (6) Uncomplicated non-falciparum or plasmodium vivax malaria Rapid diagnostic tests
Boelaert (2014) (7) Visceral leishmaniasis Rapid diagnostic tests
Odaga (2014) (8) Malaria Rapid diagnostic tests
Steingart (2014) (9) Pulmonary tuberculosis and rifampicin resistance XPERT MTB/RIF
Ochodo (2015) (10) Active schistosomiasis Urine reagent strips or circulating antigen test
Shah (2016) (11) Active tuberculosis in HIV-positive adults Lateral flow urine
lipoarabinomannan assay
Theron (2016) (12) Resistance to second-line anti- tuberculosis drugs GenoType(R) MTBDRsl assay
Wijedoru (2017) (13) Typhoid and paratyphoid (enteric) fever Rapid diagnostic tests
Research questions/aims/objectives
The aim of this project is to assess the impact of Cochrane DTA systematic reviews for infectious diseases prevalent in LMICs.
Impact will be any indication that the evidence-based recommendations made by the Cochrane DTA group are being used to inform clinical guidelines, practice or further research. In order to assess this, the project will be undertaken in three steps, the aims and rationale of each step are summarised below.
Step 1: Forward citation searching
Aim: To identify literature citing any of the nine Cochrane DTA reviews of infectious diseases prevalent in LMICs and to assess the reason for the citation
Rationale: Every Cochrane review provides recommendations for research and for practice. By identifying publications that have cited the review, it will provide a direct link from the Cochrane review to further research. Examples of the type of impact may be:
Evidence of incorporation into diagnostic guidelines
Evidence of roll-out of a diagnostic test following a positive review
Evidence of further research after an indication of a lack of data
Step 2: Diagnostic guidelines searching
Aim: To identify all diagnostic guidelines that have been recently published in each of the five disease areas to determine what evidence was used to inform them.
Rationale: The guidelines will be assessed to see if they align with the recommendations from the Cochrane review to provide an indication of impact. If the Cochrane recommendations have been incorporated into diagnostic guidelines it may lead to a greater impact on clinical practice and public health.
Step 3: Contacting manufacturers
Aim: To contact manufacturers of diagnostic tests that have had a positive recommendation from a Cochrane DTA review for sales data to assess the time trend in sales before and after the Cochrane recommendation
Rationale: By assessing the trend in sales over time, it may be possible to infer impact if demand for the test has changed following the Cochrane recommendation.
Methods
The three steps that will be used to assess impact of the Cochrane DTA reviews are detailed in Section 3.1 to Section 3.3. For all stages in the dissertation, literature will be managed using EndNote X8, while all data extraction will be undertaken in Microsoft Excel.
Note: Presentation of results will be detailed separately in Section 4, as will feasibility and limitations in Section 5, and timelines and expected volume of literature in Section 6.
Step 1: forward citations searching
To assess the direct impact of Cochrane DTA reviews, forward citation searching will be performed. This will assess what studies are citing the Cochrane review and what influence the Cochrane review had on the publication referencing it. Although there are nine systematic reviews, two have been updated, therefore citation searching will be performed on all versions of the reviews.(9, 12)
Information sources
A recent systematic review has shown the value of undertaking forward citation searching in multiple databases, therefore comprehensive searches will be conducted across multiple databases including Web of Science, Google Scholar, Medline, Embase, and Scopus.(15) Each of these databases has a cited by function that will be used to identify publications that are referencing the Cochrane review. Number of hits from scoping searches are presented in
Table 2. Google Scholar has the highest number of hits, which would be expected as it will also identify citations in grey literature, however, the number identified in Google scholar is also likely to include many duplicates as a study may be published online on several websites. Searches will be conducted on one day and citations downloaded into an Endnote database. Abstract lists will be de-duplicated in Endnote.
Table 2: Estimated number of hits from forward citation searching for each review
Author Disease Web of Science Google Scholar Medline and Embase (Ovid SP) Scopus
Abba (2011) Malaria 118 191 27 113
Abba (2014) Malaria 22 40 5 27
Boelaert (2014) Leishmaniasis 29 57 4 28
Odaga (2014) Malaria 33 50 6 38
Steingart (2014) Tuberculosis 265 735 56 253
Ochodo (2015) Schistosomiasis 24 38 3 22
Shah (2016) Tuberculosis 15 31 4 20
Theron (2016) Tuberculosis 43 16 2 47
Wijedoru (2017) Typhoid and paratyphoid 1 2 0 0
Eligibility criteria
Eligibility criteria will be kept to a minimum as the aim is to identify all literature citing the Cochrane DTA reviews.
Inclusion criteria:
Patients: Human studies only in one of the five disease areas (malaria, leishmaniasis, TB, schistosomiasis, typhoid/paratyphoid)
Study design: Primary studies (interventional or observational) including randomised controlled trials, cohort studies, case-control studies, test accuracy studies. Diagnostic guidelines will also be included.
Exclusion criteria:
Study design: case studies, reviews, editorials
Screening
Given the simplicity, and largely inclusive eligibility criteria, it is anticipated that the error rate during screening will be low. Therefore, review of both abstracts and full-papers will be done in single, with unclear studies being referred to a second reviewer.
Data extraction and synthesis
Data extraction will include:
Title, author, year
Study design
Location
Aim of the study
Section of the publication the citation was made
The quoted citation
Context for the citation.
A sample data extraction form with four studies citing the Cochrane leishmaniasis review(7) has been provided in Appendix 8.1.1. Data will be extracted by a single reviewer with 10% of the extractions being validated by a second reviewer. Only 10% will be validated as data extraction is minimal, and is only of top-line data. Given the straightforward nature of the data, error rate is expected to be low, and 10% validation should serve to act as verification of this assumption. Should considerable errors be identified, full validations will be undertaken.
A thematic approach will be taken to data analysis, with themes being identified for common reasons for citation of the reviews. In addition, summary statistics will be calculated for how many studies have assessed the roll-out of a recommended diagnostic test, the regions and locations which are using the test and whether the type of studies being performed changes depending on the Cochrane review recommendation (i.e., if the recomendation was positive, negative or more research needed).
Risk of bias assessment of the identified studies will not be undertaken as it is not the aim of this dissertation to determine the quality of the research citing Cochrane reviews, rather to determine the types of studies citing Cochrane reviews and why they are citing the review.
Step 2: systematic searching of diagnostic guidelines Systematic searching of diagnostic guidelines will be undertaken to demonstrate whether the evidence-based recommendations proposed by the Cochrane systematic
reviews have been incorporated into published diagnostic pathways. All identified guidelines will be assessed for what evidence has been used to inform the guidelines and whether the guideline recommendations align with the Cochrane recommendations.
Given this is a systematic review, the presentation of results will match PRISMA guidelines including the preparation of a PRISMA diagram (Appendix 8.2.3).
Information sources
Systematic searches for guidelines will be conducted across multiple databases including Medline (Ovid SP), Embase (Ovid SP) and Web of Science. To supplement these databases, databases specific to certain LMIC regions will be searched including African Index Medicus (African literature focus), IndMed (Indian literature focus) and LILACS (Latin American and Caribbean literature focus). Sample search strategies for Medline and Embase are presented in Appendix 8.2.1; similar searches will be developed for the other databases. These searches were developed using the guidelines search filters developed by the Canadian Agency for Drugs and Technologies in Health (CADTH).(16) One amendment was made to this published filter as terms for chemotherapy were removed as none of the diagnostic tests are assessing diseases where chemotherapy is the primary treatment.
In addition, guideline libraries will also be searched including the Agree Trust,(17) the Agency for Healthcare Research and Quality National Guideline Clearinghouse,(18) Guidelines International Network Library,(19) and the WHO website.(20)
Eligibility criteria
Eligibility criteria are presented in Table 3. Abstracts will be screened for populations that match the populations from the Cochrane DTA reviews, i.e. malaria, leishmaniasis, TB, schistosomiasis and typhoid/paratyphoid. At abstract screening, treatment guidelines will be included even if diagnosis is not mentioned in the abstract in case some publications provide diagnostic information in the full-paper. At full-paper screening, the specific outcomes of interest will be identified, i.e. a recommendation for how to diagnosis one of the diseases investigated in a Cochrane review.
Additional criteria include human studies only, and a date restriction from 2008 to present. This ten-year date limit has been applied to ensure that only the most recent versions of guidelines are being identified.
Abstracts will be reviewed in full by one reviewer. A second reviewer will screen 10% as a validation step. It is anticipated that the error rate of the first review will be low as the eligibility criteria are not complicated. The same process will be undertaken at full- paper review stage. Should there be any disagreements, a third reviewer will be consulted.
Table 3: Eligibility criteria for the systematic search for guidelines
Criteria Specification
Diseases Uncomplicated plasmodium falciparum malaria or plasmodium vivax
Visceral leishmaniasis
Pulmonary tuberculosis
Active schistosomiasis
Typhoid and paratyphoid fever
Study type Guideline, policy statement, care pathway, diagnostic algorithm
Outcomes Recommendations for diagnosis of one of the listed diseases
Other criteria Published between 2008 to present
Human studies only
If multiple versions of a guideline are identified from one organisation, the most recent guideline will be included
Data extraction and synthesis
The following data will be extracted:
Title, author, year
Organisation or body writing the guideline
Location
Relevant recommendations (quoted text)
Does it align with the Cochrane review? Yes/no
Was the Cochrane review the source of the evidence? Yes/no
If not, what was the source of the evidence?
An extraction form is presented in Appendix 8.2.2 with one study extracted as an example.(21) Data extraction will be performed by a single reviewer with a second reviewer validating 10% of the extracted data to ensure the quality.
A narrative synthesis will be undertaken of the data summarising to what degree Cochrane reviews have been used to inform diagnostic guidelines. This will include summary statistics such as the proportion of identified guidelines which have been informed by Cochrane reviews and, the average time between a Cochrane recommendation and incorporation of the evidence into guidelines.
Risk of bias assessment will not be undertaken as only minimal data will be extracted. The aim here is not to assess the guideline quality, but simply to determine the impact of Cochrane recommendations regardless of study quality.
Step 3: contacting manufacturers
For Cochrane DTA reviews which give a positive recommendation for a diagnostic test, this may lead to an increase in the use of the diagnostic test in practice. Given the breadth of the regions being investigated in this dissertation, it will be difficult to identify representative primary data from clinical practice which may give an indication of whether the use of the diagnostic test is changing in practice. Therefore, as a proxy measure of usage of the diagnostic test, manufacturers of the diagnostic tests will be contacted for information on the sales of their diagnostic test. Although this will not provide a direct measure of usage of the test, it will be inferred from the data that if sales in the test have changed, that this is an indication of changed usage of the test in practice.
Criteria for contacting manufacturers
The recommendations made by the nine Cochrane reviews is summarised in Table 21 in Appendix 8.3. These are abbreviated versions of the recommendations, however, it gives an idea of the multifaceted nature of Cochrane recommendations. Only two of the reviews give a clear positive recommendation: Steingart (2014) for XPERT for the diagnosis of TB and Abba (2011) for a series of rapid diagnostic tests (RDTs) for malaria.(5, 9) Since there is only one manufacturer of XPERT (Cepheid), they will be contacted for sales information. For malaria, given the number of tests evaluated, rather than contact all manufacturers, only the tests for which there are the greatest number of follow-up studies based on Step 1 (forward citation searching) will be contacted. Similarly, a number of reviews give a partial recommendation or do not recommend a test alone, but indicate that it may useful as part of a diagnostic algorithm.(7, 10-12) If there is evidence from forward citation searching that these tests have been incorporated into diagnostic algorithms, then these manufacturers will also be contacted.
Requesting data
Contact email addresses will be identified from the manufacturers website. Manufacturers will be followed-up two times after the initial contact if they do not reply (contact dates are in timelines: Section 6). Should manufacturers be willing to provide data or information, then the following data will be requested:
Sales data spanning several years both before and after the Cochrane recommendation (ideally from when the test was released to present year)
Information on regional specific sales
Information on other factors which may have impacted sales, for example, a large marketing campaign
Data analysis
The depth of the analysis undertaken will depend on the amount of data retrieved from manufacturers. Most likely, data will be analysed by plotting sales against time with publication dates for the Cochrane review, diagnostic guidelines, and other key dates such as marketing campaigns highlighted in the graph. From this, an assessment of a time trend and the impact of the Cochrane review will be made. Should regional data be also provided, then an assessment of what regions are rolling-out the test and the regional impact of the diagnostic test will be made.
Should extensive information be provided, then it will be determined at that time if it is possible to model the data to adjust for other variables and provide a clearer indication of the effect of the Cochrane review and guideline recommendations. However, what such an analysis would entail will be decided should such data be received. The development of such an analysis will be informed using information learned from the Advanced Statistics Module once that has been completed.
Presentation of results
A summary will be provided for the impact of each review. If possible, the data will be divided into input, process, and output. In addition, as the Cochrane reviews also highlight where there is a lack of evidence, another category called further research will be added. Examples of the kinds of data that will fit in each category and the stage of the project that these data will be identified are presented in Table 4.
By categorising the project in this way, it should be easier to identify where Cochrane reviews are best at having impact and where the reviews are failing to achieve impact. In this way, although the reviews will initially be presented individually, the aim will be to identify overarching themes about the impact Cochrane reviews are having in terms of translation into practice and into further research.
Table 4: Suggested categories for stratifying the data retrieved across the stages of the project
Examples specific to this project Stage of the project the data which will identify the data
Input Incorporation into guidelines
Evidence the test is available in hospitals, health centres etc. Step 1, 2 and 3
Process - Evidence the test is being used Step 1, 3
Output Evidence of test improving patient outcomes
Evidence of test improving diagnostic efficiency in real-world setting Step 1
Additional research Further studies of diagnostic test accuracy
Studies undertaken of new diagnostic tests. Step 1
Feasibility and limitations
It is not anticipated that there will be problems with research governance or ethics. The main feasibility issues relate to obtaining manufacturers data and the volume of literature.
Volume of literature
The main feasibility issue will be the volume of literature that needs to be reviewed within the timeframe of the dissertation. To account for this, go-stop criteria have been set up whereby the two biggest disease areas (based on scoping searches) will be undertaken first: malaria and TB. Once these two disease areas are complete, Steps 1-3 for the other three disease areas will begin. Searches will however be run for all diseases on one day, but work will begin sequentially. Similarly, manufacturers will be contacted early for all diseases, however, analysis will begin sequentially.
Obtaining manufacturer data
There may be difficulties obtaining manufacturers data as they may not wish to disclose sales data and could lead to Step 3 not being feasible. These data would be useful but should they not be received this will allow completion of all literature review steps for all diseases.
General limitations
The main issue will be interpretation of impact and disentangling other factors which may have contributed to impact; for example, assuming that a change in sales seen by a manufacturer has been caused by the Cochrane review. In order to help address this, manufacturers will be asked if they are aware of other factors which may have influenced sales.
Data sources being searched may also be a limitation as on-going studies (e.g. the WHO trials registry)(22) and lists of funded research (e.g. Medical Research Council and Wellcome Trust lists of funded research)(23, 24) are not being assessed. However, given time constraints, the more definitive measures of impact listed in the protocol have been given preference. Should the other Steps be completed early, these sources could be pursued further.
Timeline
A Gantt chart is presented in Figure 2. All calculations of time have been made assuming a five-day workweek, and a 7.5 hour working day; this will allow some leeway should additional time be needed.
Note: although there are multiple tasks listed for some weeks, additional time has been added to individual tasks to ensure there is enough time to do these concurrently.
Initiation of project
Following results of the protocol, two weeks have been allowed to incorporate this feedback into the protocol and to consult my advisor.
Step 1: forward citation searching
Presented in Table 5 are the estimated number of citations for Step 1. Pilot extractions took approximately 10 minutes per publication as minimal data is being extracted. To allow that some extractions may take longer, the estimations below have assumed 15 minutes per extraction. Total time to extract is 32.9 days or 6.6 weeks. This has been spread across nine weeks in the Gantt chart to allow other work to be done alongside it. In addition, four weeks have been left to synthesise the data.
Table 5: Step 1: estimated number of forward citation extractions
Author (Year) Disease Estimated number of papers to extract Time to extract (days)
Abba (2011) Malaria 250 8.3
Abba (2014) Malaria 50 1.7
Boelaert (2014) Leishmaniasis 65 2.2
Odaga (2014) Malaria 70 2.3
Steingart (2014) Tuberculosis 400 13.3
Ochodo (2015) Schistosomiasis 50 1.7
Shah (2016) Tuberculosis 40 1.3
Theron (2016) Tuberculosis 60 2.0
Wijedoru (2017) Typhoid and paratyphoid 2 0.1
Total days 32.9
Step 2: guideline searching
Presented in Table 6 is the expected number of abstracts and full papers to review, and the expected numbers of extractions to perform based on scoping searches. Each column is accompanied by the expected amount of time that it will take to review/extract. Abstract
review assumes 500 abstracts will be reviewed in a day leading to 16 days to review. The Gantt chart allows four weeks for reviewing but a further two weeks to identify full-papers which will provide a buffer in the timelines. Full-paper review assumes 30 papers will be reviewed in a day leading to a cumulative 2.8 days to review, this has been presented as 2 weeks in the Gantt chart to allow other aspects of the project to be done simultaneously.
Finally, data extraction will be minimal, therefore, 20 minutes has been estimated per paper, which is 2.3 days work. This has also been presented as 2 weeks in the Gantt chart to allow other work to be done simultaneously. In addition, 2 weeks has been allowed for synthesising the data.
Table 6: Step 2: estimated volume of literature and the time to review and extract it
Disease Expected number of
abstracts Time to review
(days) Expected number of
full papers Time to review
(days) Expected number of
extractions Time to extract
(days)
Malaria 2200 4.4 25 0.8 15 0.7
Leishmaniasis 250 0.5 3 0.1 2 0.1
Tuberculosis 5000 10 50 1.7 30 1.3
Schistosomiasis 300 0.6 3 0.1 2 0.1
Typhoid and paratyphoid 250 0.5 3 0.1 2 0.1
Sum of days 16 2.8 2.3
Step 3: Contacting manufacturers
Three points have been marked in the Gantt chart for follow-up with manufacturers if no response is received. In addition, 4 weeks has been allowed at the end for analysis depending on what data are received.
Write-up
Writing up will begin as soon as possible, but two weeks have been set aside for writing only. One week has been allowed for my advisor to review the document and 1.5 weeks for those comments to be addressed.
Figure 2: Gantt chart for the dissertation
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Appendices
Appendices for Step 1: forward citation searching
Data extraction forms
Presented in Table 7 and Table 8 are sample data extraction forms for Step 1 of the project. Four studies have been extracted to pilot the extraction sheet. The extractions have been presented in two tables in this document for easier reading, however, in Microsoft Excel where the extractions will be undertaken, this will be one sheet.
Table 7: Step 1: forward citation searching; data extraction form 1: study characteristics with four sample studies extracted
Author (Reference) Year Title Study design Aim Country
Ahmadi (25) 2016 Evaluation of interleukin 8+2767 A/T polymorphism in visceral leishmaniasis Cross- sectional To evaluated the relationship between the genetic variations at IL-8 +2767 position with VL pathogenesis among Iranian
patients Iran
Diro (26) 2017 Diagnosis of Visceral Leishmaniasis Using Peripheral Blood Microscopy in Ethiopia: A Prospective Phase-III Study of the Diagnostic
Performance of Different Concentration Techniques Compared to Tissue Aspiration Phase III diagnostic accuracy study We sought to determine whether peripheral blood could be used instead of invasive tissue aspirates to diagnose VL,
using three parasite concentration techniques Ethiopia
Hirve (27) 2016 Transmission Dynamics of Visceral Leishmaniasis in the Indian Subcontinent - A Systematic Literature Review Systematic review The objective of this systematic review was to synthesize existing literature on transmission dynamics and relapse rates
of VL caused by L donovani in the Indian subcontinent Indian subcontinent
Mukhtar (28) 2015 Diagnostic accuracy of rK28-based immunochromatographic rapid diagnostic tests for visceral leishmaniasis: a prospective
clinical cohort study in Sudan Prospective clinical cohort to assess test
accuracy A prospective clinical cohort study in Sudan was designed to validate a novel rK28- based RDT for Leishmania donovani
VL. Sudan
Table 8: Step 1: forward citation searching; data extraction form 2: impact of Cochrane review with four sample studies extracted
Author (Reference) Year Section of article with citation Why the Cochrane review was cited Quoted citation
Ahmadi (25) 2016 Materials and methods Justification of diagnostic method used in study An expert infectious diseases specialist diagnosed VL in participants
based on medical history, clinical presentations and laboratory findings (Boelaert, 2014)
Diro (26) 2017 Introduction Part of rationale: current tests are not sufficiently sensitive in Africa, therefore
testing new approach The widely available rK39 rapid diagnostic test (RDT) has been found to be insufficiently sensitive to rule out disease in east Africa, compared with other regions.5(Boelaert),6
Author (Reference) Year Section of article with citation Why the Cochrane review was cited Quoted citation
Hirve (27) 2016 Introduction Part of rationale: large body
of data on VL but not on transmission dynamics A large body of research has evaluated diagnostics [10 (Boelaert)
13], potential biomarkers for treatment response of VL and PKDL [14], treatment options [15], and vector control [16,17].
Mukhtar (28) 2015 Introduction Part of rationale: current tests are not sufficiently sensitive in Africa, therefore testing new approach Serological tests have variable sensitivities and specificities in different endemic areas, fail to differentiate between current and past infections, and sometimes detect subclinical infections not requiring treatment.4,5 (Boelaert)
The test had a high sensitivity and specificity in the Indian sub-
continent while it had a somewhat lower sensitivity in the VL endemic region in East Africa.5 (Boelaert),10,11
Appendices for Step 2: systematic searching for guidelines
Search strategies
Table 9: Malaria guideline search strategy for Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present (search run on 06th March 2018)
# Searches Results
1 exp MALARIA/ or exp MALARIA, FALCIPARUM/ or exp MALARIA, VIVAX/ 60298
2 exp PLASMODIUM MALARIAE/ or exp PLASMODIUM VIVAX/ or exp PLASMODIUM FALCIPARUM/ or exp PLASMODIUM OVALE/ 30157
3 (malaria or paludism or "marsh fever" or (plasmodium adj (falciparum or vivax or malariae or ovale))).ti,ab. 78379
4 or/1-3 89879
5 exp clinical pathway/ 5859
6 exp clinical protocol/ 150336
7 exp consensus/ 8457
8 exp consensus development conference/ 10846
9 exp consensus development conferences as topic/ 2558
10 critical pathways/ 5859
11 exp guideline/ 29776
12 guidelines as topic/ 36224
13 exp practice guideline/ 23161
14 practice guidelines as topic/ 102413
15 health planning guidelines/ 3977
16 (guideline or practice guideline or consensus development conference or consensus development conference, NIH).pt. 38318
17 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw. 24138
18 (standards or guideline or guidelines).ti,kf,kw. 91030
19 ((practice or treatment* or clinical) adj guideline*).ab. 31011
20 (CPG or CPGs).ti. 5143
21 consensus*.ti,kf,kw. 20289
22 consensus*.ab. /freq=2 19690
23 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kf,kw. 16184
24 recommendat*.ti,kf,kw. 33418
25 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kf,kw. 43651
26 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kf,kw. 5893
27 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kf,kw. 7588
28 or/5-27 517374
29 4 and 28 1151
30 limit 29 to yr="2008 -Current" 694
31 limit 30 to humans 592
Table 10: Malaria guideline search strategy for Embase 1974 to 2018 March 05 (search run on 06th March 2018)
# Searches Results
1 exp Plasmodium vivax malaria/ or exp malaria/ or exp malaria falciparum/ or exp malaria rapid test/ or exp malaria control/ or exp Plasmodium ovale malaria/ 85174
2 exp "Plasmodium falciparum (HB3)"/ or exp Plasmodium falciparum/ or exp Plasmodium ovale malaria/ or exp Plasmodium malariae/ or exp Plasmodium malariae infection/ or exp Plasmodium vivax/ or exp Plasmodium falciparum
3D7/ or exp Plasmodium ovale/ 42078
3 (malaria or paludism or "marsh fever" or (plasmodium adj (falciparum or vivax or malariae or ovale))).ti,ab. 92632
4 or/1-3 112665
5 exp clinical pathway/ 7605
6 exp clinical protocol/ 85283
7 exp consensus/ 52497
8 exp consensus development conference/ 22849
9 exp consensus development conferences as topic/ 22849
10 critical pathways/ 7605
11 guidelines as topic/ 292510
12 exp practice guideline/ 440911
13 practice guidelines as topic/ 226293
14 health planning guidelines/ 88405
15 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kw. 35457
16 (standards or guideline or guidelines).ti,kw. 130283
17 ((practice or treatment* or clinical) adj guideline*).ab. 46827
18 (CPG or CPGs).ti. 6177
19 consensus*.ti,kw. 26198
20 consensus*.ab. /freq=2 26016
21 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kw. 25303
22 recommendat*.ti,kw. 43445
23 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kw. 75855
24 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kw. 8037
25 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kw. 11590
26 or/5-25 818754
27 4 and 26 3478
28 limit 27 to yr="2008 -Current" 2367
29 limit 28 to human 2087
Table 11: Leishmaniasis guideline search strategy for Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present (search run on 06th March 2018)
# Searches Results
1 exp LEISHMANIASIS/ or exp LEISHMANIASIS, VISCERAL/ 20524
2 exp LEISHMANIA/ 18390
3 exp LEISHMANIA INFANTUM/ or exp LEISHMANIA DONOVANI/ 6563
4 (Kala azar or kala-azar or leishmani*).ti,ab. 31488
5 or/1-4 33543
6 exp clinical pathway/ 5859
7 exp clinical protocol/ 150336
8 exp consensus/ 8457
9 exp consensus development conference/ 10846
10 exp consensus development conferences as topic/ 2558
11 critical pathways/ 5859
12 exp guideline/ 29776
13 guidelines as topic/ 36224
14 exp practice guideline/ 23161
15 practice guidelines as topic/ 102413
16 health planning guidelines/ 3977
17 (guideline or practice guideline or consensus development conference or consensus development conference, NIH).pt. 38318
18 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw. 24138
19 (standards or guideline or guidelines).ti,kf,kw. 91030
20 ((practice or treatment* or clinical) adj guideline*).ab. 31011
21 (CPG or CPGs).ti. 5143
22 consensus*.ti,kf,kw. 20289
23 consensus*.ab. /freq=2 19690
24 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kf,kw. 16184
25 recommendat*.ti,kf,kw. 33418
26 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kf,kw. 43651
27 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kf,kw. 5893
28 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kf,kw. 7588
29 or/6-28 517374
30 5 and 29 176
31 limit 30 to yr="2008 -Current" 114
32 limit 31 to humans 60
Table 12: Leishmaniasis guideline search strategy for Embase 1974 to 2018 March 05 (search run on 06th March 2018)
# Searches Results
1 exp Leishmania/ or exp leishmaniasis/ or exp Leishmania chagasi/ or exp visceral leishmaniasis/ 37499
2 exp Leishmania infantum/ 3360
3 exp Leishmania donovani/ 6312
4 exp leishmaniasis rapid test/ 50
5 (Kala azar or kala-azar or leishmani*).ti,ab. 34942
6 or/1-5 40105
7 exp clinical pathway/ 7605
8 exp clinical protocol/ 85283
9 exp consensus/ 52497
10 exp consensus development conference/ 22849
11 exp consensus development conferences as topic/ 22849
12 critical pathways/ 7605
13 guidelines as topic/ 292510
14 exp practice guideline/ 440911
15 practice guidelines as topic/ 226293
16 health planning guidelines/ 88405
17 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kw. 35457
18 (standards or guideline or guidelines).ti,kw. 130283
19 ((practice or treatment* or clinical) adj guideline*).ab. 46827
20 (CPG or CPGs).ti. 6177
21 consensus*.ti,kw. 26198
22 consensus*.ab. /freq=2 26016
23 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kw. 25303
24 recommendat*.ti,kw. 43445
25 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kw. 75855
26 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kw. 8037
27 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kw. 11590
28 or/7-27 818754
29 6 and 28 443
30 limit 29 to yr="2008 -Current" 297
31 limit 30 to human 205
Table 13: Tuberculosis guideline search strategy for Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present (search run on 06th March 2018)
# Searches Results
1 exp LATENT TUBERCULOSIS/ or exp EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS/ or exp TUBERCULOSIS/ or exp TUBERCULOSIS,
MULTIDRUG-RESISTANT/ or exp MYCOBACTERIUM TUBERCULOSIS/ or exp TUBERCULOSIS, PULMONARY/ 202290
2 (tuberculos* or TB or (pulmonary adj (phthis?s or consumption*)) or "koch* disease").ti,ab. 183881
3 1 or 2 247293
4 exp clinical pathway/ 5859
5 exp clinical protocol/ 150336
6 exp consensus/ 8457
7 exp consensus development conference/ 10846
8 exp consensus development conferences as topic/ 2558
9 critical pathways/ 5859
10 exp guideline/ 29776
11 guidelines as topic/ 36224
12 exp practice guideline/ 23161
13 practice guidelines as topic/ 102413
14 health planning guidelines/ 3977
15 (guideline or practice guideline or consensus development conference or consensus development conference, NIH).pt. 38318
16 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw. 24138
17 (standards or guideline or guidelines).ti,kf,kw. 91030
18 ((practice or treatment* or clinical) adj guideline*).ab. 31011
19 (CPG or CPGs).ti. 5143
20 consensus*.ti,kf,kw. 20289
21 consensus*.ab. /freq=2 19690
22 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kf,kw. 16184
23 recommendat*.ti,kf,kw. 33418
24 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kf,kw. 43651
25 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kf,kw. 5893
26 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kf,kw. 7588
27 or/4-26 517374
28 3 and 27 3195
29 limit 28 to yr="2008 -Current" 1691
30 limit 29 to humans 1427
Table 14: Tuberculosis guideline search strategy for Embase 1974 to 2018 March 05 (search run on 06th March 2018)
# Searches Results
1 (tuberculos* or TB or (pulmonary adj (phthis?s or consumption*)) or "koch* disease").ti,ab. 196144
2 exp Mycobacterium tuberculosis complex/ or exp lung tuberculosis/ or exp tuberculosis/ or exp Mycobacterium tuberculosis test kit/ or exp latent tuberculosis/ or exp extensively drug resistant tuberculosis/ or exp multidrug
resistant tuberculosis/ or exp tuberculosis rapid test/ or exp drug resistant tuberculosis/ or exp Mycobacterium tuberculosis/ 236949
3 1 or 2 271904
4 exp clinical pathway/ 7605
5 exp clinical protocol/ 85283
6 exp consensus/ 52497
7 exp consensus development conference/ 22849
8 exp consensus development conferences as topic/ 22849
9 critical pathways/ 7605
10 guidelines as topic/ 292510
11 exp practice guideline/ 440911
12 practice guidelines as topic/ 226293
13 health planning guidelines/ 88405
14 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kw. 35457
15 (standards or guideline or guidelines).ti,kw. 130283
16 ((practice or treatment* or clinical) adj guideline*).ab. 46827
17 (CPG or CPGs).ti. 6177
18 consensus*.ti,kw. 26198
19 consensus*.ab. /freq=2 26016
20 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kw. 25303
21 recommendat*.ti,kw. 43445
22 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kw. 75855
23 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kw. 8037
24 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kw. 11590
25 or/4-24 818754
26 3 and 25 7984
27 limit 26 to yr="2008 -Current" 4819
28 limit 27 to human 4392
Table 15: Schistosomiasis guideline search strategy for Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present (search run on 06th March 2018)
# Searches Results
1 (schisto* or bilharzi*).ti,ab. 31595
2 exp SCHISTOSOMIASIS HAEMATOBIA/ or exp SCHISTOSOMIASIS/ or exp SCHISTOSOMIASIS MANSONI/ or exp SCHISTOSOMIASIS JAPONICA/ 22239
3 1 or 2 33923
4 exp clinical pathway/ 5859
5 exp clinical protocol/ 150336
6 exp consensus/ 8457
7 exp consensus development conference/ 10846
8 exp consensus development conferences as topic/ 2558
9 critical pathways/ 5859
10 exp guideline/ 29776
11 guidelines as topic/ 36224
12 exp practice guideline/ 23161
13 practice guidelines as topic/ 102413
14 health planning guidelines/ 3977
15 (guideline or practice guideline or consensus development conference or consensus development conference, NIH).pt. 38318
16 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw. 24138
17 (standards or guideline or guidelines).ti,kf,kw. 91030
18 ((practice or treatment* or clinical) adj guideline*).ab. 31011
19 (CPG or CPGs).ti. 5143
20 consensus*.ti,kf,kw. 20289
21 consensus*.ab. /freq=2 19690
22 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kf,kw. 16184
23 recommendat*.ti,kf,kw. 33418
24 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kf,kw. 43651
25 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kf,kw. 5893
26 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kf,kw. 7588
27 or/4-26 517374
28 3 and 27 146
29 limit 28 to yr="2008 -Current" 87
30 limit 29 to humans 59
Table 16: Schistosomiasis guideline search strategy for Embase 1974 to 2018 March 05 (search run on 06th March 2018)
# Searches Results
1 exp schistosomiasis haematobia/ or exp schistosomiasis/ or exp schistosomiasis mansoni/ or exp schistosomiasis japonica/ 22024
2 (schisto* or bilharzi*).ti,ab. 33827
3 1 or 2 37567
4 exp clinical pathway/ 7605
5 exp clinical protocol/ 85283
6 exp consensus/ 52497
7 exp consensus development conference/ 22849
8 exp consensus development conferences as topic/ 22849
9 critical pathways/ 7605
10 guidelines as topic/ 292510
11 exp practice guideline/ 440911
12 practice guidelines as topic/ 226293
13 health planning guidelines/ 88405
14 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kw. 35457
15 (standards or guideline or guidelines).ti,kw. 130283
16 ((practice or treatment* or clinical) adj guideline*).ab. 46827
17 (CPG or CPGs).ti. 6177
18 consensus*.ti,kw. 26198
19 consensus*.ab. /freq=2 26016
20 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kw. 25303
21 recommendat*.ti,kw. 43445
22 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kw. 75855
23 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kw. 8037
24 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kw. 11590
25 or/4-24 818754
26 3 and 25 423
27 limit 26 to yr="2008 -Current" 310
28 limit 27 to human 278
Table 17: Typhoid and paratyphoid guideline search strategy for Ovid MEDLINE(R) In-Process & Other Non- Indexed Citations and Ovid MEDLINE(R) 1946 to Present (search run on 06th March 2018)
# Searches Results
1 exp Typhoid Fever/ 10658
2 exp Salmonella typhi/ 6682
3 exp PARATYPHOID FEVER/ 2308
4 (typhoid* or paratyphoid* or (enteric adj2 fever*) or (typh* adj (salmonella* or abdom*))).ti,ab. 13945
5 or/1-4 20944
6 exp clinical pathway/ 5859
7 exp clinical protocol/ 150336
8 exp consensus/ 8457
9 exp consensus development conference/ 10846
10 exp consensus development conferences as topic/ 2558
11 critical pathways/ 5859
12 exp guideline/ 29776
13 guidelines as topic/ 36224
14 exp practice guideline/ 23161
15 practice guidelines as topic/ 102413
16 health planning guidelines/ 3977
17 (guideline or practice guideline or consensus development conference or consensus development conference, NIH).pt. 38318
18 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw. 24138
19 (standards or guideline or guidelines).ti,kf,kw. 91030
20 ((practice or treatment* or clinical) adj guideline*).ab. 31011
21 (CPG or CPGs).ti. 5143
22 consensus*.ti,kf,kw. 20289
23 consensus*.ab. /freq=2 19690
24 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kf,kw. 16184
25 recommendat*.ti,kf,kw. 33418
26 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kf,kw. 43651
27 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kf,kw. 5893
28 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kf,kw. 7588
29 or/6-28 517374
30 5 and 29 104
31 limit 30 to yr="2008 -Current" 55
32 limit 31 to humans 50
Table 18: Typhoid and paratyphoid guideline search strategy for Embase 1974 to 2018 March 05 (search run on 06th March 2018)
# Searches Results
1 (typhoid* or paratyphoid* or (enteric adj2 fever*) or (typh* adj (salmonella* or abdom*))).ti,ab. 12157
2 exp typhoid fever/ 11880
3 exp paratyphoid fever/ 825
4 exp Salmonella enterica serovar Typhi/ 1656
5 or/1-4 17827
6 exp clinical pathway/ 7605
7 exp clinical protocol/ 85283
8 exp consensus/ 52497
9 exp consensus development conference/ 22849
10 exp consensus development conferences as topic/ 22849
11 critical pathways/ 7605
12 guidelines as topic/ 292510
13 exp practice guideline/ 440911
14 practice guidelines as topic/ 226293
15 health planning guidelines/ 88405
16 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kw. 35457
17 (standards or guideline or guidelines).ti,kw. 130283
18 ((practice or treatment* or clinical) adj guideline*).ab. 46827
19 (CPG or CPGs).ti. 6177
20 consensus*.ti,kw. 26198
21 consensus*.ab. /freq=2 26016
22 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kw. 25303
23 recommendat*.ti,kw. 43445
24 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kw. 75855
25 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or diagnosed or diagnosing)).ti,ab,kw. 8037
26 (algorithm* adj2 (pharmacotherap* or therap* or treatment* or intervention*)).ti,ab,kw. 11590
27 or/6-26 818754
28 5 and 27 365
29 limit 28 to yr="2008 -Current" 239
30 limit 29 to human 223
Data extraction forms
Presented in Table 19 and Table 20 are sample data extraction forms for Step 2 of the project. One study has been extracted to pilot the extraction sheet. The extractions have been presented in two tables in this document for easier reading, however, in Microsoft Excel where the extractions will be undertaken, this is on one sheet.
Table 19: guideline searching; data extraction form 1: study characteristics with a sample study extracted
Author (reference) Year Title Organisation or body Country
Aronson (21) 2016 Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the
American Society of Tropical Medicine and Hygiene (ASTMH) Infectious Diseases Society of America (IDSA) and the American Society of
Tropical Medicine and Hygiene (ASTMH) United States and Canada
Table 20: guideline searching; data extraction form 2: study characteristics with a sample study extracted
Author (reference) Year Relevant recommendations Does it align with the Cochrane review? Was the Cochrane review the
source of evidence If not, what was the source
of evidence
Aronson (21) 2016 Serology with an rK39-based immunochromatographic test [76, 77(Boerlaert)] may provide supportive evidence for a diagnosis of VL, but it is not recommended as a stand-alone VL diagnostic test; however, it may be
useful to direct more invasive testing Yes Yes n/a
PRISMA diagram
A PRISMA flow diagram will be completed for Step 2: systematic searching for diagnostic guidelines.
Figure 3: PRISMA flow diagram
Appendices for Step 3: contacting manufacturers
Table 21: Summary of recommendations made by each of the Cochrane DTA reviews of infectious disease prevalent in LMICs
Author (Year) Condition Overview of diagnostic tests assessed Brief summary of conclusions
Abba (2011) Uncomplicated plasmodium falciparum malaria HRP-2 anti-body tests:
Type 1: Ten brands
Type 2: Two brands
Type 3: Three brands pLDH antibody based tests:
Type 4: Four brands
Type 5: Two brands RDTs have high sensitivity and specificity; can replace or augment microscopy for diagnosing P. falciparum malaria. No important differences in accuracy between different RDT brands within the same type
Abba (2014) Uncomplicated non- falciparum or plasmodium vivax malaria Non-falciparum only:
Type 2: Five brands
Type 3: Five brands
Type 4: Three brands
Other test types: one brand
Non-falciparum only (verified by PCR):
Type 3: Four brands
Type 4: OptiMAL P vivax:
Five brands Tests not adequately sensitive to identify P. vivax. May be useful in regions where both P. vivax and P. falciparum occur and are treated with the same drugs.
Boelaert (2014) Visceral leishmaniasis rK39 immunochromatographic test Sufficient sensitivity and sensitivity for use in the Indian subcontinent.
Sensitivity not sufficient as a stand-alone test in East Africa.
KAtex Low sensitivity: unsuitable for use
FAST, rK26 or rKE16 immunochromatographic test No recommendations made because of paucity of evidence
Odaga (2014) Malaria Diagnostic algorithms using RDTs No difference in health outcomes before and after RDT introduction
When RDT results were followed, by health workers, prescriptions of anti-malarials decreased
Steingart (2014) Pulmonary tuberculosis and
rifampicin resistance XPERT MTB/RIF In patients with or without HIV, XPERT is sensitive and specific For rifampicin resistance in adults, accurate and rapid
Ochodo (2015) Active schistosomiasis Urine reagent strips for microhaematuria - 18 brands Detects the largest proportion of infections identified by microscopy (spec 87%). Test is suitable for mass mapping of
Author (Year) Condition Overview of diagnostic tests assessed Brief summary of conclusions
school-aged children. Can continue to serve as a replacement for
microscopy for initial mapping or estimation of infection
Urine reagent strips for proteinuria - 18 brands Next best after microhaematuria (sens 61%, spec 82%)
Urine reagent strips for leukocyturia - two brands Limited by low specificity and sensitivity and is not useful in practice
Urine circulating cathodic antigen (CCA) point of care (POC) test S. Haematobium - four
brands Very low sensitivity, may not be suitable for mapping or estimating infection
Urine CCA POC test S. Mansoni - two brands Detected a large portion of infections (89%), low spec but ref standard not good, therefore could be more sensitive than ref
(microscopy).
Urine CCA POC test mixed infection - Rapid Diagnostic Tests from Pretoria South Africa Only one study
CAA ELISA test - serum or urine - all were in- house assays Unable to generate summary estimates
Shah (2016) Active tuberculosis in HIV-positive adults Alere Determine TB LAM Ag test Cannot be used alone for the diagnosis of TB in HIV positive patients but may be cost-effective as part of a diagnostic algorithm
Findings don't support use as a screening test
Theron (2016) Resistance to second-line anti- tuberculosis drugs MTBDRsl version 1.0 Assessment of culture isolate or smear-positive specimen may be useful in detecting second-line drug resistance
MTBDRsl version 2.0 Insufficient data
Wijedoru (2017) Typhoid and paratyphoid (enteric) fever Typhidot, typhidot-M and TyphiRapid Tr-02
TUBEX
Test-It Typhoid and its earlier KIT prototype (dipstick, latex agglutination and ICT lateral
flow) Diagnostic accuracy moderate: does not support replacement for blood culture
Enterocheck WB, Enteroscreen, PanBio Multi- test Dip-S-Tick, Mega Salmonella, SD Bioline,
and Onsite Typho Insufficient evidence or inferior performance
DISSERTATION PROTOCOL
TITLE
The Association Between Vitiligo and Major Adverse Pregnancy Outcomes: A Systematic Review and Meta-Analysis Protocol.
BACKGROUND
Vitiligo is an acquired chronic autoimmune disorder characterised by the loss of functional melanocytes, leading to patchy depigmentation of the skin and mucous membranes. It affects approximately 0.5-2% of the global population, with higher prevalence rates reported in certain ethnic groups, such as those of Indian, Mexican, and African descent. (Joge, R.R., Kathane, P.U. and Joshi, S.H. (2022)), (Ahmed jan, N. and Masood, S. (2020)).
The precise pathogenesis of vitiligo is not fully understood, but it is believed to involve a complex interplay of genetic, environmental, and immunological factors. Oxidative stress, dysregulation of melanocyte survival pathways, and cell-mediated autoimmune responses against melanocytes have been implicated in the development and progression of the disease. (Hlaa, N., agar, T., Katelan, M., Brajac, I. and Prpi-Massari, L. (2022)), (Lyu, C. and Sun, Y. (2022)).
Previous studies have reported an increased risk of other autoimmune disorders, such as thyroid disease, type 1 diabetes, and pernicious anaemia, in individuals with vitiligo (Laisk, T., Lepamets, M., Koel, M., Abner, E., Metspalu, A., Nelis, M., Milani, L., Esko, T. and Mgi, R. (2021)). While several studies have explored the potential association between vitiligo and adverse pregnancy outcomes, the evidence remains limited and conflicting, with inconsistent findings across different study populations and methodologies. The paucity of large-scale, well-designed observational studies explicitly investigating this relationship could be a contributing factor to the limited evidence.
Some of the key studies that have examined this topic include:
1) A retrospective cohort study by Tawiah et al. (2020) reported higher rates of preeclampsia, preterm birth, and low birth weight among vitiligo patients compared to controls, suggesting a potential link between vitiligo and adverse pregnancy outcomes.
2) However, a case-control study by Maru et al. (2018) did not find a significant association between vitiligo and adverse pregnancy outcomes like miscarriage, preterm delivery, or low birth weight.
3) A systematic review by Liy et al. (2016) identified only a few studies investigating vitiligo and pregnancy outcomes, and the authors concluded that the evidence was insufficient to draw definitive conclusions.
4) Singh, M., Wambua, S., Lee, S.I. et al. conducted an umbrella review published in BMC Medicine (2024) that systematically evaluated the existing systematic reviews and meta-analyses on the association between autoimmune diseases, including vitiligo, and adverse pregnancy outcomes. The authors found limited and conflicting evidence, highlighting the need for larger, well-designed primary studies to establish a clearer understanding of this relationship.
These inconsistencies in the existing literature highlight the need for more rigorously designed observational studies with larger sample sizes, appropriate control groups, and comprehensive adjustment for potential confounding factors.
The proposed systematic review and meta-analysis aim to address these gaps by synthesising the available evidence from multiple studies, evaluating study quality, exploring potential sources of heterogeneity through subgroup analyses and meta-regression, and providing a more robust estimate of the association between vitiligo and major adverse pregnancy outcomes.
Potential associations, if confirmed, may be related to the underlying autoimmune nature of vitiligo, systemic inflammation, oxidative stress, or shared genetic and environmental factors contributing to both vitiligo and adverse pregnancy outcomes. However, the precise mechanisms remain speculative and warrant further investigation.
OBJECTIVES
PRIMARY OBJECTIVE:
To conduct a systematic literature review and meta-analysis of observational studies reporting rates of major adverse pregnancy outcomes (miscarriage, preeclampsia, preterm birth, still birth, and other relevant outcomes) in vitiligo and control groups, to estimate if vitiligo significantly alters the risk of these adverse outcomes.
SECONDARY OBJECTIVE:
Assess the risk of bias and methodological quality of existing studies using validated quality appraisal tools (Newcastle-Ottawa Scale)
Perform subgroup analyses and evaluate effect measure modifiers related to vitiligo characteristics (duration, severity, type, extent, and ethnicity), maternal age, parity, socioeconomic status, and other relevant factors, where data permits.
Conduct meta-regression analyses to identify key confounding variables altering the magnitude of effects on outcomes, such as comorbidities, concomitant medication use, and environmental exposures.
Formulate evidence-based recommendations for guidelines on preconception counselling, antenatal care, and management strategies for vitiligo patients planning pregnancy.
Identify knowledge gaps and future research directions around vitiligo and adverse pregnancy outcomes. (Singh, M., Wambua, S., Siang Ing Lee, Okoth, K., Wang, Z., Ahamed, F., Eastwood, K.-A., Nelson-Piercy, C., Reynolds, J.A., Krishnarajah Nirantharakumar and Crowe, F. (2024)
METHODS
ELIGIBILITY CRITERIA
Studies will be selected according to the following criteria:
INCLUSION CRITERIA:
Observational studies (cross-sectional, cohort, case-control) reporting frequencies or effect estimates (e.g. odds ratios, risk ratios, hazard ratios) of major adverse pregnancy outcomes among women with physician-diagnosed vitiligo, using established diagnostic criteria.
Studies involving pregnant women aged 18 years or older.
Studies with a control group of pregnant women without vitiligo for comparison.
Minimum sample size and follow-up duration to be determined based on feasibility and data availability.
EXCLUSION CRITERIA:
Studies involving participants below 18 years of age or with other concurrent autoimmune or systemic disorders that may independently influence pregnancy outcomes.
Studies not reporting relevant pregnancy outcomes of interest.
Case reports, case series, and narrative reviews without original data.
OUTCOMES
PRIMARY OUTCOMES:
Miscarriage (spontaneous abortion before 20 weeks of gestation).
Preeclampsia (new-onset hypertension and proteinuria or end-organ dysfunction after 20 weeks of gestation).
Preterm birth (delivery before 37 completed weeks of gestation).
Stillbirth (intrauterine foetal demise after 20 weeks of gestation).
Other relevant adverse pregnancy outcomes, such as placental abnormalities, foetal growth restrictions, and congenital anomalies.
SECONDARY OUTCOMES (if data permits):
Maternal outcomes (e.g. postpartum haemorrhage, caesarean delivery).
Neonatal outcomes (e.g. low birth weight, neonatal intensive care unit admission).
The eligibility criteria, outcomes, and other aspects of the methods section can be further expanded and refined as needed based on the specific requirements and scope of the systematic review and meta-analysis. (Mohamedain, A., Rayis, D.A., AlHabardi, N., et al. (2022).
DATA SOURCES AND SEARCH STRATEGY
A comprehensive systematic search will be executed across major electronic databases, including PubMed, EMBASE, SCOPUS, Web of Science, Cochrane Library, CINAHL, and Google Scholar, using relevant keywords and medical subject headings (MeSH) terms related to vitiligo (e.g. vitiligo, leucoderma, depigmentation disorders) ,pregnancy (e.g. pregnancy, pregnancy outcome, maternal exposure), and adverse outcomes (e.g. preeclampsia, miscarriage, preterm birth, stillbirth).
No language or publication date restrictions will be applied to the search. Additionally, reference lists of eligible full-text articles and relevant systematic reviews will be hand-searched for potential additional studies. Grey literature sources, such as conference proceedings, dissertations, and clinical trial registries, will also be explored to minimise publication bias. (Bramer, W.M., Rethlefsen, M.L., Kleijnen, J., et al. (2017)).
Before proceeding with the review, a preliminary search will be conducted to identify any existing systematic reviews or meta-analyses on a similar topic. If such reviews are found, the proposed review will highlight how it differs in terms of objectives, inclusion criteria, methodological approaches, or the time frame of included studies. (Goossen, K., Hess, S., Lunny, C., et al. (2020)).
STUDY SELECTION AND DATA EXTRACTION
Screening of titles/abstracts and full-text articles will be undertaken independently by two reviewers, with any conflict resolved through consensus or consultation with a third reviewer. A standardised data extraction form will be used to collect relevant data from eligible studies, including study characteristics (design, setting, sample size), participant demographics (age, ethnicity, comorbidities), vitiligo characteristics (duration, severity, type, extent), exposure and outcome definitions, effect estimates (odds ratios, risk ratios, hazard ratios) with corresponding intervals, and potential confounding variables adjusted for in the analyses.
Data extraction will be performed independently by two reviewers, with disagreements resolved through discussion or involvement of a third reviewer. If required data is not reported in the published study, efforts will be made to contact the corresponding authors for additional information.
QUALITY ASSESSMENT
Quality assessments will be performed using the Newcastle-Ottawa Scales for cohort and case-control studies, which evaluate the selection of study groups, comparability of groups, and ascertainment of exposure and outcomes. For cross-sectional studies, the modified Newcastle-Ottawa Scale for cross-sectional studies will be employed. Additional appropriate tools, such as the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool, will be used for other study designs if necessary.
Two reviewers will independently assess the quality of included studies, with disagreements resolved through consensus or consultation with a third reviewer. Studies with a high risk of bias will be subjected to sensitivity analyses to evaluate their impact on the overall findings. (Veginadu, P., Calache, H., Gussy, M., et al. (2022)).
DATA SYNTHESIS AND ANALYSIS
Pooled odds ratios or risk ratios, along with 95% confidence intervals, for each outcome will be estimated through meta-analysis using fixed or random effects models, as appropriate, based on the assessment of heterogeneity (quantified using I-Squared statistics or Cochrans Q test). If significant heterogeneity is present (I-Squared > 50%), a random-effects model will be employed; otherwise, a fixed-effect model will be used. (Dettori, J.R., Norvell, D.C. and Chapman, J.R. (2022)).
If meta-analysis is not feasible due to significant heterogeneity or lack of sufficient data, a systematic narrative synthesis will be conducted to summarise the findings from individual studies.
Subgroup analyses will be conducted to explore potential effect modifiers, including vitiligo characteristics (duration, severity, type, extent), ethnicity, maternal age, parity, socioeconomic status, comorbidities, and other relevant factors, where data permits. Meta-regression analyses will be performed to identify key confounding variables altering the magnitude of effects on outcomes, such as concomitant medication use, environmental exposures, and healthcare access or utilisation.
Sensitivity analyses will be conducted to assess the robustness of the findings by excluding studies with high risk of bias, using alternative statistical models, or employing different assumptions for handling missing data. (Barker, T.H., Migliavaca, C.B., Stein, C., et al. (2021)).
ASSESSMENT OF PUBLICATION BIAS
Publication bias will be assessed using funnel plots and statistical tests if enough studies (typically more than 10) are included in the meta-analysis. If publication bias is detected, trim-and-fill methods or other appropriate techniques will be used to adjust for potential missing studies and provide an estimate of the unbiased effect size.
IMPLICATIONS
This systematic review and meta-analysis will provide a comprehensive evaluation of the association between vitiligo and major adverse pregnancy outcomes. The findings will help inform preconception counselling, screening, and management guidelines for vitiligo patients planning pregnancy. Additionally, it will identify gaps in the existing literature, highlight areas for future research, and potentially guide the development of interventions or strategies to mitigate the risks of adverse pregnancy outcomes in women with vitiligo.
The review will also contribute to a better understanding of the potential mechanisms underlying the association between vitiligo and adverse pregnancy outcomes, such as the role of autoimmunity, systematic inflammation, oxidative stress, or shared genetic and environmental factors.
Overall, this systematic review and meta-analysis will provide a comprehensive and up-to-date synthesis of the available evidence, addressing the limitations and inconsistencies in previous studies through rigorous methodology and data synthesis.
POTENTIAL LIMITATIONS
One potential limitation of this systematic review and meta-analysis is the possibility of publication bias, where studies with positive or statistically significant results are more likely to be published than those with negative or non-significant findings. This could lead to an overestimation of the association between vitiligo and adverse pregnancy outcomes. To address this, I will attempt to identify and include unpublished studies or grey literature through comprehensive database searches and hand-searching reference lists. Additionally, I will assess publication bias using funnel plots and appropriate statistical tests if sufficient studies are available.
Another limitation is the potential for heterogeneity in study designs, populations, and methodologies across the included studies. Observational studies may differ in their definitions of vitiligo, diagnostic criteria, ascertainment of pregnancy outcomes, and adjustment for confounding factors. This heterogeneity could lead to variability in effect estimates and potential bias. I will assess heterogeneity using appropriate statistical measures (e.g. I-squared) and, if significant heterogeneity is present, I will employ random-effects models and explore potential sources through subgroup analyses and meta-regression.
Furthermore, the availability and completeness of relevant data in the published studies may be a limitation. Some studies may not report specific details on vitiligo characteristics, effect modifiers, or confounding variables, which could limit the subgroup and meta-regression analyses planned in this review.
ETHICAL CONSIDERATIONS
This systematic review and meta-analysis will not involve the collection of primary data or direct participant involvement. Instead, it will synthesise and analyse data from previously published studies.
As such, no direct ethical concerns related to participant recruitment, consent, or data collection is anticipated.
However, it is crucial to ensure that the included studies have obtained ethical approvals and adhered to ethical standards for conducting research involving human participants. During the study selection and data extraction process, I will assess whether the included studies reported obtaining ethical approval from relevant institutional review boards or ethics committees.
Additionally, I will maintain the confidentiality and anonymity of any individual-level data extracted from the published studies and ensure that the findings are reported in an unbiased and responsible manner.
APPENDIX
APPENDIX 1: Sample search strategy
