Download Commercial serological tests for the diagnosis of active pulmonary

Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary
tuberculosis: An updated systematic review and meta-analysis - Protocol
I. Aim and review questions
Our aim will be to review studies on this topic published since 2006 and to perform a metaanalysis with advanced statistical methods
1. How accurate are commercial serological antibody detection tests for the diagnosis of
pulmonary TB?
2. How accurate are commercial serological antibody detection tests for the diagnosis of
extrapulmonary TB?
We will follow standard methods for the performance of systematic reviews of diagnostic test
accuracy as described in Leeflang et al. on behalf of the Cochrane Diagnostic Test Accuracy
Working Group. Ann Intern Med. 2008;149:889-897. In addition we will look for studies that
use serology as an add-on test, studies of patient-important outcomes, and studies on patient
values and preferences concerning these tests.
II. Search strategy
We updated the database searches that were done in previous systematic reviews [PubMed (1990
to May, 2006), BIOSIS (1990 to October, 2005), Embase (1990 to October, 2005), and Web of
Science (1990 to October, 2005)] and searched the literature for relevant studies (June 2010) that
reported data on commercial serological antibody detection tests for active tuberculosis. We
reviewed citations of all original articles published in all languages.
The search terms used in database searching included: tuberculosis[mh] OR mycobacterium
tuberculosis[mh], sensitivity and specificity"[mh] OR diagnostic*[tiab] OR predictive value of
tests[mh] OR immunologic tests[mh] OR immunochemistry[mh] OR serology[ti] OR
serological[ti] OR serodiagnosis[tiab] OR serodiagnostic[tiab] OR immunodiagnosis[tiab] OR
immunodiagnostic[tiab] OR antibody[tiab] OR antibodies[tiab] OR elisa[tiab] OR
immunosorbent[tiab] OR (western[tiab] AND blot*[tiab]) OR immunoassay[tiab] OR "humoral
immune" OR "humoral immunity" OR "humoral antibody" OR "immune based" OR "antibody
detection"
In addition to database searches, we reviewed bibliographies of previous reviews and also
screened the citations of relevant original articles. Experts in the field and commercial test
manufacturers were also contacted to obtain relevant citations.
III. Selection criteria
[Population, intervention, comparison, outcome (PICO)]
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P - Patients of all ages with suspected/confirmed pulmonary or extrapulmonary TB untreated or
receiving treatment for less than 14 days
I - Commercial serological antibody detection test
C - Sputum smear, other commercial test
O - Sensitivity, specificity
Study designs: randomized controlled trials, longitudinal cohort, cross-sectional, case-control
Include: Commercial antibody-based detection tests; specimens: serum, plasma, and blood;
studies with at least 10 TB cases; sufficient data for constructing 2x2 contingency table;
reference standard: culture, smear, histopathology (see IV)
Exclude: Studies published before 1990, case reports; animal studies; conference abstracts and
proceedings; studies on latent TB infection; studies on nontuberculous mycobacterial infection;
studies that look at antibody response during/after TB treatment; studies that used nonimmunological methods for detection of antigens or antibodies; basic science literature that
focuses on detection/cloning of new antigens or their immunological properties (e.g. epitope
mapping); basic science literature that focuses on new methods of antigen/antibody detection
IV. Reference standards and definitions
A. Pulmonary TB - Mycobacterial culture
B. Extrapulmonary TB - Culture and/or smear and/or histopathology
Extrapulmonary tuberculosis is defined as active TB in which the major site of involvement was
outside the lungs. Nine forms of extrapulmonary disease will be classified: lymph node, pleural,
meninges and/or central nervous system (CNS), bone and/or joint, disseminated/miliary,
genitourinary, abdominal, skin, and other sites. Other cases with concurrent extrapulmonarypulmonary tuberculosis are classified as PTB according to the World Health Organization
surveillance definition and are not included. (Global tuberculosis control: epidemiology,
strategy, financing: WHO report 2009; WHO/HTM/TB/2009.411; page 174). This classification
was changed to ten forms of extrapulmonary TB with the addition of the category ‘multiple sites’
to include a subgroup in which cases with one form of extrapulmonary disease are combined
with cases with different forms to obtain at least 10 TB cases.
Participants without TB disease, choose most appropriate group starting with (a) patients with
other respiratory disease/PTB suspects; (b) non-respiratory “mixed” disease; (c) healthy
V. Data extraction
Author; year study published; study design, age group (children defined as < 15 years old); HIV
status; case country of residence; World Bank country income status; sputum smear status
(pulmonary TB); site of TB (extrapulmonary TB); HIV status; assay type (e.g., ELISA,
immunochromatographic test); antibody class; commercial test name; antigen composition;
outcome data (e.g., sensitivity, specificity); industry involvement
VI. Outcomes
A. Sensitivity TP/(TP +FN)
B. Specificity TN/(FP + TN)
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VII. Assessment of methodological quality
We will use 11 core QUADAS quality items as recommended by GRADE Working Group. We
added one quality item on industry involvement.
Quality items
1. Was the spectrum of patients representative of the patients who will receive the test in
practice? (representative spectrum). Score ‘yes’ if persons suspected of having active TB were
consecutively enrolled. For pulmonary TB, a score of ‘yes’ for representative spectrum also
requires that patients were ambulatory
2. Is the reference standard likely to classify the target condition correctly? (acceptable reference
standard). Score ‘yes’ for all studies
3. Is the time period between reference standard and index test short enough to be reasonably
sure that the target condition did not change between the two tests? (acceptable delay between
tests). Score ‘yes’ for all studies
4. Did the whole sample or a random selection of the sample, receive verification using the
intended reference standard? (partial verification avoided) Score ‘yes’ for all studies
5. Did patients receive the same reference standard irrespective of the index test result?
(differential verification avoided) . Score ‘yes’ if all participants suspected of TB received a
culture or if participants without TB were asymptomatic and healthy
6. Was the reference standard independent of the index test (i.e. the index test did not form part
of the reference standard)? (incorporation avoided). Score ‘yes’ for all studies
7. Were the reference standard results interpreted without knowledge of the results of the index
test? (reference standard results blinded). Score ‘’yes’ for all studies in pulmonary group as
culture result was considered to be entirely objective in interpretation)
8. Were the index test results interpreted without knowledge of the results of the reference
standard? (index test results blinded) Score ‘yes’ if explicitly stated
9. Were the same clinical data available when test results were interpreted as would be available
when the test is used in practice? (relevant clinical information) Score “yes” for all studies.
10. Were uninterpretable/ intermediate test results reported? (uninterpretable results reported)
Score yes, if indeterminate/equivocal results are reported.
11. Were withdrawals from the study explained? (withdrawals explained). Score ‘yes’ if a flow
diagram is included in paper and/or withdrawals and/or exclusions after enrollment are
explained.
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12. Was there industry involvement in the study (industry involvement)? Score ‘yes’, ‘no’, or
‘unclear’.
If Yes, characterize type (Select one: answers ordered from least to most industry involvement)
__Donation of test materials or kits
__Receipt of educational support, grants, or speaking fees
__Work/financial relationship (author is an employee/consultant or owns company stock)
__Involvement in design, analysis, or manuscript production
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a
tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews.
BMC Med Res Methodol. Nov 10 2003;3:25.
Reitsma JB, Rutjes AWS, Whiting P, Vlassov VV, Leeflang MMG, Deeks JJ,. Chapter 9:
Assessing methodological quality. In: Deeks JJ, Bossuyt PM, Gatsonis C (editors), Cochrane
Handbook for Systematic Reviews of Diagnostic Test Accuracy Version 1.0.0. The Cochrane
Collaboration, 2009. Available from: http://srdta.cochrane.org/
VIII. Analysis plan
Meta-analysis method: HSROC random effects model accounting for sampling variability and
unexplained heterogeneity in sensitivity and specificity; at least 4 studies required for metaanalysis
A. Pulmonary TB
All commercial tests
Subgroup analysis (if at least 4 studies), data stratified by
1. commercial test
2. sputum smear status
3. income (high vs middle/low countries according to World Bank; countries (World Bank
List of Economies 2009
http://siteresources.worldbank.org/DATASTATISTICS/Resources/CLASS.XLS)
B. Extrapulmonary TB
All commercial tests
Subgroup analysis (if at least 4 studies), data stratified by
1. commercial test
2. site of TB
IX. Exploration of heterogeneity
A. Select ‘comparable’ subgroups to decrease heterogeneity
B. Visual inspection of forest plots
X. GRADE evidence profiles/summary of findings tables
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