Diagnostic Test Accuracy Review

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Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults

  1. Karen R Steingart1,*,
  2. Ian Schiller2,
  3. David J Horne3,
  4. Madhukar Pai4,
  5. Catharina C Boehme5,
  6. Nandini Dendukuri4

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 21 JAN 2014

Assessed as up-to-date: 7 FEB 2013

DOI: 10.1002/14651858.CD009593.pub3


How to Cite

Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD009593. DOI: 10.1002/14651858.CD009593.pub3.

Author Information

  1. 1

    Liverpool School of Tropical Medicine, Cochrane Infectious Diseases Group, Liverpool, UK

  2. 2

    McGill University Health Centre, Department of Clinical Epidemiology, Montreal, QC, Canada

  3. 3

    University of Washington, Division of Pulmonary and Critical Care Medicine, Seattle, WA, USA

  4. 4

    McGill University, Department of Epidemiology, Biostatistics and Occupational Health, Montreal, QC, Canada

  5. 5

    Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland

*Karen R Steingart, Cochrane Infectious Diseases Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK. karen.steingart@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions), comment added to review
  2. Published Online: 21 JAN 2014

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Characteristics of included studies [ordered by study ID]
Al-Ateah 2012

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of participants, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Not stated

Age: Not stated

Sex, female: 46.2%

HIV infection: 0.6%

History of TB: Not stated

Sample size: 172

Clinical setting: Laboratory-based evaluation of respiratory specimens

Laboratory level: Intermediate

Country: Saudi Arabia

World Bank Income Classification: High-income

TB incidence rate: 17 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.8% (Source: Nationwide survey 2010) and among retreatment cases = 16% (Source: Nationwide survey 2010)

Proportion of TB cases in the study: 25.6%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Processed

Xpert MTB/RIF version: Not stated


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesThe majority of specimens were obtained from bronchoalveolar lavage


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
High

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Balcells 2012

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Patients who fulfilled at least one of the following criteria: cough (> 10 days), bloody sputum, pneumonia unresponsive to previous antibiotics, fever (> 10 days), abnormal CXR or weight loss

Age: Mean 37.4 years (range 19 to 65)

Sex, female: 20.6%

HIV infection: 100%

History of TB: 11.8%

Sample size: 160

Clinical setting: Five hospitals and their respective HIV clinics

Laboratory level: Intermediate

Country: Chile

World Bank Income Classification: Middle-income

TB incidence rate: 18 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.7% (Source: Nationwide survey 2001) and among retreatment cases = 3.2% (Source: Nationwide surveillance 2011)

Proportion of TB cases in the study: 7.5%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Processed

Xpert MTB/RIF version: 2 and 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Barnard 2012

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Not stated

Age: Predominantly adult, median age 41

Sex, female: 43.6%

HIV infection: Not stated

History of TB: 100%

Sample size: 68

Clinical setting: Laboratory-based evaluation of clinical specimens from previously treated patients

Laboratory level: Intermediate

Country: South Africa, Cape Town

World Bank Income Classification: Middle-income

TB incidence rate: per 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Survey in Western Cape Province, 2002) and among retreatment cases = 4.0% (Source: Survey in Western Cape Province, 2002)

Proportion of TB cases in the study: 76.5%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Processed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960


Flow and timing


Comparative


NotesFifteen patients submitted specimens for treatment monitoring, not diagnosis; three patients were 5, 7, and 10 years of age; all other patients were 16 years of age or older; according to GenoType MTBDRplus (v1.0) assay as the reference standard, Xpert MTB/RIF sensitivity and specificity for rifampicin resistance detection were 100% (based on three rifampicin resistant samples; 33 rifampicin susceptible samples).


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Boehme 2010a

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Persistent productive cough for ≥ two weeks

Age: Median 37 years; range 20 to 69 years

Sex, female: 0%

HIV infection: 4.7%

History of TB: 54.6%

Sample size: 216

Clinical setting: Special treatment facility for prisoners, high MDR-TB setting

Laboratory level: Central

Country: Azerbaijan

World Bank Income Classification: Middle-income

TB incidence rate: 113 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 22% (Source: survey in Baku City, 2007) and among retreatment cases = 56% (Source: survey in Baku City, 2007)

Proportion of TB cases in study centre: 68.1%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


NotesWomen were not included, but otherwise considered representative spectrum

Data for one specimen per patient were provided by the study author


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?No
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Boehme 2010b

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Persistent productive cough for ≥ two weeks

Age: Median 31 years; range 18 to 79 years

Sex, female: 43.3%

HIV infection: 1.7%

History of TB: 23.7%

Sample size: 310

Clinical setting: Primary health care DOTS (directly observed treatment, short-course) centres in shanty towns

Laboratory level: Intermediate

Country: Peru

World Bank Income Classification: Middle-income

TB incidence rate: 101 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 5.3% (Source: Nationwide survey 2006) and among retreatment cases = 24% (Source: Nationwide survey 2006)

Proportion of TB cases in study centre: 67.4%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


NotesData for one specimen per patient were provided by the study author


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Boehme 2010c

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Persistent productive cough for ≥ two weeks

Age: Median 36 years; range 18 to 80 years

Sex, female: 34.1%

HIV infection: 76.1%

History of TB: 43.0%

Sample size: 332

Clinical setting: Clinic, high HIV setting

Laboratory level: Intermediate

Country: South Africa, Cape Town

World Bank Income Classification: Middle-income

TB incidence rate: per 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Survey in Western Cape Province, 2002) and among retreatment cases = 4.0% (Source: Survey in Western Cape Province, 2002)

Proportion of TB cases in study centre: 44.0%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rfiampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesData for one specimen per patient were provided by the study author


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Boehme 2010d

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Persistent productive cough for ≥ two weeks

Age: Median 32 years; range 18 to 68 years

Sex, female: 59.4%

HIV infection: 71.4%

History of TB: 45.1%

Sample size: 261

Clinical setting: TB clinics, high HIV setting

Laboratory level: Central

Country: South Africa, Durban

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.7% (Source: Survey in Kwazulu-Natal Province, 2002) and among retreatment cases = 7.7% (Source: Survey in Kwazulu-Natal Province, 2002)

Proportion of TB cases in study centre: 16.5%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Middlebrook 7H11 culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


NotesData for one specimen per patient were provided by the study author


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?No
Were all patients included in the analysis?Yes

Boehme 2010e

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Persistent productive cough for ≥ two weeks

Age: Median 30 years; range 17 to 88 years

Sex, female: 39.1%

HIV infection: 4.4%

History of TB: 75.2%

Sample size: 222

Clinical setting: Tertiary hospital, high MDR-TB setting

Laboratory level: Intermediate

Country: India

World Bank Income Classification: Middle-income

TB incidence rate: 181 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.1% (Source: Survey in Andhra Pradesh, 2009) and among retreatment cases = 12% (Source: Survey in Andhra Pradesh, 2009)

Proportion of TB cases in study centre: 84.2%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesData for one specimen per patient were provided by the study author


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?No
Were all patients included in the analysis?Yes

Boehme 2011a

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least two weeks

Age: Median 36 years; IQR 30 to 44 years

Sex, female: < 1%

HIV infection: < 1%

History of TB: Not stated

Sample size: 536 for detection of MTB; 211 for detection of rifampicin resistance

Clinical setting: MDR-TB screening facility

Laboratory level: Intermediate

Country: Azerbaijan

World Bank Income Classification: Middle-income

TB incidence rate: 113 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 22% (Source: survey in Baku City, 2007) and among retreatment cases = 56% (Source: survey in Baku City, 2007)

Proportion of TB cases in study centre: 42.7%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesFollow-up reported for all sites combined: 24/153 patients with culture-negative, clinically diagnosed TB had positive results on MTB/RIF testing. 20/24 patients had follow-up, and all 20 improved on TB treatment


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Boehme 2011b

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least two weeks

Age: Median 37 years; IQR 26 to 53 years

Sex, female: 49%

HIV infection: < 1%

History of TB: Not stated

Sample size: 1005 for detection of TB; 185 for detection of rifampicin resistance

Clinical setting: Two health centres and one district hospital

Laboratory level: Intermediate

Country: Peru

World Bank Income Classification: Middle-income

TB incidence rate: 101 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 5.3% and among retreatment cases = 23.6% (Source: Nationwide survey, 2006)

Proportion of TB cases in study centre: 17.6%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesFollow-up was reported for all sites combined, see Boehme 2011a


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Boehme 2011c

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least two weeks

Age: Median 36 years; IQR 29 to 46 years

Sex, female: 49%

HIV infection: 38%

History of TB: Not stated

Sample size: 904 for detection of TB; 188 for detection of rifampicin resistance

Clinical setting: One health centre and one provincial hospital

Laboratory level: Intermediate

Country: South Africa, Cape Town

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% and among retreatment cases = 4.0% (Source: Survey in Western Cape Province, 2002)

Proportion of TB cases in study centre: 25.8%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960 and MTBDRplus


Flow and timing


Comparative


NotesFollow-up was reported for all sites combined, see Boehme 2011a

MTBDRplus was done on culture isolates for smear-negative sputum


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?No
Were all patients included in the analysis?Yes

Boehme 2011d

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least two weeks

Age: Median 32 years; IQR 26 to 38 years

Sex, female: < 46%

HIV infection: < 68%

History of TB: Not stated

Sample size: 289 for detection of TB; 116 for detection of rifampicin resistance

Clinical setting: Emergency unit of referral hospital

Laboratory level: Intermediate

Country: Uganda

World Bank Income Classification: Low-income

TB incidence rate: 193 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.4% (Source: Nationwide survey, 2011) and among retreatment cases = 12% (Source: Nationwide survey, 2011)

Proportion of TB cases in the study centre: 50.2%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media and line probe assay


Flow and timing


Comparative


NotesFollow-up was reported for all sites combined, see Boehme 2011a

Line-probe assay and, for 10% of culture positive patients (every tenth patient), Löwenstein–Jensen proportion was performed on MGIT isolates (except when only positive on Löwenstein–Jensen).


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?No
Were all patients included in the analysis?Yes

Boehme 2011e

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least two weeks

Age: Median 45 years; IQR 32 to 58 years

Sex, female: 30%

HIV infection: 4%

History of TB: Not stated

Sample size: 788 for detection of TB; 103 for detection of rifampicin resistance

Clinical setting: Health centre

Laboratory level: Intermediate

Country: India

World Bank Income Classification: Middle-income

TB incidence rate: 181 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.1% (Source: Survey in Andhra Pradesh, 2009) and among retreatment cases = 12% (Source: Survey in Andhra Pradesh, 2009)

Proportion of TB cases in the study centre: 12.8%


Index testsXpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


NotesFollow-up was reported for all sites combined, see Boehme 2011a


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Boehme 2011f

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants; site in a multicentre study


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least two weeks

Age: Median 47 years; IQR 34 to 58 years

Sex, female: 36%

HIV infection: < 1%

History of TB: Not stated

Sample size: 387 for detection of TB; 257 for detection of rifampicin resistance

Clinical setting: MDR-TB screening facility

Laboratory level: Intermediate

Country: Philippines

World Bank Income Classification: Middle-income

TB incidence rate: 270 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 4% (Source: Nationwide survey, 2004) and among retreatment cases = 21% (Source: Nationwide survey, 2004)

Proportion of TB cases in the study centre: 38.2%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Ogawa culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


NotesFollow-up was reported for all sites combined, see Boehme 2011a


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Unclear
Were all patients included in the analysis?Yes

Bowles 2011

Study characteristics

Patient samplingProspective and retrospective study with enrolment of participants by convenience


Patient characteristics and settingPresenting signs and symptoms: Not reported

Age: Not stated

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 89

Clinical setting: Laboratory-based evaluation of respiratory specimens (predominantly sputum specimens) from a TB reference clinic

Laboratory level: Central

Country: Netherlands

World Bank Income Classification: High-income

TB incidence rate: 6.8 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.7% and among retreatment cases = 4.5% (Source: Nationwide surveillance, 2011)

Proportion of TB cases in the study: 71.9%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: 26 fresh and 63 frozen (previously stored) samples

Specimen Preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesSample included two extrapulmonary specimens (one pleural fluid and one gastric aspirate)

One patient whose sample was smear and culture-negative was culture-positive on a sample 11 days later


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?No
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Unclear

Carriquiry 2012

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Cough for greater than 10 days with abnormal chest X-ray and at least one of the following symptoms: fever, fatigue, night sweats, haemoptysis, chest pain, or weight loss

Age: Median 35 years (IQR 29 to 42)

Sex, female: 27.5%

HIV infection: 100%

History of TB: 57.3%

Sample size: 131

Clinical setting: Two tertiary hospitals

Laboratory level: Intermediate

Country: Peru

World Bank Income Classification: Middle-income

TB incidence rate: 101 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 5.3% (Source: Nationwide survey 2006) and among retreatment cases = 24% (Source: Nationwide survey 2006)

Proportion of TB cases in the study: 34.4%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 2


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Ciftci 2011

Study characteristics

Patient samplingProspective study; the sampling method was unclear


Patient characteristics and settingPresenting signs and symptoms: Symptoms suggestive of TB

Age: Not stated

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 85

Clinical setting: Laboratory-based evaluation of respiratory specimens (predominantly sputum) at a university hospital

Laboratory level: Intermediate

Country: Turkey

World Bank Income Classification: Middle-income

TB incidence rate: 24 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Survey in Ankara City 2011) and among retreatment cases = 38% (Source: Survey in Ankara City 2011)

Proportion of TB cases in the study: 29.4%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: BACTEC 460

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: BACTEC 460


Flow and timing


Comparative


NotesPaper was written in Turkish: sample included 10 extrapulmonary specimens (five pleural fluid and five urine samples); no patients were found to have rifampicin resistance


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Unclear
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Unclear

Friedrich 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingCross-sectional design with consecutive enrolment of participants, prospective data collection

Presenting signs and symptoms: Patients recently diagnosed with smear-positive first time TB, untreated

Age: Eligible aged 18 to 65 years

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 126

Clinical setting: Two medical centres

Laboratory level: Intermediate

Country: South Africa, Cape Town

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Survey in Western Cape Province, 2002) and among retreatment cases = 4.0% (Source: Survey in Western Cape Province, 2002)

Proportion of TB cases in the study: 100.0%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Processed

Xpert MTB/RIF version: 2 and 4


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesThe aim of this study was to assess NAATs for selecting patients for clinical trials of anti-TB medication. Patients with severe co-morbidities were excluded. This study was used only for determination of sensitivity because all enrolled patients were predetermined to have TB disease.


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?No
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Hanif 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Presumed TB based on presence of cough and radiographic findings

Age: Range 20 to 57 years old

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 206

Clinical setting: Laboratory-based evaluation of respiratory specimens (predominantly sputum) at a university hospital

Laboratory level: Central

Country: Kuwait

World Bank Income Classification: High-income

TB incidence rate: 36 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0% and among retreatment cases = 12% (Source: Nationwide surveillance, 2011)

Proportion of TB cases in the study: 29.1%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: BACTEC 460


Flow and timing


Comparative


NotesNo patients were found to have rifampicin resistance


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?No
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?No
Were all patients included in the analysis?Yes

Hanrahan 2013

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Prolonged (> two weeks) cough and/or other TB symptoms

Age: 18 and older

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 551

Clinical setting: Primary care clinic

Laboratory level: Peripheral

Country: South Africa, Johannesburg

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.4% (Source: Survey in Gauteng province, 2002) and among retreatment cases = 5.5% (Source: Survey in Gauteng province, 2002)

Proportion of TB cases in the study: 11.6%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Helb 2010

Study characteristics

Patient samplingRetrospective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least two weeks

Age: Median 34 years; range 18 to 76 years

Sex, female: 30.8%

HIV infection: 0.9%

History of TB: 1.9%

Sample size: 107

Clinical setting: TB hospital

Laboratory level: Intermediate

Country: Vietnam

World Bank Income Classification: Middle-income

TB incidence rate: 199 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.7% (Source: Nationwide survey, 2006) and among retreatment cases = 19% (Source: Nationwide survey, 2006)

Proportion of TB cases in the study: 76.6%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard: Löwenstein-Jensen culture and MGIT 960


Flow and timing


Comparative


NotesRifampicin resistance data were not reported


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Unclear

Ioannidis 2011

Study characteristics

Patient samplingProspective and retrospective study with enrolment of participants by convenience


Patient characteristics and settingPresenting signs and symptoms: High suspicion of TB in patients found to be predominantly smear negative by microscopy examination

Age: Not stated

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 66

Clinical setting: Laboratory-based evaluation in routine hospital setting

Laboratory level: Central

Country: Greece

World Bank Income Classification: High-income

TB incidence rate: 3.8 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Nationwide surveillance, 2010) and among retreatment cases = 6.7% (Source: Nationwide surveillance, 2010)

Proportion of TB cases in the study: 48.0%


Index testsIndex: Xpert MTB/RIF assay

Condition: Fresh

Preparation: Processed

Xpert MTB/RIF version: 2


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on Löwenstein-Jensen media


Flow and timing


Comparative


NotesSpecimens were predominantly smear-negative


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?No
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Kurbatova 2013

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Presumptive or recently diagnosed TB

Age: Not stated

Sex, female: Not stated

HIV infection: estimated < 5 %

History of TB: Not stated

Sample size: 238

Clinical setting: Laboratory-based evaluation

Laboratory level: Central and intermediate

Country: Russia

World Bank Income Classification: Middle-income

TB incidence rate: 97 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 20% (Source: Surveillance in 20 Oblasts 2010) and among retreatment cases = 46% (Source: Surveillance in 20 Oblasts 2008)

Proportion of TB cases in the study: 46.9%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 4


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesFresh, unconcentrated sputum was initially homogenized using a vortex with glass beads


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Lawn 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: HIV-infected patients with advanced immunodeficiency; the majority of patients had one or more of the following TB symptoms: current cough, fever, night sweats, or weight loss

Age: Median 34 years; IQR 28 to 41 years

Sex, female: 65.4%

HIV infection: 100%

History of TB: 26.5%

Sample size: 394

Clinical setting: HIV anti-retroviral clinic; all patients were screened for TB

Laboratory level: Intermediate

Country: South Africa, Cape Town

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Survey in Western Cape Province, 2002) and among retreatment cases = 4.0% (Source: Survey in Western Cape Province, 2002)

Proportion of TB cases in the study: 18.3%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Processed

Xpert MTB/RIF version: Not stated


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesThis study evaluated the use of Xpert to screen HIV-infected patients with advanced immunodeficiency enrolling in antiretroviral therapy services regardless of symptoms, although the majority of patients in the study had TB symptoms. Of three patients with apparent false-positive Xpert MTB/RIF results, on follow-up, two patients had overt pulmonary and systemic symptoms suggestive of TB and improved on anti-TB treatment. The third patient was lost to follow-up.

Median CD4 cell count, 171 cells/ml; IQR 102 to 236


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
High

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Malbruny 2011

Study characteristics

Patient samplingProspective and retrospective study with enrolment of participants by convenience


Patient characteristics and settingPresenting signs and symptoms: Clinical symptoms suggestive of TB

Age: Median 52 years

Sex, female: 40.2%

HIV infection: Not stated

History of TB: Not stated

Sample size: 58

Clinical setting: Laboratory-based evaluation of respiratory specimens (predominantly bronchial aspirates) at a university hospital

Laboratory level: Intermediate

Country: France

World Bank Income Classification: High-income

TB incidence rate: 4.3 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.0% (Source: Nationwide surveillance, 2009) and among retreatment cases = 13% (Source: Nationwide surveillance, 2009)

Proportion of TB cases in the study: 20.7%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh and frozen

Specimen Preparation: Processed

Xpert MTB/RIF version: 1 and 2


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Solid culture, type unspecified, and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


Notes31/58 (53.4%) of samples were bronchial aspirates

One rifampicin-resistant isolate was identified


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?No
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
High

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Marlowe 2011

Study characteristics

Patient samplingProspective and retrospective study with selection of specimens by convenience at two sites and consecutive selection of smear-positive specimens at one site


Patient characteristics and settingPresenting signs and symptoms: Not reported

Age: Not stated

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 216

Clinical setting: Laboratory-based evaluation of respiratory samples

Laboratory level: Central (one laboratory) and intermediate (two laboratories)

Country: USA

World Bank Income Classification: High income

TB incidence rate: 3.9 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.4% (Source: Nationwide surveillance, 2011) and among retreatment cases = 7.6% (Source: Nationwide surveillance, 2011)

Proportion of TB cases in the study: 60.2%


Index testsIndex: Xpert MTB/RIF assay

Condition: Fresh and frozen

Preparation: Processed

Xpert MTB/RIF version: Not stated


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture, Middlebrook 7H11 culture, and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: phenotypic drug susceptibility testing with agar-based solid media and MGIT 960


Flow and timing


Comparative


NotesUnit of analysis was specimen

Different reference standards were used at each of the three sites


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?No
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?No
Were all patients included in the analysis?Yes

Miller 2011

Study characteristics

Patient samplingRetrospective study; with enrolment of participants by convenience


Patient characteristics and settingPresenting signs and symptoms: Not reported

Age: Data provided for patients with pulmonary and extrapulmonary combined; 95% of patients were 15 years and older

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 89 pulmonary specimens (in addition, study included 23 extrapulmonary specimens)

Clinical setting: Laboratory-based evaluation of clinical specimens at a university hospital

Laboratory level: Intermediate

Country: USA

World Bank Income Classification: High income

TB incidence rate: 3.9 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.4% (Source: Nationwide surveillance, 2011) and among retreatment cases = 7.6% (Source: Nationwide surveillance, 2011)

Proportion of TB cases in the study: 32.6%


Index testsIndex: Xpert MTB/RIF assay

Condition: Frozen

Preparation: Processed

Xpert MTB/RIF version: Not stated


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesOf specimens tested, four were positive by Xpert MTB/RIF for rifampicin resistance; three were positive by the reference standard


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?No
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Moure 2011

Study characteristics

Patient samplingRetrospective study with enrolment of participants by convenience


Patient characteristics and settingPresenting signs and symptoms: Patients found to be smear negative by microscopy examination

Age: All patients were 15 years of age or older

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 107

Clinical setting: Laboratory-based evaluation of clinical specimens at a university hospital

Laboratory level: Intermediate

Country: Spain

World Bank Income Classification: High income

TB incidence rate: 15 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.2% (Source: Survey in Galicia region, 2005) and among retreatment cases = 1.5% (Source: Survey in Galicia region, 2005)

Proportion of TB cases in the study: 72.9%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Lowenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Bactec 460


Flow and timing


Comparative


NotesSample set included one pulmonary biopsy specimen

Of 85 pulmonary and extrapulmonary specimens tested, six were positive by Xpert MTB/RIF for rifampicin resistance, and seven specimens were positive by the reference standard


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?No
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Rachow 2011

Study characteristics

Patient samplingRetrospective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Presumed pulmonary TB based on clinical and radiographic findings

Age: Mean 39 years (SD = 13.8)

Sex, female: 51.7%

HIV infection: 58.9%

History of TB: Not stated

Sample size: 172

Clinical setting: Referral hospital, high HIV setting

Laboratory level: Central

Country: United Republic of Tanzania

World Bank Income Classification: Low-income

TB incidence rate: 169 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.1% (Source: Nationwide survey, 2007) and among retreatment cases = 0% (Source: Nationwide survey, 2007)

Proportion of TB cases in the study: 40.1%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesPatients were followed for a period of 56 days. Among 77 patients classified as smear negative, culture negative 'clinical TB', Xpert MTB/RIF was positive in seven (9.1%) patients

No patients were found to have rifampicin resistance


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Unclear

Safianowska 2012

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Patients presumed to have TB

Age: Mean 61 years; range 20 to 97 years

Sex, female: 36.6%

HIV infection: 0%

History of TB: Not stated

Sample size: 145

Clinical setting: Laboratory-based evaluation

Laboratory level: Intermediate

Country: Poland

World Bank Income Classification: High-income

TB incidence rate: 23 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.5% (Source: Nationwide surveillance, 2011) and among retreatment cases = 3.5% (Source: Nationwide surveillance, 2011)

Proportion of TB cases in the study: 11.8%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Processed

Xpert MTB/RIF version: 1 and 2


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Löwenstein-Jensen media, method not specified


Flow and timing


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Scott 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Patients presumed to have TB, presenting with cough, fever, night sweats, and/or weight loss

Age: Mean 32 years; range 19 to 75 years

Sex, female: 41.1%

HIV infection: 69.0%

History of TB: Not stated

Sample size: 177

Clinical setting: Primary care clinic

Laboratory level: Intermediate

Country: South Africa, Johannesburg

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.4% (Source: Survey in Gauteng province, 2002) and among retreatment cases = 5.5% (Source: Survey in Gauteng province, 2002)

Proportion of TB cases in the study: 37.9%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Xpert MTB/RIF version: 1 and 2


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesOne follow-up visit was performed approximately 60 days after enrolment

Xpert MTB/RIF was performed on frozen specimens while MGIT culture and smear microscopy were performed on fresh specimens


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Teo 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Patients thought to have TB based on symptoms and radiographic findings

Age: Not stated

Sex, female: Not stated

HIV infection: Not stated

History of TB: Not stated

Sample size: 106

Clinical setting: University hospital

Laboratory level: Central

Country: Singapore

World Bank Income Classification: High-income

TB incidence rate: 37 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.6% (Source: Nationwide surveillance, 2011) and among retreatment cases = 0% (Source: Nationwide surveillance, 2011)

Proportion of TB cases in the study: 58.5%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Processed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Gene sequencing


Flow and timing


Comparative


NotesRespiratory specimens (predominantly sputum) submitted for routine testing; only one rifampicin-resistant isolate was identified


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Unclear

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?No
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?No
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Theron 2011

Study characteristics

Patient samplingRetrospective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Patients presumed to have TB based on compatible signs and symptoms

Age: Median 36 years; range 18 to 83 years

Sex, female: 32.3%

HIV infection: 31.3%

History of TB: 34.3%

Sample size: 480

Clinical setting: Two primary care clinics in a high HIV prevalence area

Laboratory level: Intermediate

Country: South Africa, Cape Town

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Survey in Western Cape Province, 2002) and among retreatment cases = 4.0% (Source: Survey in Western Cape Province, 2002)

Proportion of TB cases in the study: 29.4%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Unprocessed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesShort-term follow-up cultures were obtained; 16 of 19 Xpert MTB/RIF-positive culture-negative patients were considered likely to be TB cases based on follow-up cultures, gene sequencing, and the presence of characteristic radiographic features using a standardised scoring system


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Van Rie 2013

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Prolonged (> two weeks) cough or other TB symptoms, or both, and had two prior-negative smear by fluorescence microscopy

Age: Median 36 years (IQR 30 to 34)

Sex, female: 56.8%

HIV infection: 72.4%

History of TB: 17.6%

Sample size: 199

Clinical setting: Primary care clinic

Laboratory level: Peripheral

Country: South Africa, Johannesburg

World Bank Income Classification: Middle-income

TB incidence rate: 993 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.4% (Source: Survey in Gauteng province, 2002) and among retreatment cases = 5.5% (Source: Survey in Gauteng province, 2002)

Proportion of TB cases in the study: 9.3%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


NotesOnly those patients presumed to have TB who returned for results of the initial smear microscopy examinations were enrolled


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?No

Williamson 2012

Study characteristics

Patient samplingCross-sectional design with consecutive enrolment of smear-positive patients, prospective data collection


Patient characteristics and settingPresenting signs and symptoms: Clinical symptoms not reported: smear-positive specimens

Age: > 15 years

Sex, female: Not stated

HIV infection: estimated < 1%

History of TB: Not stated

Sample size: 89

Clinical setting: Laboratory-based evaluation

Laboratory level: Intermediate

Country: New Zealand

World Bank Income Classification: High-income

TB incidence rate: 7.6 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.5% (Source: Nationwide surveillance 2009) and among retreatment cases = 13% (Source: Nationwide surveillance 2009)

Proportion of TB cases in the study: 75.3%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Processed

Xpert MTB/RIF version: 3


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: MGIT 960

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: MGIT 960


Flow and timing


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?No
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?Yes
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?Yes
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

Zeka 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of patients


Patient characteristics and settingPresenting signs and symptoms: Clinical findings of possible TB

Age: Median 48 years; range 25 to 70 years

Sex, female: 42.4%

HIV infection: Not stated

History of TB: Not stated

Sample size: 103

Clinical setting: Laboratory-based evaluation of routine sputum specimens at a university hospital

Laboratory level: Intermediate

Country: Turkey

World Bank Income Classification: Middle-income

TB incidence rate: 24 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 0.9% (Source: Survey in Ankara City 2011) and among retreatment cases = 38% (Source: Survey in Ankara City 2011)

Proportion of TB cases in the study: 34.0%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Xpert MTB/RIF version: 1


Target condition and reference standard(s)Target condition: Pulmonary TB

Reference standard for pulmonary TB: Löwenstein-Jensen culture and MB/MBacT liquid medium

Target condition: Rifampicin resistance

Reference standard for rifampicin resistance: Proportion method on 7H10 media


Flow and timing


Comparative


NotesOnly one rifampicin resistant isolate was identified. Data for sputum specimens were provided by the study author


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Yes
Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Yes
If a threshold was used, was it pre-specified?Yes
Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?Yes
Were the reference standard results for TB detection interpreted without knowledge of the results of the index test?No
Were the reference standard results for rifampicin resistance detection interpreted without knowledge of the results of the index test?No
Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Yes
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Alvarez-Uria 2012Reference standard not satisfied.

Andersen 2011Editorial and comment.

Armand 2011This was a case-control study that compared Xpert MTB/RIF with an in-house IS6110-based real-time PCR using TaqMan probes (IS6110-TaqMan assay) for TB detection.

Banada 2010Technical paper.

Bates 2013This study evaluated Xpert MTB/RIF for the diagnosis of TB in children.

Blakemore 2010Technical paper.

Blakemore 2011This was a technical paper that compared bacterial load quantitation determined by Xpert MTB/RIF with the load determined by conventional quantitative methods.

Causse 2011This study evaluated Xpert MTB/RIF for the diagnosis of extrapulmonary TB.

Chegou 2011Narrative review.

Clouse 2012Study on patient impact.

Cuevas 2011Narrative review.

Dorjee 2012Case report.

Dorman 2012Prevalence survey.

Dowdy 2011Cost-effectiveness study.

Evans 2011Editorial and comment.

Farga 2011Narrative review.

Fenner 2011Editorial and comment.

Ferrara 2011Editorial and comment.

FIND 2011This study compared Xpert MTB/RIF G3 and G4. We excluded it because of concern about duplicate data. In addtion, the crieria for the reference standard for rifampicin resistance detection were not satisfied.

Friedrich 2011aThis study evaluated Xpert MTB/RIF for the diagnosis of pleural TB.

Gotuzzo 2011Editorial and comment.

Hesseling 2011Editorial and comment.

Hillemann 2011This study evaluated Xpert MTB/RIF for the diagnosis of extrapulmonary TB.

Hoek 2011Narrative review.

Ioannidis 2010We could not obtain this article.

Kim 2012Case-control study.

Kirwan 2012Editorial and comment.

Lawn 2011aThis was a narrative review that covered the development, technical details, and diagnostic accuracy of Xpert MTB/RIF in adults and children.

Lawn 2011bEditorial and comment.

Lawn 2012Study on patient impact.

Lawn 2012aData insufficient for 2 x 2 table.

Lawn 2012bCorrespondence.

Lawn 2012cPrimarily a lipoarabinomannan detection study.

Lawn 2012dDuplicate data.

Ligthelm 2011This study evaluated Xpert MTB/RIF for the diagnosis of TB lymphadenitis.

Melzer 2011Editorial and comment.

Miotto 2012Treatment monitoring.

Morris 2010Editorial and comment.

Morris 2011Editorial and comment.

Moure 2012This study evaluated Xpert MTB/RIF for the diagnosis of extrapulmonary TB.

Muñoz 2013Study on patient impact.

Narasimooloo 2012Study on patient impact.

Nhu 2013This study evaluated Xpert MTB/RIF for the diagnosis of TB in children.

Nicol 2011This study evaluated Xpert for the diagnosis of TB in children.

Ntinginya 2012This study included both adults and children. The study used an active case finding strategy involving previously known TB cases and identified five additional culture-confirmed TB cases (5/219). Xpert MTB/RIF showed a positive result in all five culture-confirmed TB cases (sensitivity = 100%). We considered the study design to be different from a diagnostic test accuracy study and therefore did not include this study in the review.

O'Grady 2012This study evaluated Xpert MTB/RIF in patients able to produce sputum, irrespective of admission diagnosis, not presumed TB patients.

Perkins 2011Correspondence.

Peter 2012aThis study evaluated Xpert MTB/RIF for the diagnosis of extrapulmonary TB.

Peters 2012Correspondence.

Rachow 2012This study evaluated Xpert for the diagnosis of TB in children.

Salvo 2011Editorial and comment.

Scott 2012Technical paper.

Swaminathan 2012Relevance. This study disucssed lipoarabinomannan.

Tansey 2009Editorial and comment.

Taylor 2012This study evaluated Xpert for the diagnosis of extrapulmonary TB.

Theron 2011aEditorial and comment.

Theron 2012Treatment monitoring.

Theron 2012aDuplicate data.

Theron 2012bDuplicate data.

Tortoli 2012This study evaluated Xpert MTB/RIF for the diagnosis of extrapulmonary TB.

Trebucq 2012Editorial and comment.

Trebucq 2012aCorrespondence.

Vadwai 2011This study evaluated Xpert MTB/RIF for the diagnosis of extrapulmonary TB.

Vadwai 2012Correspondence.

Van Rie 2010This was a review that covered technical details of Xpert MTB/RIF and the test's potential value as a point-of-care test.

Van Rie 2011Case report.

van Zyl-Smit 2011Technical paper.

Walters 2012This study evaluated Xpert MTB/RIF for the diagnosis of TB in children.

Williamson 2012aCase-control study.

Wood 2012This study evaluated Xpert MTB/RIF for the diagnosis of extrapulmonary TB.

Yoon 2012Duplicate data.

Zar 2012This study evaluated Xpert MTB/RIF for the diagnosis of TB in children.

 
Characteristics of ongoing studies [ordered by study ID]
Durovni 2013

Trial name or titleGeneXpert MTB/RIF, a new tool for the diagnosis of pulmonary tuberculosis in two municipalities in Brazil

Target condition and reference standard(s)TB cases bacteriologically confirmed

Index and comparator testsXpert MTB/RIF assay and smear microscopy

Starting dateJanuary 2012

Contact informationBetina Durovni bdurovni@saude.rio.rj.br

NotesGroup-randomized pragmatic trial following a stepped-wedge design. Identifier: NCT01363765

Luetkemeyer 2012

Trial name or titleEvaluation of Xpert MTB/RIF assay for the rapid identification of TB and TB rifampin resistance in HIV-infected and HIV-uninfected patients with presumed pulmonary tuberculosis

Target condition and reference standard(s)TB: reference standard: MGIT culture

Index and comparator testsXpert MTB/RIF assay

Starting date24 April 2012

Contact informationJay (John) Dwyer jdwyer@php.ucsf.edu    

NotesCohort study of diagnostic accuracy of Xpert MTB/RIF in HIV-infected and HIV-uninfected patients presumed to have pulmonary TB. Identifier: NCT01587469

Peter 2012

Trial name or titleA randomised control trial of sputum induction, and new and emerging technologies in a high HIV prevalence primary care setting

Target condition and reference standard(s)TB: liquid culture

Index and comparator testsXpert MTB/RIF assay

Starting dateAugust 2009

Contact informationJonny Peter Jonny.Peter@uct.ac.za

NotesRCT to evaluate sputum induction for TB diagnosis in a primary care clinic for adults presumed to have TB. Identifier: NCT01545661

 
Table 1. Xpert MTB/RIF assay for detection of TB and rifampicin resistance

Type of analysis (Number of studies, participants)Median pooledsensitivity

(95% credible interval)
Median pooledspecificity

(95% credible interval)
Median predicted sensitivity

(95% credible interval)
Median predicted specificity

(95% credible interval)

Xpert MTB/RIF used as an initial test for TB detection replacing microscopy (22, 8998) 89% (85, 92)99% (98, 99)89% (63, 97)99% (90, 100)

Xpert MTB/RIF used as an add-on test for TB detection following a negative smear microscopy result (21, 6950)67% (60, 74)99% (98, 99)67% (42, 85)99% (89, 100)

Xpert MTB/RIF used as an initial test for rifampicin resistance detection replacing conventional DST as the initial test *95% (90, 97)98% (97, 99)95% (80, 99)98% (94, 100)

 * For rifampicin resistance detection, pooled sensitivity and specificity estimates were determined separately by univariate analyses. Pooled sensitivity, number of studies = 17 (555 participants); pooled specificity, number of studies = 24 (2411 participants).
 
Table 2. Impact of covariates on heterogeneity of Xpert MTB/RIF sensitivity and specificity, TB detection

Covariate (Number of studies)Median pooled sensitivity

(95% credible interval)
Median pooled specificity

(95% credible interval)

Smear status

Smear + (21) 98% (97, 99)***

Smear - (21) 67% (60, 74)99% (98, 99)

Difference (Smear+ minus Smear-) 31% (24, 38)***

P (Smear+ > Smear-) 1.00***

HIV status 

HIV- (7) 86% (76, 92)99% (98, 100)

HIV+ (7) 79% (70, 86)98% (96, 99)

Difference (HIV- minus HIV+) 7% (-5, 18)1% (-1, 3)

P (HIV- > HIV+)  0.900.85

Covariate (number of studies)Within smear positiveWithin smear negative


Median pooled sensitivity

(95% credible interval)
Median pooled sensitivity

(95% credible interval)
Median pooled specificity

(95% credible interval)

HIV status 

HIV-*********

HIV+ (4)97% (90, 99)**61% (40, 81)**99% (97, 100)#

Difference (HIV- minus HIV+)*********

P (HIV- > HIV+)*********

Condition of specimen 

Fresh (12)99% (98, 100)67% (58, 76)99% (98, 100)

Frozen (6)97% (95, 99)61% (48, 73)98% (95, 99)

Difference (Fresh minus Frozen)1% (-0.4, 4)6% (-9, 22)1% (-0.4, 4)

P (Fresh > Frozen)0.920.790.92

Specimen preparation 

Unprocessed (10)98% (97, 99)69% (60, 78)98% (97, 99)

Processed (11)99% (97, 99)64% (54, 75)99% (98, 100)

Difference (Unprocessed minus Processed)-0.1% (-2, 2)5% (-9, 18)-1% (-2, 1)

P (Unprocessed > Processed)0.450.760.20

Proportion TB cases in the study 

> 30% (12)*99% (97, 99)70% (62, 78)98% (96, 99)

≤ 30% (9)*98% (96, 99)61% (50, 73)99% (98, 100)

Difference (> 30% minus ≤ 30%)0.5% (-1, 2)9% (-5, 22)-1% (-3, 0.2)

P (> 30% minus ≤ 30%)0.740.900.05

Country income level 

High-income (8)99% (98, 100)73% (62, 83)99% (97, 100)

Low-income and middle-income (13)98% (97, 99)64% (56, 73)99% (97, 99)

Difference (High-income minus Low- and middle-income)1% (-1, 2)9% (-5, 22)0.3% (-1, 2)

P (High-income > Low- and middle-income)0.880.900.69

 * We selected 30% as a cut-off based on the median proportion of TB cases in the included studies
**Results are from a univariate analysis
***Values could not be determined
#Results are from a univariate analysis based on three studies
 
Table 3. Impact of covariates on heterogeneity of Xpert MTB/RIF sensitivity and specificity, rifampicin resistance detection

CovariateMedian pooled sensitivity

(95% credible interval)
Median pooled specificity

(95% credible interval)

Xpert MTB/RIF assay version*  

G2, G3, G493% (87, 97)98% (96, 99)

G197% (91, 99)99% (98, 100)

Difference (G2, G3, G4 minus G1)-4% (-10, 3)-1% (-3, -0.2)

P (G2, G3, G4 > G1)0.090.01

Proportion rifampicin resistance in the study**  

> 15%96% (91, 98)97% (94, 99)

≤ 15%91% (79, 97)99% (98, 99)

Difference (> 15% minus ≤ 15%)4% (-3, 16)-2% (-4, 0.1)

P (> 15% greater than ≤ 15%)0.870.03

 Pooled sensitivity and specificity estimates were determined separately by univariate analyses.
*Xpert MTB/RIF assay version G2, G3, G4: pooled sensitivity (13 studies) and pooled specificity (16 studies); Xpert MTB/RIF assay version G1: pooled sensitivity (four studies) and pooled specificity (seven studies).
** Proportion rifampicin resistance > 15%: pooled sensitivity (six studies) and pooled specificity (six studies); proportion rifampicin resistance ≤ 15%: pooled sensitivity (11 studies) and pooled specificity (18 studies).
 
Table 4. Sensitivity analyses

Type of analysis (Number of studies, participants)Median pooled sensitivity

(95% credible interval)
Median pooled specificity

(95% credible interval)
Median predicted sensitivity

(95% credible interval)
Median predicted specificity

(95% credible interval)

TB detection, without Boehme 2010 and Boehme 2011 (20, 3748)88% (83, 92)98% (97, 99)88% (62, 97)98% (89, 100)

TB detection, studies that provided data by age that met the criterion for adults (14, 7880) 87% (81, 92)99% (98, 99)87% (58, 97)99% (95, 100)

TB detection, studies where consecutive patients were selected (17, 8465)87% (82, 91)99% (98, 99)87% (59, 97)99% (90, 100)

TB detection, studies where a single specimen yielded a single Xpert MTB/RIF result for a given patient (14, 7912)85% (79, 91)99% (98, 99)85% (54, 97)99% (95, 100)

TB detection, studies that clearly represented the use of the test for diagnosis of patients with presumed TB (16, 7974)89% (85, 93)99% (97, 99)89% (69, 97)99% (89, 100)

Rifampicin resistance detection by bivariate analyses (17, 2621)95% (90, 97)98% (97, 99)95% (80, 99)98% (93, 100)

 
Table 5. Selected patient-important outcomes as reported in the included studies

StudyTime to TB detectionTime to rifampicin resistance detectionTime to treatment initiation

Balcells 2012Median (range)

Xpert MTB/RIF: 0 days

Liquid culture 10 days (5 to 22 days)

8 days for smear-positive,

15 days for smear-negative cases

Boehme 2011Median (IQR)  

Xpert MTB/RIF: 0 days (0, 1)

Smear: 1 day (0, 1)

Solid culture: 30 days (23, 43)

Liquid culture: 16 days (13, 21)
Median (IQR) 

Xpert MTB/RIF: 1 day (0, 1)

Line probe assay (direct testing): 20 days (10, 16)

Phenotypic DST: 106 days (30, 124)
Median (IQR)

Smear-, culture+ TB

Before Xpert MTB/RIF introduced: 56 days (39, 81)

After Xpert MTB/RIF introduced: 5 days (2, 8)

Helb 2010Xpert MTB/RIF (1 sample): 1 hour 55 minutes

Xpert MTB/RIF (8 samples processed together): 2 hours
  

Lawn 2011Median* (IQR)

Xpert MTB/RIF: 4 days (3, 6)

Smear: 3 days (2, 5)

Liquid culture (smear+): 12 days (10,14)

Liquid culture (smear-): 20 days (17, 27)
Xpert MTB/RIF: mean 2 days

MTBDRplus assay (with positive culture isolate): mean 21 days

Phenotypic DST (liquid culture): mean 40 days

 
 

Marlowe 2011Xpert MTB/RIF: hands-on time was 5 minutes; run time was less than 2 hours  

Miller 2011Xpert MTB/RIF: hands-on time was 15 minutes: run time was 113 minutes  

Moure 2011Xpert MTB/RIF: total time of 2 hours  

Rachow 2011Xpert MTB/RIF: within two hours  

Van Rie 2013Xpert MTB/RIF: results were available the same dayXpert MTB/RIF positive patients: 0 days (0,0)

Patients diagnosed by other methods: 13 days (10, 20)

Zeka 2011**Xpert MTB/RIF (routine practice): 3 to 24 hours

Liquid culture: 19 days mean (range 3 to 42 days)
  

 *Median delay between sputum collection and results being available to the clinic.
**Times provided for both pulmonary and extrapulmonary specimens jointly.
Abbreviations: DST, drug susceptibility testing; IQR, interquartile range.