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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. Hojoon Sohn2,
  3. Ian Schiller3,
  4. Lorie A Kloda4,
  5. Catharina C Boehme5,
  6. Madhukar Pai2,
  7. Nandini Dendukuri2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 31 JAN 2013

Assessed as up-to-date: 7 SEP 2012

DOI: 10.1002/14651858.CD009593.pub2


How to Cite

Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, Pai M, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD009593. DOI: 10.1002/14651858.CD009593.pub2.

Author Information

  1. 1

    University of Washington, School of Public Health, Department of Health Services, Seattle, Washington, USA

  2. 2

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

  3. 3

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

  4. 4

    McGill University, Library, Montreal, Quebec, Canada

  5. 5

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

*Karen R Steingart, Department of Health Services, University of Washington, School of Public Health, Seattle, Washington, 98195-7230, USA. karenst@uw.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 31 JAN 2013

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Characteristics of included studies [ordered by study ID]
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 ≥ 2 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: Reference laboratory

Country: Azerbaijan

World Bank Income Classification: Middle-/low-income

TB incidence rate: 110 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 22.3% and among retreatment cases = 55.8% (Source: survey in Baku, 2007)

TB prevalence in study centre: 68.1%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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
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

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 ≥ 2 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: Reference laboratory

Country: Peru

World Bank Income Classification: Middle-/low-income

TB incidence rate: 106 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)

TB prevalence in study centre: 67.4%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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
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

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 ≥ 2 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: Reference laboratory

Country: South Africa, Cape Town

World Bank Income Classification: Middle-/low-income

TB incidence rate: 981 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)

TB prevalence in study centre: 44.0%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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
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

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 ≥ 2 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: Reference laboratory

Country: South Africa, Durban

World Bank Income Classification: Middle-/low-income

TB incidence rate: 981 per 100,000

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

TB prevalence in study centre: 16.5%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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
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?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 ≥ 2 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: Reference laboratory

Country: India

World Bank Income Classification: Middle-/low-income

TB incidence rate: 185 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.1% and among retreatment cases = 11.9% (Source: Survey in Andhra Pradesh, 2009)

TB prevalence in study centre: 84.2%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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
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?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 2 weeks

Age: median 36 years; interquartile range 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: Microscopy area of MDR-TB screening facility

Country: Azerbaijan

World Bank Income Classification: Middle-/low-income

TB incidence rate: 110 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 22.3% for new cases and among retreatment cases = 55.8% (Source: survey in Baku, 2007)

TB prevalence in study centre: 42.7%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 5


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 2 weeks

Age: median 37 years; interquartile range 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: Microscopy area of health centres and district hospital

Country: Peru

World Bank Income Classification: Middle-/low-income

TB incidence rate: 106 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)

TB prevalence in study centre: 17.6%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 5


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 2 weeks

Age: median 36 years; interquartile range 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: Microscopy area of health centre and provincial hospital

Country: South Africa, Cape Town

World Bank Income Classification: Middle-/low-income

TB incidence rate: 981 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)

TB prevalence in study centre: 25.8%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 5


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 2 weeks

Age: median 32 years; interquartile range 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: Microscopy area of referral hospital

Country: Uganda

World Bank Income Classification: Middle-/low-income

TB incidence rate: 226 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.1% and among retreatment cases = 11.7% (Source: Survey in Kampala, 2008)

TB prevalence in study centre: 50.2%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 5


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 2 weeks

Age: median 45 years; interquartile range 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: Microscopy area of health centre

Country: India

World Bank Income Classification: Middle-/low-income

TB incidence rate: 185 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.1% and among retreatment cases = 11.9% (Source: Survey in Andhra Pradesh, 2009)

TB prevalence in study centre: 12.8%


Index testsXpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 5


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 2 weeks

Age: median 47 years; interquartile range 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: Microscopy area of MDR-TB screening facility

Country: Philippines

World Bank Income Classification: Middle-/low-income

TB incidence rate: 275 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 4.0% and among retreatment cases = 20.9% (Source: Nationwide survey, 2004)

TB prevalence in study centre: 38.2%


Index testsIndex: Xpert MTB/RIF assay

Specimen condition: Fresh

Specimen preparation: Unprocessed

Parameter value for rifampicin resistance: 5


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: Reference laboratory

Country: Netherlands

World Bank Income Classification: High-income

TB incidence rate: 7.3 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.3% and among retreatment cases = 3.4% (Source: Nationwide surveillance, 2010)

TB prevalence in study: 71.9%


Index testsIndex: Xpert MTB/RIF assay

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

Specimen Preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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 2 extrapulmonary specimens (1 pleural fluid and 1 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
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?Unclear

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: Reference laboratory

Country: Turkey

World Bank Income Classification: Middle/low income

TB incidence rate: 28 per 100,000

MDR-TB prevalence: Data not available

TB prevalence in study: 29.4%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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 (5 pleural fluid and 5 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
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?Unclear

Friedrich 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting 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: Reference laboratory

Country: South Africa, Cape Town

World Bank Income Classification: Middle-/low-income

TB incidence rate: 981 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)

TB prevalence in study: 100.0%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 5


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 comorbidities 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?Unclear
Did the study avoid inappropriate exclusions?No
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

Hanif 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Suspected 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: Reference laboratory

Country: Kuwait

World Bank Income Classification: High-income

TB incidence rate: 41 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.1% and among retreatment cases = 0% (Source: Nationwide surveillance, 2010)

TB prevalence in study: 29.1%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Unprocessed

Parameter value for rifampicin resistance: 3.5


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
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?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

Helb 2010

Study characteristics

Patient samplingRetrospective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Cough lasting at least 2 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: Reference laboratory

Country: Vietnam

World Bank Income Classification: Middle/low income

TB incidence rate: 180 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.7% and among retreatment cases = 19.3% (Source: Nationwide survey, 2006)

TB prevalence in study: 76.6%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 3.5


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
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?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: Reference laboratory

Country: Greece

World Bank Income Classification: High-income

TB incidence rate: 4.6 per 100,000

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

TB prevalence in study: 48.0%


Index testsIndex: Xpert MTB/RIF assay

Condition: Fresh

Preparation: Processed

Parameter value for rifampicin resistance: 5


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?No
Did the study avoid inappropriate exclusions?No
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

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; interquartile range 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

Laboratory: Reference laboratory

Country: South Africa, Cape Town

World Bank Income Classification: Middle-/low-income

TB incidence rate: 981 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)

TB prevalence in study: 18.3%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 5


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 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; interquartile range 102–236


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 consecutive enrolment of participants


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 at a university hospital

Laboratory: Reference laboratory

Country: France

World Bank Income Classification: High-income

TB incidence rate: 9.3 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.0% and among retreatment cases = 13.2% (Source: Nationwide surveillance, 2009)

TB prevalence in study: 20.7%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh and frozen

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 5


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?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

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: Three different reference laboratories

Country: USA

World Bank Income Classification: High income

TB incidence rate: 4.1 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.1% and among retreatment cases = 4.4% (Source: Nationwide surveillance, 2010)

TB prevalence in study: 60.2%


Index testsIndex: Xpert MTB/RIF assay

Condition: Fresh and frozen

Preparation: Processed

Parameter value for rifampicin resistance: 5


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
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?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 (study also included 23 extrapulmonary specimens)

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

Laboratory: Reference laboratory

Country: USA

World Bank Income Classification: High-income

TB incidence rate: 4.1 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.1% and among retreatment cases = 4.4% (Source: Nationwide surveillance, 2010)

TB prevalence in study: 32.6%


Index testsIndex: Xpert MTB/RIF assay

Condition: Frozen

Preparation: Processed

Parameter value for rifampicin resistance: 5


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 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
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

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: Reference laboratory

Country: Spain

World Bank Income Classification: High income

TB incidence rate: 16 per 100,000

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

TB prevalence in study: 72.9%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 3.5


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 Include 1 pulmonary biopsy specimen

Of 85 pulmonary and extrapulmonary specimens tested, 6 were positive by Xpert for rifampicin resistance: 7 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?No
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?Unclear
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: Suspected 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: Reference laboratory

Country: United Republic of Tanzania

World Bank Income Classification: Middle-/low-income

TB incidence rate: 177 per 100,000

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

TB prevalence in study: 40.1%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 3.5


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 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
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?Unclear

Scott 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Suspected 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 health care clinic

Laboratory: Reference laboratory

Country: South Africa, Johannesburg

World Bank Income Classification: Middle-/low-income

TB incidence rate: 981 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 1.8% and among retreatment cases = 6.7% (Source: Nationwide survey, 2002)

TB prevalence in study: 37.9%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 3.5


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 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
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

Teo 2011

Study characteristics

Patient samplingProspective study with consecutive enrolment of participants


Patient characteristics and settingPresenting signs and symptoms: Patients suspected of having 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: Reference laboratory

Country: Singapore

World Bank Income Classification: High-income

TB incidence rate: 35 per 100,000

MDR-TB prevalence: Percent MDR-TB among new TB cases = 2.3% and among retreatment cases = 6.4% (Source: Nationwide surveillance, 2010)

TB prevalence in study: 58.5%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Fresh

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 3.5


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
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?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: Suspected 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: Reference laboratory

Country: South Africa, Cape Town

World Bank Income Classification: Middle-/low-income

TB incidence rate: 981 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)

TB prevalence in study: 29.4%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 3.5


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-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
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

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: Reference laboratory

Country: Turkey

World Bank Income Classification: Middle-/low-income

TB incidence rate: 28 per 100,000

MDR-TB prevalence: Data not available

TB prevalence in study: 34.0%


Index testsIndex: Xpert MTB/RIF assay

Specimen Condition: Frozen

Specimen Preparation: Processed

Parameter value for rifampicin resistance: 3.5


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: Proportional 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
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?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

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

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

Causse 2011This study evaluated Xpert for the diagnosis of extrapulmonary TB

Friedrich 2011aThis study evaluated Xpert for the diagnosis of pleural TB, a form of extrapulmonary TB

Hillemann 2011This study evaluated Xpert for the diagnosis of extrapulmonary TB

Lawn 2011bThis was a narrative review that covered the development, technical details, and diagnostic accuracy of Xpert in adults and children

Ligthelm 2011This study evaluated Xpert for the diagnosis of TB lymphadenitis, a form of extrapulmonary TB

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

Vadwai 2011This study evaluated Xpert for the diagnosis of extrapulmonary TB

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

 
Characteristics of ongoing studies [ordered by study ID]
Dheda 2012

Trial name or titleMulticentre randomised control trial of point-of-treatment (Clinic-based) Xpert MTB/RIF assay

Target condition and reference standard(s)TB: reference standard: MGIT 960

Index and comparator testsXpert MTB/RIF assay and smear microscopy

Starting date7 July 2011

Contact informationKeertan.Dheda@uct.ac.za; Jonny.Peter@uct.ac.za

NotesRCT to assess the impact of Xpert on time-to-treatment and TB-related patient morbidity in primary care clinics. Identifier: NCT01554384

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 pulmonary tuberculosis suspects

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 in HIV-infected and HIV-uninfected patients suspected of having 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@uct.ac.za

NotesRCT to evaluate sputum induction for TB diagnosis in a primary care clinic for adults suspected of having TB. Identifier: NCT01545661

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

Type of analysis

(Number of studies)
Pooled sensitivity

Median (95% credible interval)
Pooled specificity

Median (95% credible interval)
Predicted sensitivity

Median (95% credible interval)
Predicted specificity

Median (95% credible interval)

Xpert used as an initial test for TB detection replacing microscopy (15)*

 
88%

(83, 92)
98%

(97, 99)
88%

(66, 97)
98%

(92, 100)

Xpert used as an add-on test for TB detection following a negative smear microscopy result (14)67%

(58, 74)
98%

(97, 99)
66%

(40, 86)
98%

(93, 100)

Xpert used as an initial test for rifampicin resistance detection replacing conventional drug susceptibility testing as the initial test (11)94%

(87, 97)
98%

(97, 99)
94%

(75, 99)
98%

(91, 100)

 *Three studies that preferentially enrolled smear-positive or smear-negative patients were excluded
 
Table 2. Impact of covariates on heterogeneity of Xpert sensitivity and specificity for TB detection

CovariateSensitivity

Median (95% credible interval)
Specificity

Median (95% credible interval)

Smear status  

Smear +98% (97, 99)***

Smear -68% (59, 75)98% (97, 99)

Difference (Smear+ minus Smear-)31% (23, 39)**

P (Smear+ > Smear-)1.00**

HIV status  

HIV+80% (67, 88)97% (93, 99)

HIV-89% (81, 94)99% (96, 99)

Difference (HIV+ minus HIV-)-9% (-22, 3)-1% (-5, 2)

P (HIV+ > HIV-)0.060.21

Condition of specimen  

Fresh88% (80, 93)99% (98, 100)

Frozen85% (77, 91)97% (95, 99)

Difference (Fresh minus Frozen)3% (-7, 13)2% (0.1, 4)

P (Fresh > Frozen)0.730.98

Specimen preparation  

Unprocessed92% (87, 96)99% (97, 99)

Processed85% (79, 90)98% (96, 99)

Difference (Unprocessed minus Processed)7% (0.2, 14)0.8% (-1, 3)

P (Unprocessed > Processed)0.980.84

TB prevalence  

High (> 30%)89% (84, 93)98% (96, 99)

Low (≤ 30%)86% (77, 92)99% (97, 99)

Difference (High minus Low)3% (-5, 12)-0.4% (-2, 1)

P (High > Low)0.800.29

Country income level  

High-income92% (86, 96)98% (95, 99)

Low- and middle-income85% (79, 90)99% (97, 99)

Difference (High-income minus Low- and middle-income)6% (-1, 14)-1% (-3, 1)

P (High-income > Low- and middle-income)0.960.23

 P = probability
 
Table 3. Impact of covariates on heterogeneity of Xpert sensitivity and specificity for rifampicin resistance detection

CovariateSensitivity

Median (95% credible interval)
Specificity

Median (95% credible interval)

Parameter value (delta cycle threshold cutoff)  

Parameter value 594% (86, 97)98% (96, 99)

Parameter value 3.596% (81, 100)100% (98, 100)

Difference (Parameter value 5 minus Parameter value 3)-3% (-10, 11)-2% (-4, -0.3)

P (Parameter value 5 > Parameter value 3)0.260.01

Rifampicin resistance prevalence  

High (> 15%)94% (85, 98)98% (95, 99)

Low (≤ 15%)93% (80, 99)98% (96, 99)

Difference (High minus Low)0.4% (-8, 13)-0.4% (-4, 2)

P (High > Low)0.540.34

 P = probability
 
Table 4. Selected patient-important outcomes as reported in the included studies

Study and year of publicationTime to TB detectionTime to detection of rifampicin resistanceTime to treatment initiation

 

Boehme 2011a; Boehme 2011b; Boehme 2011c; Boehme 2011d; Boehme 2011e; Boehme 2011fMedian (IQR)  

Xpert: 0 days (0, 1)

Smear: 1 day (0, 1)

Solid culture: 30 days (23, 43)

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

Xpert: 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 introduced: 56 days (39, 81)

After Xpert introduced: 5 days (2, 8)

Helb 2010Xpert (1 sample): 1 hour 55 minutes

Xpert (8 samples processed together): 2 hours
  

Lawn 2011Median* (IQR)

Xpert: 4 days (3, 6)

Smear: 3 days (2, 5)

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

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

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

Phenotypic DST (liquid culture): mean 40 days

 
 

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

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

Moure 2011Xpert: total time of 2 hours  

Rachow 2011Xpert: within two hours  

Zeka 2011**Xpert (routine practice): 3-24 hours

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

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