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Study flow diagram
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Figure 1

Study flow diagram

'Risk of bias' and applicability concerns summary: review authors' judgements about each domain for each included study
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Figure 2

'Risk of bias' and applicability concerns summary: review authors' judgements about each domain for each included study

'Risk of bias' and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies
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Figure 3

'Risk of bias' and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies

Forest plot of studies with Activity > background as the criterion for test positivity
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Figure 4

Forest plot of studies with Activity > background as the criterion for test positivity

Forest plot of studies with SUVmax ≥ 2.5 as the criterion for test positivity
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Figure 5

Forest plot of studies with SUVmax ≥ 2.5 as the criterion for test positivity

Forest plot of studies with Other/mixed/unclear criteria for test positivity
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Figure 6

Forest plot of studies with Other/mixed/unclear criteria for test positivity

Summary ROC Plot of studies with Activity > background as the criterion for test positivity. Empty squares represent individual study estimates, with the size of the square proportional to the study sample size. The solid line represent the SROC curve. The filled circle is the summary point representing the average sensitivity and specificity estimates. The ellipses around this summary point are the 95% confidence region (dotted line) and the 95% prediction region (dashed line). The dashed upward diagonal represents the completely uninformative test
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Figure 7

Summary ROC Plot of studies with Activity > background as the criterion for test positivity. Empty squares represent individual study estimates, with the size of the square proportional to the study sample size. The solid line represent the SROC curve. The filled circle is the summary point representing the average sensitivity and specificity estimates. The ellipses around this summary point are the 95% confidence region (dotted line) and the 95% prediction region (dashed line). The dashed upward diagonal represents the completely uninformative test

Summary ROC Plot of studies with SUVmax > 2.5 as the criterion for test positivity. Empty squares represent individual study estimates, with the size of the square proportional to the study sample size. The solid line represent the SROC curve. The filled circle is the summary point representing the average sensitivity and specificity estimates. The ellipses around this summary point are the 95% confidence region (dotted line) and the 95% prediction region (dashed line). The dashed upward diagonal represents the completely uninformative test
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Figure 8

Summary ROC Plot of studies with SUVmax > 2.5 as the criterion for test positivity. Empty squares represent individual study estimates, with the size of the square proportional to the study sample size. The solid line represent the SROC curve. The filled circle is the summary point representing the average sensitivity and specificity estimates. The ellipses around this summary point are the 95% confidence region (dotted line) and the 95% prediction region (dashed line). The dashed upward diagonal represents the completely uninformative test

Investigations of possible sources of heterogeneity
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Figure 9

Investigations of possible sources of heterogeneity

PET/CT.
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Test 1

PET/CT.

Summary of findings 'Summary of findings' table

PET‐CT for assessing mediastinal lymph node involvement in participantswith suspected resectable non‐small cell lung cancer

Population

Participants with suspected/confirmed NSCLC who are considered potentially suitable for primary resection

Index test

PET‐CT carried out on the various available integrated PET‐CT scanners with cut‐off values for test positivity as reported in the included studies

Target condition

Resectable NSCLC defined as NSCLC that has not spread to either the ipsilateral mediastinal lymph nodes, subcarinal (N2) lymph nodes, or both

Reference standard

Pathological confirmation of PET‐CT results

Included studies

45 studies with 6095 participants available for analysis (median = 112, interquartile range (IQR) = 54 to 169), 4551 of whom were N0 or N1 and 1544 participants were N2 or N3

Different criteria for test positivity were used in the included studies:

Activity > background (18 studies; N = 2823; prevalence of N2 and N3 nodes = 679/2328)

SUVmax ≥ 2.5 (12 studies; N = 1656; prevalence of N2 and N3 nodes = 465/1656)

Other/mixed criteria for test positivity (15 studies; N = 1616; prevalence of N2 and N3 nodes = 400/1616)

None of the studies reported (any) adverse events

Test subgroup

Number of participants

(studies)

Prevalence %

Summary accuracy % (95% CI)

Implications

Quality and comments

Activity > background

2823 (18)

29.2

Sensitivity: 77.4 (65.3 to 86.1)

Specificity: 90.1 (85.3 to 93.5)

With the observed prevalence,

there will be 66 missed cases

and 70 cases who will receive futile surgery

Participant selection, index test, and flow and timing poorly reported

Population spectrum narrower than in standard clinical practice in a substantial number of studies

Results sensitive to selection bias, reference standard bias, and clear definition of test positivity

Substantial heterogeneity was observed

SUVmax ≥ 2.5

1656 (12)

28.1

Sensitivity: 81.3 (70.2 to 88.9)

Specificity: 79.4 (70.0 to 86.5)

With the observed prevalence,

there will be 53 missed cases

and 148 cases who will receive futile surgery

Participant selection, index test and flow, and timing poorly reported

Population spectrum narrower than in standard clinical practice in a substantial number of studies

Results sensitive to flow and timing bias and commercial funding bias

Substantial heterogeneity was observed

All included studies

6095

25.3

Heterogeneity analyses showed significant contributions to between‐study heterogeneity from the following covariates: country of study origin, percentage of participants with adenocarcinoma, FDG dose, type of PET‐CT scanner, and study size. Study design, consecutive recruitment, attenuation correction, year of publication, and tuberculosis incidence rate per 100,000 population did not contribute significantly to the observed heterogeneity

CAUTION: The results in this table should not be interpreted in isolation from the results of the individual included studies contributing to each summary test accuracy measure. These are reported in the main body of the review

CI = confidence interval.
FDG = (¹⁸F)‐2‐fluoro‐deoxy‐D‐glucose.
IQR = interquartile range.
NSCLC = non‐small cell lung cancer.
PET‐CT = positron emission tomography–computed tomography.
SUVmax = maximum standardised uptake value.

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Summary of findings 'Summary of findings' table
Table 1. Study details

Study ID

First author, year of publication

Patient sampling

Prospective/retrospective, case‐control/consecutive/random patient series

Patient characteristics and setting

Inclusion and exclusion criteria, previous tests for lung cancer (diagnosis and staging), clinical setting, sample size, age, sex, comorbidities, country, histology of primary tumour

Index test

Details of the index test used including the type of PET‐CT scanner, FDG dose, injection‐to‐scan time, attenuation correction, and the cut‐off values for test positivity (malignancy)

Reference standard(s)

The reference standard(s) used

Flow and timing

All participants were accounted for in results, missing/uninterpretable test results, reasons for withdrawal, adverse events caused by test, the time interval, and any interventions between index test(s) and reference standard

Notes

Source of funding, anything else of relevance

FDG = (¹⁸F)‐2‐fluoro‐deoxy‐D‐glucose.
PET‐CT = positron emission tomography and computed tomography.

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Table 1. Study details
Table 2. Risk of bias and applicability items and criteria for their assessment

Item

Description

Domain 1: Patient selection

A. Risk of bias

Patient sampling

The study design will be listed here 

Was a consecutive or random sample of participants enrolled?

'Yes' if a consecutive or random sample of participants were enrolled
'No' if a consecutive or random sample of participants were not enrolled
'Unclear' if the study does not describe the method of participants enrolment

Was a case‐control design avoided?

'Yes' if the study has not used a case‐control design
'No' if the study has used a case‐control design
'Unclear' if the study does not report enough information to ascertain whether a case‐control design was used

Did the study avoid inappropriate exclusions?

'Yes' if the characteristics of the participants are well described and probably typical of a secondary healthcare setting
'No' if the sample is unrepresentative of people with potentially resectable lung cancer in general
'Unclear' if the source or characteristics of participants is not adequately described

Could the selection of participants have introduced bias?

A judgement of low, high, or unclear risk of bias will be made based on a balanced assessment of the responses to the above signalling questions

B. Concerns about applicability

Patient characteristics and setting

The information detailed under 'Patient characteristics and setting' in the 'Characteristics of included studies' table will be listed here

Are there concerns that the included participants and setting do not match the review question?

A judgement of low, high, or unclear concerns about applicability will be made based on a balanced assessment of the response to the third signalling question above and on how closely the sample matches the target population of interest

Domain 2: Index test

Index test

The information detailed under 'Index test' in the 'Characteristics of included studies' table will be listed here

Were the index test results interpreted without knowledge of the results of the reference standard?

'Yes' if the report stated that the person undertaking the index test did not know the results of the reference tests or if the 2 tests were carried out in different places
'No' if the report stated that the same person performed both tests or that the results of the index tests were known to the person undertaking the reference tests
'Unclear' if insufficient information provided

Did the study provide a clear definition of what was considered to be a positive result?

'Yes' if the definition of a positive result is clearly stated (e.g., SUV)
'No' if no definition of what was considered a positive result is stated or the definition of a positive result varied between the participants
'Unclear' if not enough information is given to permit judgement

If a threshold was used, was it prespecified?

'Yes' if prespecified
'No' if the authors selected the optimal cut‐off value based on the results of the study
'Unclear' if there is a range of cut‐off values and there is doubt which cut‐off has been used, or if there is no mention at all of a cut‐off value

Could the conduct or interpretation of the index test have introduced bias?

A judgement of low, high, or unclear risk of bias will be made based on a balanced assessment of the responses to the above signalling questions

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

A judgement of low, high, or unclear concerns about applicability will be made based on a balanced assessment of the information detailed under 'Index test' with particular reference to the definition of test positivity/malignancy

Domain 3: Reference standard

Target condition and reference standard(s)

The information detailed under 'Reference standard(s)' in the 'Characteristics of included studies' will be listed here

Is the reference standards likely to correctly classify the target condition?

'Yes' if reference standard is sampling of mediastinal nodes with pathological diagnosis
'No' if there is no sampling of mediastinal nodes with pathological diagnosis

'Unclear' if insufficient information is provided

Were the reference standard results interpreted without knowledge of the results of the index tests?

'Yes' if the report stated that the person undertaking the index test did not know the results of the reference tests, or if the 2 tests were carried out in different places
'No' if the report stated that the same person performed both tests, or that the results of the index tests were known to the person undertaking the reference tests
'Unclear' if insufficient information provided

Could the reference standard, its conduct, or its interpretation have introduced bias?

A judgement of low, high, or unclear risk of bias will be made based on a balanced assessment of the responses to the above signalling questions

Are there concerns that the target condition as defined by the reference standard does not match the question?

The answer to this question will always be 'low' because the target condition that the reference standard defines will always be the target condition of the review, i.e., pathologically confined non‐small cell lung cancer. Otherwise, the study will not be included

Domain 3: Flow and timing

Flow and timing

The information detailed under 'Flow and timing' in the 'Characteristics of included studies' will be listed here

Was there an appropriate interval between index test and reference standard?

'Yes' if the time period between PET‐CT and the reference standard is ≤ 8 weeks
'No' if the time period between PET‐CT and the reference standard is > 8 weeks

'Unclear' if insufficient information is provided

Did all participants receive the same reference standard?

'Yes' if the same reference test was used regardless of the index test results
'No' if different reference tests are used depending on the results of the index test
'Unclear' if insufficient information is provided
If any participants received a different reference test, what were the reasons stated for this, and how many participants were involved?

Were all participants included in the analysis?

'Yes' if there are no participants excluded from the analysis, or if exclusions are adequately described
'No' if there are participants excluded from the analysis and there is no explanation given
'Unclear' if not enough information is given to assess whether any participants were excluded from the analysis
Report how many participants were excluded from the analysis for reasons other than uninterpretable results

Report how many results were uninterpretable (of the total)

Could the patient flow have introduced bias?

A judgement of low, high, or unclear risk of bias will be made based on a balanced assessment of the responses to the above signalling questions and of the information listed under 'Flow and timing'

Was the study free of commercial funding?

'Yes' if the funding source is clearly stated and is not commercial
'No' if the funding source is clearly stated and is commercial
'Unclear' if not enough information is given to assess whether the funding source is commercial

PET‐CT = positron emission tomography and computed tomography.
SUV = standardised uptake value.

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Table 2. Risk of bias and applicability items and criteria for their assessment
Table 3. Sensitivity analysis of PET‐CT accuracy for assessing mediastinal lymph node involvement

Covariate

N

Sen

(95% CI)

Spe

(95% CI)

Activity > background

18

77.4

(65.3 to 86.1)

90.1

(85.3 to 93.5)

Selection bias (low RoB)

6

67.2

(55.7 to 76.9)

89.7

(81.9 to 94.3)

Participants and setting (no concerns with applicability)

5

86.0

(55.2 to 96.8)

87.7

(77.7 to 93.5)

Index test bias (low RoB)

11

68.2

(59.1 to 76.1)

92.0

(87.4 to 95.0)

Index text (no concerns with applicability)

18

77.4

(65.3 to 86.1)

90.1

(85.3 to 93.5)

Reference standard (low RoB)

17

73.6

(63.0 to 82.0)

89.6

(84.6 to 93.1)

Reference standard bias (no concerns with applicability)

18

77.4

(65.3 to 86.1)

90.1

(85.3 to 93.5)

Flow and timing (low RoB)

10

77.0

(64.1 to 86.3)

90.5

(83.2 to 94.8)

Clear definition of test positivity (yes)

16

68.5

(60.7 to 75.4)

89.2

(84.1 to 92.7)

Non‐commercial funding (yes)

6

62.0

(53.5 to 69.8)

92.8

(85.8 to 96.5)

SUVmax ≥ 2.5

12

81.3

(70.2 to 88.9)

79.4

(70.0 to 86.5)

Selection bias (low RoB)

6

81.4

(62.3 to 92.1)

81.8

(72.1 to 88.7)

Participants and setting (no concerns with applicability)

4

88.2

(79.7 to 93.5)

76.2

(63.9 to 85.2)

Index test bias (low RoB)

7

82.7

(66.6 to 92.0)

75.8

(62.2 to 85.7)

Index text (no concerns with applicability)

12

81.3

(70.2 to 88.9)

79.4

(70.0 to 86.5)

Reference standard bias (low RoB)

12

81.3

(70.2 to 88.9)

79.4

(70.0 to 86.5)

Reference Standard (no concerns with applicability)

11

79.6

(67.8 to 87.9)

81.1

(72.7 to 87.4)

Flow and timing (low RoB)

6

74.4

(55.6 to 87.0)

75.6

(63.6 to 84.6)

Clear definition of test positivity (yes)

12

81.3

(70.2 to 88.9)

79.4

(70.0 to 86.5)

Non‐commercial funding (yes)

5

74.2

(54.6 to 87.3)

76.6

(61.4 to 87.1)

CI = confidence interval
N = number of participants

RoB = risk of bias
Sen = sensitivity
Spe = specificity

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Table 3. Sensitivity analysis of PET‐CT accuracy for assessing mediastinal lymph node involvement
Table Tests. Data tables by test

Test

No. of studies

No. of participants

1 PET/CT Show forest plot

45

6095

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Table Tests. Data tables by test