Xpert MTB/RIF test for detection of pulmonary tuberculosis ... Cochrane Review... · [Diagnostic...

Xpert 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 in The Cochrane

Library 2012, Issue 1

http://www.thecochranelibrary.com

Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iXpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)


[Diagnostic Test Accuracy Protocol]

Xpert MTB/RIF test for detection of pulmonary tuberculosisand 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 of

Epidemiology & 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. 5Life

Sciences 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. [email protected].

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:

10.1002/14651858.CD009593.


A B S T R A C T

This is the protocol for a review and there is no abstract. The objectives are as follows:

Primary objectives

Review question A: To obtain summary estimates of the diagnostic accuracy 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 diagnostic accuracy of Xpert MTB/RIF for detection of rifampicin resistance,

using solid or liquid culture as a reference standard (WHO 2008).


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 accuracy

studies.

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.

1Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance (Protocol)


mailto:[email protected]

B 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 who

has infectious active TB. Although TB most commonly affects the

lungs, any organ or tissue may be involved. Signs and symptoms of

pulmonary TB include cough for at least two weeks, fever, chills,

night sweats, weight loss, haemoptysis (coughing up blood), and

fatigue; symptoms of extrapulmonary TB depend on the site of

disease. From 1970 to 1986, wide-scale international multicen-

tre randomized controlled trials conducted by the British Medical

Research Council and its collaborators established the pivotal role

of rifampicin in TB treatment leading to modern short-course TB

therapy (Fox 1999). TB, even when resistant to rifampicin, can be

cured; 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 WHO

Expert Group and are regularly updated. The current WHO treat-

ment guidelines are based on evidence assessed according to the

GRADE (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 the

GeneXpert© platform. Xpert MTB/RIF can detect TB as well as

rifampicin resistance in less than two hours with minimal hands-

on technical time. Xpert MTB/RIF is considered to be ground-

breaking because the test comes close to meeting the niche for a

TB point-of-care test. Unlike conventional NAA tests, this test

is unique because all steps involved in the PCR are completely

automated and self-contained, allowing the technology to be taken

out of the laboratory, into the clinic setting, where it can be used

nearer to the patient (Small 2011).

Although, Xpert MTB/RIF provides testing for both M. tubercu-

losis and rifampicin resistance, it is really only one test. The test

uses five molecular beacons. Molecular beacons are nucleic acid

probes that recognize and report the presence or absence of the

normal, susceptible, ’wild type’ sequence of the RNA polymerase

(rpoB) gene of M. tuberculosis. When a beacon fluoresces or ’lights

up’, this indicates the presence of the gene sequence which is char-

acteristic of rifampicin-susceptible M. tuberculosis. The number of

positive beacons allows the test to distinguish among the following

results: ’No TB detected’ (none of the five beacons is positive);

’TB detected, rifampicin resistance detected’ (from two to four

beacons 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 and

uses the same sputum sample to provide results for both detection

of M. 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 resis-

tance testing when reporting to the healthcare provider.



The 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 of M. tuberculosis complex. In

greater than 95% of M. 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 for M. tuberculosis

DNA was found to be 4.5 genomes per PCR reaction (95% confi-

dence interval (CI) 3.3 to 9.7) and for M. 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 multicen-

tre study (Boehme 2010) and other preliminary data, reviewed by

an Expert Group (WHO 2010b). These studies showed that Xpert

MTB/RIF has a comparable level of diagnostic performance to

mycobacterial culture, even in resource-limited settings. A subse-

quent implementation study (Boehme 2011) demonstrated high

sensitivity 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 tests

have 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 of

MDR-TB or HIV-associated TB (WHO 2010b). Furthermore,

Xpert may be used as an add-on test to microscopy in settings

where 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 been

fully validated in all settings. Since the WHO’s endorsement, sev-

eral new studies have been published on Xpert MTB/RIF, and

several others are expected to be published shortly. At the time of

this writing, a systematic review on the diagnostic accuracy of this

new 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 diagnostic

accuracy of Xpert MTB/RIF for the diagnosis of pulmonary TB,

using solid or liquid culture as a reference standard.


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).


B.1 Xpert MTB/RIF as a replacement test for WHO-approved

tests 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 re-

viewed, we will extract data when present in the included accuracy

studies.



Investigation 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 negatives (TN), false positives (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

negative).

Index tests

We will include studies that evaluated the Xpert MTB/RIF assay.

Comparator tests

For review question A, we will include studies that evaluated smear

microscopy as a comparator.

Target conditions

Review question A: Active pulmonary TB.

Review question B: Rifampicin resistance.

Reference standards

Review question A: The reference standard for the diagnosis of

active 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 liquid

culture system (BACTEC 460, MGIT 960, and MGIT Manual

System, 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 lan-

guage or publication status (published, unpublished, in press, and

ongoing).

Electronic searches

To identify all relevant studies, we will search the follow-

ing databases using the search terms and strategy described

in Appendix 1: Cochrane Infectious Diseases Group Special-

ized Register; MEDLINE; EMBASE; ISI Web of Knowledge;

MEDION; LILACS; BIOSIS; and SCOPUS. We will also search

the metaRegister of Controlled Trials (mRCT) and the search por-

tal of the WHO International Clinical Trials Registry Platform (

www.who.int/trialsearch), to identify ongoing trials.

Searching other resources

We will review reference lists of included articles and any relevant

review articles identified through the above methods. We will con-

tact the test manufacturer (Cepheid Inc.) to identify unpublished

studies. We will also handsearch WHO reports on Xpert MTB/

RIF. We will contact researchers at the Foundation for Innovative

New Diagnostics (FIND), members of the Stop TB Partnership’s

New Diagnostics Working Group, and other experts in the field of

TB diagnostics for information on ongoing or unpublished stud-

ies.



http://www.who.int/trialsearch

http://www.who.int/trialsearch

Data 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 TB

incidence.

Review question A: Additional data about (a) proportion of inde-

terminate results, and (b) discordant results between Xpert MTB/

RIF and the reference standard (Xpert positive/culture negative

results) will be recorded.

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 of

tests classified as ’invalid’, error’, or ’no result’ divided by the total

number of tests performed.

Review question B: RIF indeterminate means that the M. tuber-

culosis concentration was very low and resistance could not be de-

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-TB

bacteria or fungi or 2) cross-contamination as determined after a

standard 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 or

clarifications. All data will be entered into a database manager. A

draft data extraction form is included in Appendix 2..

Assessment of methodological quality

Two reviewers will independently assess study quality with the

modified version of Quality Assessment of Diagnostic Accuracy

Studies (QUADAS) (Reitsma 2009). Items 1 to 11 from the

QUADAS list will be scored as yes, no, or unclear. Disagreements

will be resolved by discussion between the reviewers or by a third

reviewer (MP). Results will be described in the text and presented

graphically. Appendix 3 describes the criteria that need to be met

for each study to be rated as yes, no, or unclear for each of the

QUADAS items.

Statistical analysis and data synthesis

The first step in data analysis will be a descriptive analysis of the

results of the primary studies. For both review question A and

review question B, the results will be based on categorical (binary)

test results. For both review questions, the index test results are

automatically generated and the user is provided with a printable

test 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.



Descriptive analysis will be performed using Stata 2009 and 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-

ing Review 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 of M. 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 results, 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 pooled

estimates and the predicted interval for indeterminate index test

results.

For both review questions A and B, where data are available, we

will perform sensitivity analyses to determine the potential impact

of indeterminate index test results considered to be false/true pos-

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/delayed

diagnosis, with potential for increased morbidity, mortality, and

TB transmission), or considered to be true positive result (may

lead to unnecessary treatment with adverse effects and increased

anxiety).

Subgroup analyses

For both review questions A and B, we will first stratify studies

by country income status (low- and middle-income versus high-

income). We expect the majority of studies to report TP, TN, FP,

and FN stratified by smear status and/or HIV status. For these

subgroups, we will compare summary estimates of accuracy in

HIV infected and uninfected subgroups, and smear positive and

smear negative subgroups. If there are sufficient studies, we will

also determine summary accuracy estimates for smear-negative,

HIV-infected versus smear-positive, HIV-infected subgroups.

Investigations of heterogeneity

Heterogeneity between diagnostic accuracy studies is to be ex-

pected (Harbord 2007). Initially, heterogeneity will be addressed

by pre-specifying subgroups. We will assess heterogeneity by vi-

sual inspection of forest plots. We will further investigate potential

sources of heterogeneity by adding covariates in the models. All

covariates will be study level, dichotomous.

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, di-

chotomous): 1. Versions 1 and 2 (cycle threshold 3.5); 2. Versions

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 anal-

ysis for QUADAS items to explore whether the results we found

are robust with respect to methodological quality of the studies.



Assessment 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 discussion

and present summary data in additional tables. In addition, if data

are 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 follow

up.

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 Tropical

Medicine, for help with the search strategy. The editorial base for

the Cochrane Infectious Disease Group is funded by the Depart-

ment for International Development (DFID), UK, for the benefit

of low- and middle-income countries.

R E F E R E N C E S

Additional references

Armand 2011

Armand S, Vanhuls P, Delcroix G, Courcol R, Lemaitre

N. Comparison of the Xpert MTB/RIF test with an

IS6110-TaqMan real-time PCR assay for direct detection of

Mycobacterium tuberculosis in respiratory and nonrespiratory

specimens. Journal of Clinical Microbiology 2011;49(5):

1772–6.

Balshem 2010

Balshem H, Helfand M, Schunemann HJ, Oxman AD,

Kunz R, Brozek J, et al.GRADE guidelines: 3. Rating the

quality of evidence. Journal of Clinical Epidemiology 2010;

64(4):401–6.

Banada 2010

Banada PP, Sivasubramani SK, Blakemore R, Boehme C,

Perkins MD, Fennelly K, et al.Containment of bioaerosol

infection risk by the Xpert MTB/RIF assay and its

applicability to point-of-care settings. Journal of Clinical

Microbiology 2010;48(10):3551–7.

Blakemore 2010

Blakemore R, Story E, Helb D, Kop J, Banada P, Owens

MR, et al.Evaluation of the analytical performance of the

Xpert MTB/RIF assay. Journal of Clinical Microbiology

2010;48(7):2495–501.

Boehme 2010

Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S,

Krapp F, et al.Rapid molecular detection of tuberculosis and

rifampin resistance. New England Journal of Medicine 2010;

363:1005–15.

Boehme 2011

Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo

E, Tahirli R, et al.Feasibility, diagnostic accuracy, and

effectiveness of decentralised use of the Xpert MTB/RIF

test for diagnosis of tuberculosis and multidrug resistance: a

multicentre implementation study. Lancet 2011;377(9776):

1495–505.

Canetti 1963

Canetti G, Froman S, Grosset J, Hauduroy P, Langerova M,

Mahler HT, et al.Mycobacteria: Laboratory methods for

testing drug sensitivity and resistance. Bulletin of the World

Health Organization 1963;29:565–78.

Ciftci 2011

Ciftci IH, Aslan MH, Asik G. Evaluation of Xpert MTB/

RIF results for the detection of Mycobacterium tuberculosis

in clinical samples. Mikrobiyoloji Bulteni 2011;45(1):43–7.

Dye 2010

Dye C, Williams BG. The population dynamics and control

of tuberculosis. Science 2010;328(5980):856–61.

Fendall 1972

Fendall NR. Auxiliaries and primary medical care. Bulletin

of the New York Academy of Medicine 1972;48(10):

1291–300.

Flores 2005

Flores LL, Pai M, Colford JM Jr, Riley LW. In-house nucleic

acid amplification tests for the detection of Mycobacterium

tuberculosis in sputum specimens: meta-analysis and meta-

regression. BMC Microbiology 2005;5:55.

Foundation

Foundation for Innovative Diagnostics. Automated

molecular detection in 90 minutes for tuberculosis

and rifampicin resistance. Available from http://

www.finddiagnostics.org/export/sites/default/media/press/pdf/

XpertTB_factsheet.pdf (accessed 7 March 2011).

Fox 1999

Fox W, Ellard G A, Mitchison D A. Studies on the

treatment of tuberculosis undertaken by the British Medical



Research Council tuberculosis units, 1946-1986, with

relevant subsequent publications. International Journal of

Tuberculosis and Lung Disease 1999;3(10 Suppl 2):S231–79.

Gatsonis 2006

Gatsonis C, Paliwal P. Meta-analysis of diagnostic and

screening test accuracy evaluations: methodologic primer.

American Journal of Roentgenology 2006;187(2):271–81.

Getahun 2007

Getahun H, Harrington M, O’Brien R, Nunn P. [Diagnosis

of smear–negative pulmonary tuberculosis in people with

HIV infection or AIDS in resource–constrained settings:

informing urgent policy changes]. Lancet 2007;369(9578):

2042–9.

Greco 2006

Greco S, Girardi E, Navarra A, Saltini C. Current evidence

on diagnostic accuracy of commercially based nucleic

acid amplification tests for the diagnosis of pulmonary

tuberculosis. Thorax 2006;61(9):783–90.

Guyatt 2008

Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE,

Liberati A, et al.Going from evidence to recommendations.

BMJ 2008;336(7652):1049–51.

Harbord 2007

Harbord RM, Deeks JJ, Egger M, Whiting P, Sterne JA.

A unification of models for meta-analysis of diagnostic

accuracy studies. Biostatistics 2007;8(2):239–51.

Harries 2004

Harries A. [16. How does the diagnosis of tuberculosis in

persons infected with HIV differ from diagnosis in persons

not infected with HIV?]. In: Frieden T editor(s). Toman’s

Tuberculosis. Case detection, treatment and monitoring -

questions and answers. 2nd Edition. Geneva: World Health

Organization, 2004:80–3.

Helb 2009

Helb D, Jones M, Story E, Boehme C, Wallace E, Ho K,

et al.Rapid detection of Mycobacterium tuberculosis and

rifampin resistance by use of on-demand, near-patient

technology. Journal of Clinical Microbiology 2009;48(1):

229–37.

Hesseling 2011

Hesseling AC, Graham SM, Cuevas LE. Rapid molecular

detection of tuberculosis. New England Journal of Medicine

2011;364(2):183–5.

Hillemann 2011

Hillemann D, Ruesch-Gerdes S, Boehme C, Richter E.

Rapid molecular detection of extrapulmonary tuberculosis

by automated GeneXpert(R) MTB/RIF system. Journal of

Clinical Microbiology 2011;49(4):1202–5.

Laszlo 1997

Laszlo A, Rahman M, Raviglione M, Bustreo F. Quality

assurance programme for drug susceptibility testing

of Mycobacterium tuberculosis in the WHO/IUATLD

Supranational Laboratory Network: first round of

proficiency testing. International Journal of Tuberculosis and

Lung Disease 1997;1(3):231–8.

Leeflang 2008

Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM.

Systematic reviews of diagnostic test accuracy. Annals of

Internal Medicine 2008;149(12):889–97.

Lijmer 2002

Lijmer JG, Bossuyt PM, Heisterkamp SH. Exploring

sources of heterogeneity in systematic reviews of diagnostic

tests. Statistics in Medicine 2002;21(11):1525–37.

Ling 2008

Ling DI, Flores LL, Riley LW, Pai M. Commercial

nucleic-acid amplification tests for diagnosis of pulmonary

tuberculosis in respiratory specimens: meta-analysis and

meta-regression. PLoS One 2008;3(2):e1536.

Macaskill 2010

Macaskill P, Gatsonis C, Deeks JJ, Harbord RM, Y

Takwoingi. [Chapter 10: Analysing and Presenting Results.

In: Deeks JJ, Bossuyt PM, C Gatsonis (editors). Cochrane

Handbook for Systematic Reviews of Diagnostic Test

Accuracy Version 1.0. The Cochrane Collaboration 2010].

Available from http://srdta.cochrane.org/.

Malbruny 2011

Malbruny B, Le Marrec G, Courageux K, Leclercq R,

Cattoir V. Rapid and efficient detection of Mycobacterium

tuberculosis in respiratory and non-respiratory samples.

International Journal of Tuberculosis and Lung Disease 2011;

15(4):553–5.

Marais 2010

Marais BJ, Gupta A, Starke JR, El Sony A. Tuberculosis in

women and children. Lancet 2010;375(9731):2057–9.

Marais 2010a

Marais BJ, Schaaf HS. Childhood tuberculosis: an emerging

and previously neglected problem. Infect Disease Clinics of

North America 2010;24(3):727–49.

Marlowe 2011

Marlowe EM, Novak Weekley SM, Cumpio J, Sharp

SE, Momeny MA, Babst A, et al.Evaluation of the

Cepheid Xpert MTB/RIF assay for the direct detection

of Mycobacterium tuberculosis complex from respiratory

specimens. Journal of Clinical Microbiology 2011;49(4):

1621–3.

Moher 2009

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred

reporting items for systematic reviews and meta-analyses:

the PRISMA statement. PLoS Medicine 2009;6(7):

e1000097.

Moure 2011

Moure R, Munoz L, Torres M, Santin M, Martin R, Alcaide

F. Rapid detection of Mycobacterium tuberculosis complex

and rifampin resistance in smear-negative clinical samples

by use of an integrated real-time PCR method. Journal of

Clinical Microbiology 2011;49(3):1137–9.

Mugusi 2006

Mugusi F, Villamor E, Urassa W, Saathoff E, Bosch RJ,

Fawzi WW. HIV co-infection, CD4 cell counts and clinical

correlates of bacillary density in pulmonary tuberculosis.



International Journal of Tuberculosis and Lung Disease 2006;

10(6):663–9.

Pai 2004

Pai M, McCulloch M, Enanoria W, Colford JM Jr.

Systematic reviews of diagnostic test evaluations: what’s

behind the scenes?. ACP Journal Club 2004;141(1):A11–3.

Pai 2010

Pai M, Minion J, Steingart K, Ramsay A. New and improved

tuberculosis diagnostics: evidence, policy, practice, and

impact. Current Opinion in Pulmonary Medicine 2010;16

(3):271–84.

Pai 2010a

Pai M, Minion J, Steingart K, Ramsay A. New and improved

tuberculosis diagnostics: evidence, policy, practice, and

impact. Current Opinion in Pulmonary Medicine 2010;16

(3):271–84.

Perkins 2002

Perkins MD, Kritski AL. Diagnostic testing in the control

of tuberculosis. Bulletin of the World Health Organization

2002;80(6):512–3.

Perkins 2006

Perkins MD, Small PM. Admitting defeat. International

Journal of Tuberculosis and Lung Disease 2006;10(1):1.

Perkins 2007

Perkins MD, Cunningham J. Facing the crisis: improving

the diagnosis of tuberculosis in the HIV era. Journal of

Infectious Disease 2007;196(Suppl 1):S15–27.

Raja 2005

Raja S, Ching J, Xi L, Hughes SJ, Chang R, Wong W,

et al.Technology for automated, rapid, and quantitative

PCR or reverse transcription-PCR clinical testing. Clinical

Chemistry 2005;51(5):882–90.

Ramsay 2010

Ramsay A, Steingart KR, Pai M. Assessing the impact of new

diagnostics on tuberculosis control. International Journal of

Tuberculosis and Lung Disease 2010;14(12):1506–7.

Reitsma 2005

Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt

PM, Zwinderman AH. Bivariate analysis of sensitivity and

specificity produces informative summary measures in

diagnostic reviews. Journal of Clinical Epidemiology 2005;

58(10):982–90.

Reitsma 2009

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. The Cochrane Collaboration

2010. Available from: http://srdta.cochrane.org/.

Review Manager 5

The Nordic Cochrane Centre, The Cochrane Collaboration.

Review Manager (RevMan). 5.0. Copenhagen: The Nordic

Cochrane Centre, The Cochrane Collaboration, 2008.

Rutter 2001

Rutter CM, Gatsonis CA. A hierarchical regression approach

to meta-analysis of diagnostic test accuracy evaluations.

Statistics in Medicine 2001;20(19):2865–84.

Schünemann 2008

Schünemann HJ, Oxman AD, Brozek J, Glasziou P,

Jaeschke R, Vist GE, et al.Grading quality of evidence

and strength of recommendations for diagnostic tests and

strategies. BMJ 2008;336(7653):1106–10.

Schünemann 2011

Schünemann HJ, Oxman AD, Gunn EV, Higgins JPT,

Deeks JL, Glasziou P, et al.[Chapter 11. Presenting results

and “Summary of findings” tables. In: Higgins JPT, Green

S (editors). Cochrane Handbook for Systematic Reviews of

Interventions Version 5.0.2. The Cochrane Collaboration

2011]. Available from www.cochrane-handbook.org.

Small 2011

Small PM, PaiM. Tuberculosis diagnosis--time for a game

change. New England Journal of Medicine 2011;363(11):

1070–1.

Spiegelhalter 2004

Spiegelhalter D, Thomas A, Best N, Lunn D. WinBUGS

user manual, Version 1.4.1. Available from http://www.mrc-

bsu.cam.ac.uk/bugs.

Stata 2009

StataCorp. Stata Statistical Software: Release 11. College

Station, TX: StataCorp LP, 2009.

Steingart 2006

Steingart KR, Ng V, Henry M, Hopewell PC, Ramsay

A, Cunningham J, et al.Sputum processing methods to

improve the sensitivity of smear microscopy for tuberculosis:

a systematic review. Lancet Infectious Disease 2006;6(10):

664–74.

Steingart 2007

Steingart KR, Henry M, Laal S, Hopewell P C, Ramsay

A, Menzies D, et al.A systematic review of commercial

serological antibody detection tests for the diagnosis of

extrapulmonary tuberculosis. Thorax 2007;62(10):911–8.

Tatsioni 2005

Tatsioni A, Zarin DA, Aronson N, Samson DJ, Flamm

CR, Schmid C, et al.Challenges in systematic reviews of

diagnostic technologies. Annals of Internal Medicine 2005;

142(12 Pt 2):1048–55.

Telenti 1993

Telenti A, Imboden P, Marchesi F, Lowrie D, Cole S,

Colston M J, et al.Detection of rifampicin-resistance

mutations in Mycobacterium tuberculosis. Lancet 1993;341

(8846):647–50.

Traore 2000

Traore H, Fissette K, Bastian I, Devleeschouwer M, Portaels

F. Detection of rifampicin resistance in Mycobacterium

tuberculosis isolates from diverse countries by a commercial

line probe assay as an initial indicator of multidrug

resistance. International Journal of Tuberculosis and Lung

Disease 2000;4(5):481–4.



Van Rie 2010

Van Rie A, Page-Shipp L, Scott L, Sanne I, Stevens W. Xpert

((R)) MTB/RIF for point-of-care diagnosis of TB in high-

HIV burden, resource-limited countries: hype or hope?.

Expert Review of Molecular Diagnostics 2010;10(7):937–46.

Whiting 2003

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 Medical Research Methodology

2003;3:25.

WHO 2008

World Health Organization. Policy guidance on drug-

susceptibility testing (DST) of second-line antituberculosis

drugs. Available at http://www.who.int/tb/publications/

2008/whohtmtb_2008_392/en/index.html.. Geneva:

WHO, 2008.

WHO 2009

World Health Organization. Treatment of tuberculosis:

guidelines - 4th edition. Available at http://

whqlibdoc.who.int/publications/2010/9789241547833_

eng.pdf.. Geneva: World Health Organization, 2009

(accessed 8 June 2011).

WHO 2010

[World Bank List of Economies]. Available: http:

//siteresources.worldbank.org/DATASTATISTICS/

Resources/CLASS.XLS. 2010 (accessed 7 June 2011).

WHO 2010a

World Health Organization. Global tuberculosis control:

WHO report 2010. Geneva: World Health Organization,

2010; Vol. WHO/HTM/TB/2010.7.

WHO 2010b

World Health Organization. Roadmap for rolling out

Xpert MTB/RIF for rapid diagnosis of TB and MDR-TB.

Available at http://www.who.int/tb/laboratory/roadmap_

xpert_mtb-rif.pdf 2010 (accessed 6 March 2011).

WHO 2010c

World Health Organization. Multidrug and extensively

drug-resistant TB (M/XDR-TB): 2010 global report on

surveillance and response.. 2010;WHO/HTM/TB/2010.3.

WHO 2010d

World Health Organization. WHO endorses new rapid

tuberculosis test.. Available at http://www.who.int/tb/

features_archive/new_rapid_test/en/index.html 2010 (accessed

7 March 2011).

WHO 2011

World Health Organization. Rapid implementation of the

Xpert MTB/RIF diagnostic test. Technical and Operational

“How-to” Practical Considerations. Available at http://

whqlibdoc.who.int/publications/2011/9789241501569_

eng.pdf 2011.

WHO 2011a

World Health Organization. Global tuberculosis control:

WHO report. WHO; Geneva 2011:WHO/HTM/TB/

2011.16.∗ Indicates the major publication for the study

A P P E N D I C E S

Appendix 1. Detailed search strategies

1. Xpert*.tw .

2. GeneXpert*.tw.

3. Cepheid.tw.

4. near* patient ti, ab

5. or 1-4

6. Tuberculosis/

7. exp Tuberculosis, Pulmonary/

8. exp Tuberculosis, Multidrug-Resistant/

9. Mycobacterium tuberculosis/

10. TB.tw.

11. tuberculosis.tw.

12. or/6-11

13. 5 and 12

14. limit 13 to yr=“2007 -Current”



This is the preliminary search strategy for MEDLINE. It will adapted for other electronic databases. All search strategies will be reported

in full in the final version of the review.

Appendix 2. Data extraction form

ID

ID substudy (for site-specific data: a, b, c, etc)

First Author

Corresponding author & email

Was author contacted? 1 - Yes

2 - No

If yes, dates(s)

Title

Year (of publication)

Year (study start date)

Language 1 - English

2 - Other

If other, specify:

Was the study conducted without industry sponsorship? 1 - Yes

2 - No

9 - Unk/NR

If industry sponsorship was present, select one item from the list Select one: answers ordered from least to most industry involve-

ment:

Donation of Xpert® for use in study

Xpert® at a special preferred price

Receipt of educational support, grants, or speaking fees

Financial relationship - author is employee/consultant/stock-

holder

Involvement in design, analysis, or manuscript production

Study addresses question A (detection of MTB) and/or B (detec-

tion of RIF resistance)?

1 - A

2 - B

3 - A and B

What was the purpose of this study? * if smear results are stratified,

indicate #3

1 - Only accuracy of Xpert as replacement test for microscopy?

2 - Only accuracy of Xpert as add-on test to microscopy

(include studies that evaluate incremental value of Xpert to the

index test)?

3 - Both purposes, 1 and 2



(Continued)

4 - Unclear/could not tell

For review question A, what reference standard was used? 1 - Solid Culture

(specify 1a)

2 - Liquid Culture

(specify 2a)

3 - Both Solid & Liquid Culture (specify 1a & 2a)

9 - Unk/NR

1a - Solid Culture

LJ

7H10

7H11

Other

2a - Liquid Culture

MGIT960

Bactec460

Other

For review question B, what reference standard was used? 1 - Solid Culture

(specify 1a)

2 - Liquid Culture

(specify 2a)

3 - Both Solid & Liquid Culture (specify 1a & 2 a)

9 - Unk/NR

1a - Solid Culture

LJ

7H10

7H11

Other

2a - Liquid Culture

MGIT960

Bactec460

Other

Review question A: smear status 1 - Positive only

2 - Negative only

3 - Both smear negative & smear positive

9 - Unk/NR

Clinical setting; describe as written in the paper 1 - Outpatient

2- Inpatient

3 - Both out- and in-patient

4 - Other, specify

5 - Laboratory

9 - Unk/NR

Also describe as in paper:



(Continued)

Country where study was conducted

Case country World Bank Classification 1 - Middle/Low

2 - High

3 - Both middle/low and high

Study design 1 - Randomized Trial

2 - Cross-sectional

3 - Cohort

4 - Other, specify

9 - Unk/NR

If other, specify:

Participant selection 1 - Consecutive

2 - Random

3 - Convenience

7 - Other

9 - NR/Unclear

Direction of study data collection 1 - Prospective

2 - Retrospective

9 - Unk/NR

Comments about study design

Number after screening by exclusion & inclusion criteria 9 - Unk/NR

Number included in analysis (# screened - # withdrawals) 9 - Unk/NR

Did study include treated patients? 1 - Yes

2 - No

9 - Unk/NR

If yes, percentage treated patients included %

Unit of analysis 1 - Patient

2 - Specimen

9 - NR/Unclear

Describe as in paper, if unclear:

Prior testing by microscopy for triage

Review question A

1 - Yes

2 - No

9 - Unk/NR

Has the study included patients with previous TB history? 1 - Yes

2 - No



(Continued)

9 - Unk/NR

If so, what is the percentage? %

Specify numerator/denominator

HIV status of participants 0 - HIV -

1 - HIV +

2 - Both HIV+/-

9 - Unk/NR

If HIV-positive participants included, what is the percentage? %

Specify numerator/denominator

Type of specimen (may include expectorated, induced, bronchial

alveolar lavage (BAL), tracheal aspirates, gastric aspirates)

1 - All expectorated

2 - All induced

3 - All BAL

4 - Multiple types

5 - Other

9 - Unk/NR

If 4 or 5, describe types and record numbers:

Were Xpert sample and culture obtained from same specimen? 1 - Yes

2 - No

9 - Unk/NR

Number of cultures used to exclude TB 1 - One

2 - Two

3 - Three

4 - Four

5 - Other, specify

9 - Unk/NR

Specify, if > 4:

NOTES:

Pre-treatment processing procedure for Xpert 1 - None

2 - NALC-NaOH

3 - NaOH (Petroff )

4 - Other

9 - Unk/NR

Was microscopy used 1 - Yes

2 - No

9 - Unk/NR

Type of microscopy used 1 - Ziehl-Neelsen

2 - FM

9 - Unk/NR



(Continued)

Smear type 1 - Direct

2 - Concentrated (processed)

9 - Unk/NR

Minimum number of sputum specimens used to determine smear

positivity

1 - One

2 - Two

3 - Three

4 - >3

9 - Unk/NR

How was a positive smear defined? (if guideline referenced, look

up guideline)

≥˙˙˙˙bacilli per˙˙˙˙ high power fields

9 - Unk/NR

* complete both fields

For Xpert specimen, what was the condition of the specimen when

tested?

1 - Fresh

2 - Frozen

9 - Unk/NR

If fresh, specify: 1 - Tested after storage at room temperature or refrigerated w/in

48 hours of collection

2 - Tested after storage at room temperature or refrigerated >48

hours of collection

9 - Unk/NR

If frozen, specify: 1 - Tested after frozen < 1 year of storage

2 - Tested frozen ≥ 1 year of storage

9 - Unk/NR

Version of software for test interpretation 1 - Version 1

2 - Version 2

3 - Version 3

4 - Version 4

9 - Unk/NR

Enter percentage contaminated cultures, if provided:

# of contaminated culture

Total # cultures performed

˙˙˙˙˙˙˙˙˙˙˙˙˙

9 - Unk/NR

Were indeterminate results reported? Review question A 1 - Yes

2 - No

9 - Unk/NR

Were indeterminate results reported? Review question B 1 - Yes

2 - No

9 - Unk/NR



(Continued)

Were patient important outcomes evaluated 1 - Yes

2 - No

9 - Unk/NR

Time to diagnosis Xpert:

Culture:

9 - Unk/NR

Time to treatment initiation Xpert:

Culture:

9 - Unk/NR

Other patient outcomes Specify:

TABLES

Question A: MTB Detection, Overall

* Only extract if not reporting by smear status

Definite TB

Yes No Total

Index Test Result Positive

Negative

Total

Indeterminate

Question A: MTB Detection, Smear

Positive

Definite TB

Yes No Total


Negative

Total

Indeterminate



Question A: MTB Detection, Smear

Negative

Confirmed TB

Yes No Total


Negative

Total

Indeterminate

Question A: MTB Detection, Culture

Negative

Probable TB*

Yes No Total


Negative

Total

Indeterminate

* Clinical TB (describe criteria used by authors)

Question A: MTB Detection,

HIV Positive

Definite TB

Yes No Total


Negative

Total

Indeterminate



Question A: MTB Detection,

HIV Negative

Definite TB

Yes No Total


Negative

Total

Indeterminate

Question B: RIF Resistance Confirmed rifampicin resistance

Yes No Total

Index Test Result Yes (resistant)

No (susceptible)

Total

Indeterminate

Discrepant analysis

Comments:

Criteria Number

Xpert+/culture - baseline

Deemed TB after further evaluation

Percent found to be TB on discrepant anal-

ysis

* Follow-up test included, circle all that apply

** Repeat culture, DNA sequencing, GenoType® MTBDRplus test, other, describe



Question A: MTB Detection

Direct comparison with

microscopy

Definite TB

Yes No Total

Microscopy Result Positive

Negative

Total

Appendix 3. Assessment of methodological quality

Quality Item How to Score

Was the spectrum of patients representative of the patients who

will receive the test in practice?

Answer separately for review question A and B.

Review question A: Yes if persons suspected of having pulmonary

TB were consecutively or randomly enrolled in an outpatient set-

ting

No if patient sample is unrepresentative of spectrum of patients

with pulmonary TB

Unclear if patient characteristics or setting are inadequately de-

scribed

Review question B: Yes, if persons suspected of having pulmonary

TB were consecutively enrolled in an outpatient setting or persons

suspected of MDR-TB who presented for resistance detection

No if patients were not consecutively or randomly enrolled.

Unclear if patient characteristics or setting are inadequately de-

scribed

Acceptable reference standard? Yes for all studies. Review question A: The reference standard for

detection of pulmonary TB is culture, solid or liquid. Although

imperfect (culture may miss culture-negative TB cases), mycobac-

terial culture is considered to be the optimal reference standard

for pulmonary TB and is a criterion for inclusion of studies in the

review

Review question B: The reference standard for rifampicin suscep-

tibility testing is 1) solid culture or 2) a commercial liquid culture

system (BACTEC 460, MGIT 960, and MGIT Manual System,

Becton Dickinson, USA; BacT/ALERT MP, Biomerieux, France;

VersaTREK, Trek Diagnostic Systems, USA)

Acceptable delay between tests? Yes if index test and reference standards are collected on the same

patients at the same time or within 30 days of each other. (Ideally



(Continued)

specimens for Xpert and culture are collected on the same patients

at the same time. However, if this is not possible and a delay of

several weeks occurs between results, misclassification is unlikely,

as TB is a chronic disease and little change in disease status is

expected during this time)

No if the time period between index test and reference standard

collection is > 30 days

Unclear if the time period between index test and reference stan-

dard collection is not described

Partial verification avoided? Yes if all participants who received Xpert also received the reference

test

No if not all participants received both index and reference tests

Unclear if not enough information is provided.

Differential verification avoided? Yes if all participants received the same reference test regardless of

Xpert results

No if different reference tests were used depending on Xpert results

Unclear if not enough information is provided for judgment.

Incorporation avoided Yes for all studies. Xpert does not form part of the reference stan-

dard for studies in this review

Were the reference standard results interpreted without knowledge

of Xpert results

Answer separately for review question A and B.

Yes if stated that the person reading the reference test result did

not know the results of Xpert or if the two tests were carried out

in different places

No if stated that the same person performed both tests or Xpert

results were known to the person undertaking the reference test


Were the Xpert results interpreted without knowledge of reference

standard results

Yes for all studies. Xpert is a fully automated system that provides

a print out of test results

Relevant clinical information Yes for all studies. In this review the availability or absence of clin-

ical information such as age and presence and severity of symp-

toms should not affect test performance for the index test (fully

automated system) or reference standard

Were uninterpretable results reported? Answer separately for review question A and B.

Yes if the numbers in 2x2 table = number enrolled or if explanation

is provided for any discrepancy

No if the numbers in 2x2 table number enrolled and there is

insufficient explanation as to why


Withdrawals explained? Yes if a flow diagram or statement was included making it clear

what happened to all participants in the study

No if participants are excluded and no reason is provided.



(Continued)


H I S T O R Y

Protocol first published: Issue 1, 2012

C O N T R I B U T I O N S O F A U T H O R S

MP had the original idea for the review. The protocol was written by KRS and MP, with input from HS and ND. The search strategy

was written by LAK. HS and KRS will review articles for relevance, and extract and analyse data. HS, MP, ND, CCB, and KRS will

interpret data and write the manuscript.

D E C L A R A T I O N S O F I N T E R E S T

KRS serves as Co-ordinator of the Evidence Synthesis and Policy Subgroup of Stop TB Partnership’s New Diagnostics Working Group.

MP is a recipient of a New Investigator Award from the Canadian Institutes of Health Research (CIHR). MP serves as an external

consultant for the Bill & Melinda Gates Foundation. CCB is employed by the Foundation for Innovative New Diagnostics FIND) and

has conducted studies and published on Xpert MTB/RIF as part of a collaborative project between FIND, a Swiss non-profit, Cepheid,

a US company, and academic partners. The product developed through this partnership was developed under a contract that obligated

FIND to pay for development costs and trial costs and that obligated Cepheid to make the test available at specified preferential pricing

to the public sector in developing countries. The authors have no financial involvement with any organization or entity with a financial

interest in or financial conflict with the subject matter or materials discussed in the protocol apart from those disclosed.



Xpert MTB/RIF test for detection of pulmonary tuberculosis ... Cochrane Review... · [Diagnostic...

Documents

Transcript of Xpert MTB/RIF test for detection of pulmonary tuberculosis ... Cochrane Review... · [Diagnostic...