Xpert MTB/RIF test for detection of pulmonary tuberculosisand rifampicin resistance Protocol Sohn H, Pai M, Dendukuri N, Kloda LA, Boehme CC, Steingart KR This is a reprint of a Cochrane
Trang 1Xpert MTB/RIF test for detection of pulmonary tuberculosis
and rifampicin resistance (Protocol)
Sohn H, Pai M, Dendukuri N, Kloda LA, Boehme CC, Steingart KR
This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library 2012, Issue 1
http://www.thecochranelibrary.com
Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 2T A B L E O F C O N T E N T S
1HEADER
1ABSTRACT
2
3OBJECTIVES
4METHODS
7
7REFERENCES
10APPENDICES
21HISTORY
21
21DECLARATIONS OF INTEREST
i Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 3[Diagnostic Test Accuracy Protocol]
Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance
Hojoon Sohn2, Madhukar Pai3, Nandini Dendukuri4, Lorie A Kloda5, Catharina C Boehme6, Karen R Steingart1
1Department of Health Services, University of Washington, School of Public Health, Seattle, Washington, USA.2Department ofEpidemiology & Biostatistics, McGill University, Montreal, Canada.3Dept of Epidemiology and Biostatistics, McGill University,Montreal, Canada.4Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.5LifeSciences Library, McGill University, Montreal, Canada.6FIND, Geneva, Switzerland
Contact address: Karen R Steingart, Department of Health Services, University of Washington, School of Public Health, Seattle,Washington, 98195-7230, USA.karenst@uw.edu
Editorial group: Cochrane Infectious Diseases Group.
Publication status and date: New, published in Issue 1, 2012.
Citation: Sohn H, Pai M, Dendukuri N, Kloda LA, Boehme CC, Steingart KR Xpert MTB/RIF test for detection of
pul-monary tuberculosis and rifampicin resistance.Cochrane Database of Systematic Reviews 2012, Issue 1 Art No.: CD009593 DOI:
Purpose of index test:
A.1 Xpert MTB/RIF as a replacement test for smear microscopy
A.2 Xpert MTB/RIF as an add-on test after smear microscopy
Review question B: To obtain summary estimates of the diagnostic accuracy of Xpert MTB/RIF for detection of rifampicin resistance,using solid or liquid culture as a reference standard (WHO 2008)
Purpose of index test:
B.1 Xpert MTB/RIF as a replacement test for WHO-approved tests for detection of rifampicin resistance
1 To summarize evidence on time to treatment initiation
2 To summarize evidence on time to diagnosis
Although these secondary outcomes will not be systematically reviewed, we will extract data when present in the included accuracystudies
We will investigate whether HIV-infection status; sputum smear status; country income status; setting; or storage conditions of specimencan explain the expected heterogeneity in estimates of test sensitivity and specificity
1 Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 4B A C K G R O U N D
Tuberculosis (TB) is one of the world’s most important infectious
causes of morbidity and mortality among adults An estimated
one-third of the world’s population is infected with TB In 2010,
there were 8.8 million new, and 12.0 million prevalent cases of
TB; 1.1 million deaths occurred among HIV-uninfected people
and an additional 0.35 million deaths among HIV-infected
peo-ple (WHO 2011a) Of the total new TB cases, an estimated 12%
to 14% occurred among people living with HIV Approximately
one million TB cases occur in children younger than 15 years old
annually (Marais 2010a) In 2010, the three countries with the
highest number of new TB cases were India, China, and South
Africa (WHO 2011a) In 2010, there were an estimated 650,000
cases of multidrug-resistant TB (MDR-TB), defined as resistance
to at least isoniazid and rifampicin, the two most powerful
first-line anti-TB drugs (WHO 2011a) TB is a treatable and curable
disease; according to the World Health Organization (WHO), up
to six million lives were saved with the expansion of Directly
Ob-served Treatment Short-Course (DOTS; the basic package that
underpins the Stop TB Strategy) (WHO 2010a) Early and
ac-curate diagnosis and effective treatment is the cornerstone of TB
care and control (Dye 2010) A basic tenet of early and accurate
diagnosis is the identification of smear-negative disease (associated
with HIV infection) and MDR-TB (WHO 2010b)
In 2011, poor diagnosis remains an obstacle to TB care and
con-trol, partly because TB diagnosis continues to rely on
century-old tests In most TB endemic countries, TB diagnosis is based
on direct Ziehl-Neelsen sputum microscopy or chest radiography,
tests with known shortcomings, especially in people with HIV
in-fection (Harries 2004;Perkins 2007;Steingart 2006)
Mycobac-terial cultures are time consuming and have biosafety and
train-ing requirements, and culture capacity is limited in underserved
and remote areas Nucleic acid-amplification (NAA) tests,
includ-ing polymerase chain reaction (PCR) tests, can rapidly detect
My-cobacterium tuberculosis (M tuberculosis), but studies of
conven-tional NAA tests have shown relatively low sensitivity in sputum
smear-negative patients (Flores 2005;Greco 2006;Ling 2008) and
these assays can only be performed in laboratories with specialized
equipment and expertise The disappointing performance of these
tools is compounded by the lack of access to health services with
diagnostic laboratories (WHO 2010a) A substantial proportion
(~35%) of the estimated TB cases worldwide remain undiagnosed,
including a staggering proportion (~85%) of patients with
MDR-TB (WHO 2011a) In addition, because of delays in diagnosis,
TB patients have often been symptomatic for months, leading to
increased illness and mortality, secondary drug resistance, and
on-going transmission Simple and rapid diagnostic tests at the point
of treatment in high-TB burden countries are urgently needed
Target condition being diagnosed
TB is an airborne disease caused by the bacterium,M tuberculosis,
and is spread primarily by droplet nuclei expelled by a person whohas infectious active TB Although TB most commonly affects thelungs, any organ or tissue may be involved Signs and symptoms ofpulmonary TB include cough for at least two weeks, fever, chills,night sweats, weight loss, haemoptysis (coughing up blood), andfatigue; symptoms of extrapulmonary TB depend on the site ofdisease From 1970 to 1986, wide-scale international multicen-tre randomized controlled trials conducted by the British MedicalResearch Council and its collaborators established the pivotal role
of rifampicin in TB treatment leading to modern short-course TBtherapy (Fox 1999) TB, even when resistant to rifampicin, can becured; however,to be effective, TB treatment regimens must con-tain multiple drugs to which the organisms are susceptible Inter-national guidelines for the treatment of TB are issued by a WHOExpert Group and are regularly updated The current WHO treat-ment guidelines are based on evidence assessed according to theGRADE (Grading of Recommendations Assessment, Develop-ment and Evaluation) approach for developing health care recom-mendations (Guyatt 2008;WHO 2009)
Index test(s)
The Xpert MTB/RIF© test is an automated PCR test utilizing theGeneXpert© platform Xpert MTB/RIF can detect TB as well asrifampicin resistance in less than two hours with minimal hands-
on technical time Xpert MTB/RIF is considered to be breaking because the test comes close to meeting the niche for a
ground-TB point-of-care test Unlike conventional NAA tests, this test
is unique because all steps involved in the PCR are completelyautomated and self-contained, allowing the technology to be takenout of the laboratory, into the clinic setting, where it can be usednearer to the patient (Small 2011)
Although, Xpert MTB/RIF provides testing for bothM losis and rifampicin resistance, it is really only one test The test
tubercu-uses five molecular beacons Molecular beacons are nucleic acidprobes that recognize and report the presence or absence of thenormal, susceptible, ’wild type’ sequence of the RNA polymerase(rpoB) gene ofM tuberculosis When a beacon fluoresces or ’lights
up’, this indicates the presence of the gene sequence which is acteristic of rifampicin-susceptibleM tuberculosis The number of
char-positive beacons allows the test to distinguish among the followingresults: ’No TB detected’ (none of the five beacons is positive);
’TB detected, rifampicin resistance detected’ (from two to fourbeacons are positive); ’TB detected, no rifampicin resistance de-tected’ (five beacons are positive); and an ’invalid result’ (one bea-con is positive) Xpert MTB/RIF occupies one physical unit anduses the same sputum sample to provide results for both detection
ofM tuberculosis and rifampicin resistance One cannot switch
rifampicin resistance testing off and only do TB testing, although
it is possible for the laboratory to omit results for rifampicin tance testing when reporting to the healthcare provider
resis-2 Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 5The physical unit for Xpert MTB/RIF has two main components:
1) a plastic cartridge containing liquid sample processing buffers
and PCR buffers and reagents; and 2) a device that controls the
fluidics inside the cartridge and performs real-time PCR analysis
(Helb 2009) The Xpert MTB/RIF assay amplifies a sequence of
the rpoB gene specific to members ofM tuberculosis complex In
greater than 95% ofM tuberculosis clinical isolates, resistance to
rifampicin has been associated with single amino acid alterations
in a limited region (81 base pairs (bp) also called
rifampicin-re-sistance determining region of the rpoB gene (Telenti 1993)
Ri-fampicin-susceptible isolates show no mutations in this region
With Xpert MTB/RIF, the limit of detection forM tuberculosis
DNA was found to be 4.5 genomes per PCR reaction (95%
confi-dence interval (CI) 3.3 to 9.7) and forM tuberculosis cells in
clin-ical sputum samples, 131 colony-forming units (cfu)/mL (95%
CI 106.2 to 176.4)Helb 2009) In investigations using clinical or
experimental samples, all 23 81-bp mutants were correctly
iden-tified as rifampicin-resistant (Helb 2009)
Alternative test(s)
The most widely used test for TB diagnosis in low- and
middle-income countries is Ziehl-Neelsen smear microscopy Sensitivity is
low (from 50 to 60% on average) and variable (from 20 to 80%),
and microscopy does not detect smear-negative TB which may
account for 24% to 61% of all pulmonary cases in HIV-infected
individuals (Steingart 2006;Getahun 2007)
Chest radiography for TB diagnosis is limited by high inter- and
intra-observer differences in reporting of radiographs, and absence
of typical findings in people living with HIV who have advanced
immunosuppression (Harries 2004)
Improved diagnostic tests such as mycobacterial culture and NAA
tests are available in high-income countries, but are often too
ex-pensive and complex for routine use by TB control programmes
in resource-limited TB-endemic settings Lack of access to
diag-nostic services in resource-limited settings presents an additional
barrier to using these tests
Rationale
Existing diagnostic tools for TB are not accurate, or cannot be
done rapidly at the point-of-care; therefore, there is an urgent need
for a diagnostic tool that is accurate, simple to operate, and can be
placed nearer to the patient in facilities such as health posts and
mi-croscopy centres While rapid, simple point-of-care tests exist for
infections like HIV and malaria, there is currently no such option
for TB Such a tool would have significant impact on TB control
through interruption of transmission and potentially earlier, more
efficient diagnosis of TB, including the detection of
smear-nega-tive disease and MDR-TB In December 2010, WHO announced
its endorsement of the Xpert MTB/RIF test (WHO 2011) The
WHO decision to endorse this test was based on a large tre study (Boehme 2010) and other preliminary data, reviewed by
multicen-an Expert Group (WHO 2010b) These studies showed that XpertMTB/RIF has a comparable level of diagnostic performance tomycobacterial culture, even in resource-limited settings A subse-quent implementation study (Boehme 2011) demonstrated highsensitivity of Xpert MTB/RIF in smear-negative patients (a con-cern in HIV co-infected individuals, and in children) (Mugusi
2006;Perkins 2006;Perkins 2007), while conventional NAA testshave low sensitivity in smear-negative patients (Greco 2006;Ling
2008) The WHO now recommends that Xpert MTB/RIF should
be used as the initial diagnostic test in individuals suspected ofMDR-TB or HIV-associated TB (WHO 2010b) Furthermore,Xpert may be used as an add-on test to microscopy in settingswhere MDR-TB or HIV, or both, are of lesser concern, especially
in smear-negative patients While several studies of Xpert MTB/RIF have shown excellent performance, this assay has not beenfully validated in all settings Since the WHO’s endorsement, sev-eral new studies have been published on Xpert MTB/RIF, andseveral others are expected to be published shortly At the time ofthis writing, a systematic review on the diagnostic accuracy of thisnew test has not been published
O B J E C T I V E S
Primary objectives
Review question A: To obtain summary estimates of the diagnosticaccuracy of Xpert MTB/RIF for the diagnosis of pulmonary TB,using solid or liquid culture as a reference standard
Purpose of index test:
A.1 Xpert MTB/RIF as a replacement test for smear microscopy.A.2 Xpert MTB/RIF as an add-on test after smear microscopy.Review question B: To obtain summary estimates of the diagnosticaccuracy of Xpert MTB/RIF for detection of rifampicin resistance,using solid or liquid culture as a reference standard (WHO 2008).Purpose of index test:
B.1 Xpert MTB/RIF as a replacement test for WHO-approvedtests for detection of rifampicin resistance
Secondary objectives
1 To summarize evidence on time to treatment initiation
2 To summarize evidence on time to diagnosis
Although these secondary outcomes will not be systematically viewed, we will extract data when present in the included accuracystudies
re-3 Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 6Investigation of sources of heterogeneity
We will investigate whether HIV-infection status; sputum smear
status; country income status; setting; or storage conditions of
specimen can explain the expected heterogeneity in estimates of
test sensitivity and specificity
M E T H O D S
Criteria for considering studies for this review
Types of studies
We will include primary studies that compared the results of the
index test with the reference standard Diagnostic accuracy studies
are typically cross sectional in design However, we will also include
randomized controlled trials and cohort studies
Only studies that report data from which we can extract true
posi-tives (TP), true negaposi-tives (TN), false posiposi-tives (FP), and false
neg-atives (FN) will be included
We will exclude case-control studies We will exclude studies that
are reported in abstracts
Participants
Included participants for review question A.1 will be adults (15
years and older) suspected of having pulmonary TB or MDR-TB,
from all settings and all countries
Included participants for review question A.2 will be adults
sus-pected of having pulmonary TB or MDR-TB that are determined
to be microscopy smear negative In this diagnostic strategy, smear
microscopy may be performed prior to, or concurrently with,
Xpert MTB/RIF test
Included participants for review question B will be adults suspected
of having pulmonary TB or MDR-TB, from all settings and all
countries
Patients suspected of having MDR-TB may include patients with
a history of TB, patients on TB treatment for pulmonary TB
without sputum conversion, and symptomatic contacts of patients
with known MDR-TB
Three categories of participants will be classified:
1 Definite TB - culture positive
2 Probable TB (clinically considered as TB, culture negative)
3 Non-TB (clinically not considered as non-TB, culture
Review question A: Active pulmonary TB
Review question B: Rifampicin resistance
Reference standards
Review question A: The reference standard for the diagnosis ofactive pulmonary TB is solid or liquid mycobacterial culture.Review question B: The reference standard for detection of ri-fampicin resistance is 1) solid culture, or 2) a commercial liquidculture system (BACTEC 460, MGIT 960, and MGIT ManualSystem, Becton Dickinson, USA; BacT/ALERT MP, Biomerieux,France; VersaTREK, Trek Diagnostic Systems, USA) (Canetti
1963;Laszlo 1997;WHO 2008)
Search methods for identification of studies
We will attempt to identify all relevant studies regardless of guage or publication status (published, unpublished, in press, andongoing)
Special-www.who.int/trialsearch), to identify ongoing trials
Searching other resources
We will review reference lists of included articles and any relevantreview articles identified through the above methods We will con-tact the test manufacturer (Cepheid Inc.) to identify unpublishedstudies We will also handsearch WHO reports on Xpert MTB/RIF We will contact researchers at the Foundation for InnovativeNew Diagnostics (FIND), members of the Stop TB Partnership’sNew Diagnostics Working Group, and other experts in the field of
TB diagnostics for information on ongoing or unpublished ies
stud-4 Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 7Data collection and analysis
Selection of studies
Two independent reviewers (HS and KRS) will first look at titles
and abstracts identified by electronic literature searching to
iden-tify potentially eligible studies Any citation identified by either
reviewer during this screen (screen 1) will be selected for full-text
review Two independent reviewers (HS and KRS) will then
re-view full-text papers (screen 2) for study eligibility using the
pre-defined inclusion and exclusion criteria In screen 2, any
discrep-ancies will be resolved by discussion between the reviewers, or if
they are unable to resolve, by decision of a third reviewer (MP)
A list of excluded studies and their reasons for exclusion will be
maintained
Data extraction and management
Two independent reviewers (HS and KRS) will extract a set of data
from each study using a piloted data extraction form Based on
the pilot, the extraction form will be finalized Two independent
reviewers (HS and KRS) will then extract data on the following
characteristics:
• Details of study: first author; publication year; case country
of residence; World Bank country income status; setting
(outpatient, inpatient, laboratory); study design; manner of
participant selection; number participants enrolled; number
participants for whom results available; industry sponsorship
• Characteristics of participants: HIV status; smear status;
history of TB
• Target conditions: review question A: pulmonary TB;
review question B: rifampicin resistance
• Reference standards: review question A: culture type (solid
or liquid); percentage of contaminated cultures; review question
B: the name and manufacturer of the reference standard
• Details of index test: software version of test
• Details of comparator: type of microscopy: light or
fluorescence; type of smear: direct or concentrated; number of
smears used to determine smear positivity
• Details of sputum specimen: type (such as expectorated
sputum, induced sputum, bronchoalveolar lavage); condition
(fresh or frozen); definition of a positive smear
• Details of outcomes: the number of true positives (TP),
true negatives (TN), false positives (FP), and false negatives
(FN); number of missing or unavailable test results
Time to treatment initiation is defined as the time from specimen
collection until patient starts treatment
Time to diagnosis is defined as the time from specimen collection
until there is an available TB result in lab or clinic, if the test was
performed in a clinic
Country income status will be classified as low/middle-income or
high-income, according to the World Bank List of Economies
Country income status will serve as a surrogate indicator for TBincidence
Review question A: Additional data about (a) proportion of terminate results, and (b) discordant results between Xpert MTB/RIF and the reference standard (Xpert positive/culture negativeresults) will be recorded
inde-Indeterminates
Review question A: other possible test results are invalid, error,
or no result These results will be combined and considered as
’indeterminate’
The proportion of indeterminate results will be the number oftests classified as ’invalid’, error’, or ’no result’ divided by the totalnumber of tests performed
Review question B: RIF indeterminate means that theM culosis concentration was very low and resistance could not be de-
tuber-termined Proportion of indeterminate results will be the number
of tests classified as ’indeterminate’ divided by the total number
of tests performed
Culture contamination will be defined as 1) growth of non-TBbacteria or fungi or 2) cross-contamination as determined after astandard laboratory evaluation Percentage of contaminated cul-tures will be the (number of contaminated cultures/total number
of cultures performed) x 100
We will contact authors of primary studies for missing data orclarifications All data will be entered into a database manager Adraft data extraction form is included inAppendix 2
Assessment of methodological quality
Two reviewers will independently assess study quality with themodified version of Quality Assessment of Diagnostic AccuracyStudies (QUADAS) (Reitsma 2009) Items 1 to 11 from theQUADAS list will be scored as yes, no, or unclear Disagreementswill be resolved by discussion between the reviewers or by a thirdreviewer (MP) Results will be described in the text and presentedgraphically Appendix 3 describes the criteria that need to be metfor each study to be rated as yes, no, or unclear for each of theQUADAS items
Statistical analysis and data synthesis
The first step in data analysis will be a descriptive analysis of theresults of the primary studies For both review question A andreview question B, the results will be based on categorical (binary)test results For both review questions, the index test results areautomatically generated and the user is provided with a printabletest result Examples are:
1 MTB detected; RIF resistance not detected
2 MTB detected; RIF resistance detected
3 MTB detected; RIF resistance indeterminate
4 MTB not detected; RIF not detected
5 Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 8Descriptive analysis will be performed usingStata 2009and key
study characteristics will be displayed in tables For each study,
sensitivity and specificity of the test along with the 95% CI will
be calculated using exact methods, and forest plots generated
us-ingReview Manager 5(RevMan) The primary analysis will be
performed for participants with definite TB (culture positive) and
non-TB (culture negative) Secondary analyses will estimate
ac-curacy using definite TB and probable-TB patients combined for
sensitivity calculations, and non-TB and probable TB patients
combined for specificity calculations
For review question B, we will sort the studies in RevMan by “year
of study” to look for a trend with time, since software and cartridge
changes have been made to improve the specificity for rifampicin
detection
Where sufficient data are available, meta-analyses will be carried
out to estimate sensitivity and specificity of the index test (primary
objective) The exact method used, either bivariate or HSROC,
will depend on data provided by the included studies For review
question A, detection ofM tuberculosis, since the test uses a
com-mon threshold for a positive result, we will use the bivariate
ran-dom effects regression model (Macaskill 2010; Reitsma 2005)
The model will be estimated using a Bayesian approach with
non-subjective prior distributions and implemented using WinBUGS
(Version 1.4.1) (Spiegelhalter 2004)
For review question B, detection of rifampicin resistance, if most
studies report one or two and the same threshold (the same
am-plification cycle used for detection of rifampicin resistance),
meta-analysis can also be done by using the bivariate method However,
where the studies report several different thresholds, it may be
more appropriate to use the Hierarchical Summary Receiver
Op-erating Characteristic (HSROC) model (Rutter 2001;Macaskill
2010)
We will also compare the sensitivity and specificity of Xpert MTB/
RIF with that of smear microcopy For smear microscopy, the
re-sults will be based on categorical rere-sults, either positive or negative
If most studies report one and the same threshold (for example,
smear positive is greater than or equal to one acid-fast bacillus), we
will pool results using the bivariate method, but if studies report
several different thresholds, it may be more appropriate to use the
HSROC model (Macaskill 2010;Rutter 2001)
Our approach to Xpert MTB/RIF used as an add-on test to smear
microscopy will be as follows: in patients found to be smear
neg-ative/culture positive for pulmonary TB, we will consider
sensi-tivity and specificity estimates to be a proxy for Xpert MTB/RIF
used as an add-on test to microscopy, even if the primary study
objective was not explicit for this outcome and both tests were run
concurrently
Approach to indeterminate index test results
For both review questions A and B, we will exclude indeterminate
index test results from the main analysis
For both review questions A and B, we will determine pooledestimates and the predicted interval for indeterminate index testresults
For both review questions A and B, where data are available, wewill perform sensitivity analyses to determine the potential impact
of indeterminate index test results considered to be false/true itives or false/true negatives In the discussion section, we will dis-cuss the consequences of an indeterminate index test result con-sidered to be a true negative result (may lead to missed/delayeddiagnosis, with potential for increased morbidity, mortality, and
pos-TB transmission), or considered to be true positive result (maylead to unnecessary treatment with adverse effects and increasedanxiety)
Subgroup analyses
For both review questions A and B, we will first stratify studies
by country income status (low- and middle-income versus income) We expect the majority of studies to report TP, TN, FP,and FN stratified by smear status and/or HIV status For thesesubgroups, we will compare summary estimates of accuracy inHIV infected and uninfected subgroups, and smear positive andsmear negative subgroups If there are sufficient studies, we willalso determine summary accuracy estimates for smear-negative,HIV-infected versus smear-positive, HIV-infected subgroups
vi-Review question A
Condition of specimen (categorical covariate): 1 fresh; 2 frozen
TB prevalence (categorical covariate): 1 low; 2 high
Setting in which Xpert was used (categorical covariate): 1 clinical(outpatient or inpatient); 2 laboratory
Review question B
Software version (amplification cycle thresholds of the test, chotomous): 1 Versions 1 and 2 (cycle threshold 3.5); 2 Versions
di-3 (cycle threshold 5.0) and 4
MDR-TB prevalence (categorical covariate): 1 low; 2 high
Sensitivity analyses
If sufficient studies are available, we will perform sensitivity ysis for QUADAS items to explore whether the results we foundare robust with respect to methodological quality of the studies
anal-6 Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)
Trang 9Assessment of reporting bias
Data included in this review will not allow for formal assessment
of publication bias using methods such as funnel plots or
regres-sion tests because such techniques have not been found to be
help-ful for diagnostic test accuracy studies (Tatsioni 2005 Macaskill
2010) However, being a new test for which there is going to be
considerable attention and scrutiny, we believe reporting bias will
be minimal
Other
We will summarize, if feasible, evidence on outcomes important
to Xpert users, including time to diagnosis and time to treatment
initiation We will also summarize hands-on time for specimen
processing and work-flow, instrument ease-of-use, and user
satis-faction This information will be excluded from the formal
proto-col We will address these outcomes in a section of the discussionand present summary data in additional tables In addition, if dataare available, we will prepare a qualitative description in the dis-cussion section of Xpert positive/culture negative (false positive)patients followed longitudinally, and report the number and per-cent of these patients who become culture positive during followup
A C K N O W L E D G E M E N T S
We are grateful to Vittoria Lutje, Liverpool School of TropicalMedicine, for help with the search strategy The editorial base forthe Cochrane Infectious Disease Group is funded by the Depart-ment for International Development (DFID), UK, for the benefit
of low- and middle-income countries
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