Table 1.
Study characteristics.
| Study ID | Region | Study Design | Cases | Histology | Stage | Controls | Cohort | Number of Cases | Number of Controls | Reference Standard |
|---|---|---|---|---|---|---|---|---|---|---|
| Usadel, 2002 [32] | Northern America | Case-control study | Retrospectively selected cases | LUSC 35/99 * (35%), LUAD 47/99 (48%), other 17/99 (17%) | I 53/99 * (54%), II 23/99 (23%), III 17/99 (17%), IV 6/99 (6%) | Unmatched healthy controls | Training | 71 serum, 33 plasma (15 matched) | 50 | Histopathology or cytology. |
| Ostrow, 2009 [30] | Northern America | Case-control study | Retrospectively selected cases | LUSC 6/13 (46%), LUAD 1/13 (8%), other 6/13 (46%) | Not reported | Matched on certain characteristics | Training | 13 | 24 | Tumor tissue biopsy/histopathology |
| LUSC 7/70 (10%), LUAD 47/70 (67%), other 16/70 (23%) | I 49/70 (70%), II 2/70 (3%), III 10/70 (14%), IV 4/70 (6%), no stage 5/70 (7%) | Validation | 70 | 23 with nodules + 80 smokers with no nodules | ||||||
| Zhang, 2010 A [33] | China | Case-control study | Retrospectively selected cases | LUSC 36/78 (46%), LUAD 30/78 (38%), other 12/78 (15%) | I–II 58/78 (74%), III–IV 20/78 (26%) | Unmatched healthy controls | Training | 78 | 50 | Histopathology or cytology |
| Zhang, 2010 B [34] | China | Case-control study | Retrospectively selected cases | LUSC 36/78 (46%), LUAD 30/78 (38%), other 12/78 (15%) | I–II 58/78 (74%), III–IV 20/78 (26%) | Unmatched healthy controls | Training | 78 | 50 | Tumor tissue biopsy/histopathology |
| Begum, 2011 [35] | Northern America | Case-control study | Retrospectively selected cases | LUSC 26/76 (34%), LUAD 36/76 (47%), other 14/76 (18%) | I 41/76 (54%), II 17/76 (22%), III 11/76 (14%), IV 5/76 (7%), unknown 2/76 (3%) | Matched on certain characteristics | Training | 76 | 30 | Histopathology or cytology |
| Kneip, 2011 [29] | EU | Case-control study | Retrospectively selected cases | LUSC 38/188 (20%), LUAD 31/188 (16%), SCLC 15/188 (8%), other/unknown 104/188 (55%) | I 37/188 (20%), II 29/188 (15%), III 53/188 (28%), IV 42/188 (22%), unknown 27/188 (14%) | Combination of healthy, benign and prostate cancer | Training | 188 | 155 | Histopathology or cytology |
| Ponomaryova, 2011 [23] | Other: Russia | Case-control study | Retrospectively selected cases | LUSC 34/52 (65%), LUAD 18/52 (35%) | I–II 25/52 (48%), III–IV 27/52 (52%) | Unmatched healthy controls | Training | 52 | 26 | Histopathology or cytology |
| Vinayanuwattikun, 2011 [36] | Other: Asian country | Case-control study | Retrospectively selected cases | NSCLC, not further described | The whole cohort was described as ‘advanced’. | Matched on certain characteristics | Training | 38 | 52 | Tumor tissue biopsy/histopathology |
| Balgkouranidou, 2014 A [37] | EU | Case-control study | Retrospectively selected cases | LUSC 23/44 # (52%), LUAD 20/44 (45%), missing 1/44 (2%) | I 14/44 # (32%), II–III 29/44 (66%), missing 1/44 (2%) | Unmatched healthy controls | Training | 48 | 24 (same used for training and validation) | Histopathology or cytology |
| LUSC 24/74 (32%), non-squamous 50/74 (68%) | IV 74/74 (100%) | Validation | 74 | 24 (same used for training and validation) | ||||||
| Powrozek, 2014 [38] | EU | Case-control study | Retrospectively selected cases | LUSC 20/70 (29%), LUAD 20/70 (29%), SCLC 23/70 (33%), other 7/70 (10%) | I 0/47 € (0%), II 7/47 (15%), III 23/47 (49%), IV 17/47 (36%) | Matched on certain characteristics | Training | 70 | 100 | Not described |
| Gao, 2015 [39] | China | Cohort study | Diagnostic work-up for LC | LUSC 23/58 (40%), LUAD 18/58 (31%), SCLC 2/58 (3%), other 15/58 (26%) | All were early-stage lung cancer (T1a–T2a) | Non-cancer participants who underwent diagnostic work-up | Training | 58 plasma 40 serum |
31 with benign disease, 23 healthy | Histopathology or cytology |
| Balgkouranidou, 2016 B [22] | EU | Case-control study | Retrospectively selected cases | LUSC 21/44 # (48%), LUAD 22/44 (50%), missing 1/44 (2%) | I 14/44 # (32%), II–III 29/44 (66%), missing 1/44 (2%) | Unmatched healthy controls | Training | 48 | 49 (same used for training and validation) | Tumor tissue biopsy/histopathology |
| LUSC 24/74 (32%), non-squamous 50/74 (68%) | IV 74/74 (100%) | Validation | 74 | 49 (same used for training and validation) | ||||||
| Powrozek, 2016 [40] | EU | Case-control study | Retrospectively selected cases | LUSC 20/65 (31%), LUAD 22/65 (34%), SCLC 19/65 (29%), other 4/65 (6%) | I 0/46 (0%), II 7/46 (15%), III 22/46 (48%), IV 17/46 (37%), limited 9/19 (47%), extensive 10/19 (53%) | Unmatched healthy controls | Training | 65 | 95 | Tumor tissue biopsy/histopathology |
| Powrozek, 2016 [41] | EU | Case-control study | Retrospectively selected cases | LUSC 30/70 (43%), LUAD 25/70 (36%), SCLC 15 (21%) | I 8/55 # (15%), II 12/55 (22%), III 19/55 (35%), IV 16/55 (29%) | Unmatched healthy controls | Training | 70 | 80 | Surgery specimen/histopathology |
| Aslam, 2017 [42] | Other: Asian country | Case-control study | Retrospectively selected cases | LUSC 19/34 (56%), LUAD 7/34 (21%), other 8/34 (24%) | Not reported | Matched on certain characteristics | Training | 34 | 34 | Tumor tissue biopsy/histopathology |
| Hulbert, 2017 [43] | Northern America | Cohort study | Diagnostic work-up for LC | LUSC 26/150 (17%), LUAD 121/150 (81%), other 3/150 (2%) | I 136/150 (91%), II 14/150 (9%), III 0/150 (0%), IV 0/150 (0%) | Non-cancer participants who underwent diagnostic work-up | Training | 125 | 50 | Surgery specimen/histopathology |
| Ooki, 2017 [44] | Northern America | Case-control study | Retrospectively selected cases | LUAD 43/43 (100%) | I 43/43 (100%) | Matched on certain characteristics | Training | 43 LUAD | 42 (same used for training and validation) | Histopathology or cytology |
| LUSC 40/40 (100%) | I 40/40 (100%) | Validation | 40 LUSC | 42 (same used for training and validation) | ||||||
| Nunes, 2019 [45] | EU | Case-control study | Retrospectively selected cases | LUSC 42/129 (33%), LUAD 65/129 (50%), SCLC 19/129 (15%), other 3/129 (2%) | I 15/129, II 11/129, III 27/129, IV 76/129 | Non-cancer participants who underwent diagnostic work-up | Training | 129 | 28 | Histopathology or cytology |
| Villalba, 2019 [46] | EU | Case-control study | Retrospectively selected cases | LUSC 38/89 (43%), LUAD 51/89 (57%) | I 8/89 (9%), II 8/89 (9%), III 19/89 (21%), IV 52/89 (58%), missing 2/89 (2%) | Matched on certain characteristics | Training | 89 | 25 | Surgery specimen/histopathology |
| Yang, 2019 [31] | China | Cohort study | Diagnostic work-up for LC | LUSC 12/39 (31%), LUAD 25/39 (64%), other 2/39 (5%) | I 39/39 (100%) | Non-cancer participants who underwent diagnostic work-up | Training | 39 | 11 | Surgery specimen/histopathology |
| Chen, 2020 [47] | China | Cohort study | Diagnostic work-up for LC | LUSC 22/163 (13%), LUAD 139/163 (85%), other 2/163 (1%) | I 163/163 (100%) | Non-cancer participants who underwent diagnostic work-up | Training | 163 | 83 | Surgery specimen/histopathology |
| Huang, 2020 [48] | China | Cohort study | Diagnostic work-up for LC | LUSC 15/104 (14%), LUAD 53/104 (51%), SCLC 3/104 (3%), other 1/104 (1%), missing 32/104 (31%) | I 48/104 (46%), II 15/104 (14%), III 20/104 (19%), IV 21/104 (20%) | Unmatched patients with benign diseases | Training | 104 | 36 with benign disease, 50 healthy | Surgery specimen/histopathology |
| LUSC 4/19 (21%), LUAD 14/19 (74%), other 1/19 (5%) | I 12/19 (63%), II 4/19 (21%), III 3/19 (16%) | Validation | 19 | 11 | ||||||
| Li, 2020 [49] | China | Case-control study | Retrospectively selected cases | LUSC 24/48 (50%), LUAD 18/48 (38%), other 6/48 (13%) | I–II 15/48 (31%), III–IV 33/48 (69%) | Unmatched healthy controls | Training | 48 | 51 | Histopathology or cytology |
| Wen, 2020 [50] | EU | Case-control study | Retrospectively selected cases | LUAD 48/48 (100%) | III 3/48 (6%), IV 45/48 (94%) | Unmatched healthy controls | Training | 48 | 100 | Histopathology or cytology |
| Xu, 2020 [51] | China | Case-control study | Retrospectively selected cases | LUSC 28/302 (9%), LUAD 236/302 (78%), SCLC 32/302 (11%), other 6/302 (2%) | I 68/302 (23%), II 62/302 (21%), III 72/302 (24%), IV 100/302 (33%) | Matched on certain characteristics | Training | 302 | 153 | Not described |
| Mastoraki, 2021 [52] | EU | Case-control study | Retrospectively selected cases | LUSC 19/48 (40%), LUAD 28/48 (58%), other 1/48 (2%) | I–II 28/48 (58%), III–IV 13/48 (27%), missing 7/48 (15%) | Matched on certain characteristics | Training | 48 early stage | 60 (same used for training and validation) | Histopathology or cytology |
| Not available | IV 91/91 (100%) | Validation | 91 stage IV | 60 (same used for training and validation) | ||||||
| Park, 2021 [53] | Other: Asian country | Case-control study | Retrospectively selected cases | Not available | Not available | Unmatched healthy controls | Training | 64 | 64 | Tumor tissue biopsy/histopathology |
| Szczyrek, 2021 [54] | EU | Case-control study | Diagnostic work-up for LC | LUSC 34/101 (34%), LUAD 52/101 (51%), SCLC 8/101 (8%), other 7/101 (7%) | IA–IIIA 27/101 (27%), IIIB–IV 66/101 (65%), missing 8/101 (8%) | Unmatched healthy controls | Training | 101 | 45 | Tumor tissue biopsy/histopathology |
| Kim, 2022 [55] | Other: Asian country | Case-control study | Diagnostic work-up for LC | LUSC 30/72 (42%), LUAD 31/72 (43%), other 11/72 (15%) | I 41/72 (57%), II 26/72 (36%), III 3/72 (4%), IV 2/72 (3%) | Unmatched patients with benign diseases | Training | 72 | 61 | Surgery specimen/histopathology |
| Palanca-Ballester, 2022 [56] | EU | Case-control study | Retrospectively selected cases | LUSC 13/44 (30%), LUAD 31/44 (70%) | I 4/44 (9%), II 7/44 (16%), III 3/44 (7%), IV 30/44 (68%) | Unmatched patients with benign diseases | Training | 44 | 39 | Other: Histopathology or cytology |
| Vo, 2022 [57] | Other: Asian country | Case-control study | Retrospectively selected cases | Not available | I 2/30 (7%), II 8/30 (27%), III 15/30 (50%), IV 5/30 (17%) | Unmatched healthy controls | Training | 30 | 27 | Other: Histopathology or cytology. |
| Zeng, 2022 [58] | China | Case-control study | Retrospectively selected cases | LUSC 58/121 (48%), LUAD 63/121 (52%) | I–II 78/121 (64%), III–IV 43/121 (36%) | Unmatched patients with benign diseases | Training | 121 | 121 | Surgery specimen/histopathology |
| Zhang, 2022 [59] | China | Case-control study | Retrospectively selected cases | LUSC 8/23 (35%), LUAD 10/23 (43%), SCLC 5/23 (22%) | I–II 2/23 (9%), III–IV 21/23 (91%) | Unmatched patients with benign diseases | Training | 23 | 56 | Histopathology or cytology |
Characteristics of all studies included in the review. Studies are arranged according to year of publication, starting with the oldest study and then alphabetically if more studies were published in the same year. Study cohorts used in more than one publication are labeled with A, B, etc. Independent training and validation cohorts are reported in separate rows. Study ID consists of the first author’s last name and the year of publication, followed by the reference. Region refers to the geographical region in which the study was performed. LC, lung cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer. * A subset of patients had blood samples collected, but data on histology and stage were only reported for the whole patient cohort. # The number of plasma samples was reported as n = 48; however, in the table reporting clinicopathological data for BRMS1 methylated, only n = 44 patients were reported. € The detailed disease stage was only reported for the NSCLC patients.