High diagnostic value of miRNAs for NSCLC: quantitative analysis for both single and combined miRNAs in lung cancer

Figures & data

Figure 1. Flowchart of study selection based on the inclusion and exclusion criteria.

Figure 2. The characteristics for included miRNAs of involved articles. (a) The proportion of sample sources for researched single-miRNAs and miRNA panels miRNAs in all included articles. (b)The relationship between total reported miRNAs and LC subtypes. (c) The proportion of specimen sources among 20 included single-miRNAs. Tumour type: AD: adenocarcinoma; SCC: squamous cell carcinoma; SCLC: small cell lung carcinoma; NSCLC: non-small cell lung carcinoma. Sample sources: EBC: exhaled breath condensate; PB: peripheral blood; PBMCs: peripheral blood mononuclear cells; BALF: bronchoalveolar lavage; PLF: pleural lavage fluid.

Table 1. The main features of eligible studies that related to the diagnosis of miRNA for LC.

Study ID	Region	NO. of Case/Control	Tumor-type	Stage*	Sample sources	PMID
2020.Zhang, Z. J. [34]	China	330/312	NSCLC	I-IV	Serum exosomal	33178588
2020.Yang, C. [35]	China	74/23	NSCLC	III-IV	Serum	32466856
2020.Wu, Q. [36]	USA	48/48	NSCLC	I-II	Serum exosomal	32021461
2020.Wang, W. [37]	China	54/28	NSCLC	I	Blood	32596148
2020.Wang, J. Y. [38]	China	82/90	AD	I-IV	Serum	32388809
2020.Liu, X. [39]	China	245/245	NSCLC	I-IV	Serum	31906699
2020.Liu, C. [40]	USA	64/15	NSCLC	I-II	Serum exosomal	32265989
2020.Liao, J. [41]	USA	132/127	NSCLC	I-IV	Sputum, Plasma	31994346
2020.Ghany, S. M. A. [42]	Egypt	70/34	NSCLC	NA	Plasma	NA
2020.Fehlmann, T. [43]	USA	606/2440	LC	I-IV	Blood	32134442
2020.Asakura, K. [44]	Japan	1566/2178	LC	I-IV	Serum	32193503
2019.Zou, J. G. [45]	China	50/30	NSCLC	NA	Serum	30779079
2019.Zhang, Y. [46]	China	172/137	NSCLC	I-III	Serum exosomal	31146974
2019.Xi, K. [47]	China	67/25	NSCLC	I-II	Plasma	31632908
2019.Wang, S. [48]	China	50/24	NSCLC	NA	Plasma	31049003
2019.Szczyrek, M. [49]	Poland	160/45	NSCLC	I-IV	Plasma	31115013
2019.Switlik, W. Z. [50]	Poland	14/29	AD	NA	Serum	30950648
2019.Sui, A. [51]	China	76/60	NSCLC	I-IV	Serum	30867756
2019.Sheervalilou, R. [52]	Iran	47/41	NSCLC	I-IV	Plasma	32215263
2019.Roman-Canal, B. [53]	Spain	14/21	LC	NA	PLF	31636323
2019.Li, J. [54]	China	471/489	AD, SCC	I-IV	Plasma	31674214
2019.Hetta, H. F. [55]	USA	40/20	NSCLC	I-IV	Plasma	31244320
2019.Abdollahi, A. [56]	Iran	43/43	NSCLC	I-IV	Blood	31236600
2018.Yang, Y. L. [57]	China	194/199	NSCLC	III-IV	PBMCs	30064233
2018.Yang, Y. [58]	China	104/50	NSCLC	I-IV	Serum	29430184
2018.Xi, K. X. [59]	China	42/15	NSCLC	I-II	Plasma	30174846
2018.Sun, Y. [60]	China	28/28	AD	I-IV	Plasma	29103767
2018.Qiu, F. [61]	China	58/42	LC	NA	PB	30556877
2018.Poroyko, V. [62]	USA	20/10	LC	NA	Serum exosomal	29731983
2018.Mohamed, M. A. [63]	Egypt	50/50	LC	I-IV	Lung tissue	29437031
2018.Leng, Q. [64]	USA	56/28	NSCLC, SCC, AD	I-IV	Plasma	29783093
2018.Fan, L. H. [65]	China	128/79	NSCLC	I	Serum	NA
2018.Bao, M. [66]	China	80/75	NSCLC	I-IV	Serum, Lung tissue	31938164
2018.Bagheri, A. [67]	Iran	30/30	NSCLC, SCC, AD	I-IV	Sputum	30485511
2018.Aiso, T. [68]	Japan	56/26	NSCLC	I-IV	Serum	30405804
2018.Abu-Duhier, F.M. [69]	Saudi Arabia	80/80	AD, SCC	I-IV	Plasma	30256067
2017.Zhang, H. [70]	China	129/83	NSCLC	I-II	Plasma	28356944
2017.Yu, Y. [71]	USA	50/30	SCLC	I-IV	Plasma	28106539
2017.Sheervalilou, R. [72]	Iran	30/30	NSCLC	I-III	BALF, Sputum	NA
2017.Shang, A. Q. [73]	China	127/112	NSCLC	I-IV	Serum	28253725
2017.Lv, S. [74]	China	160/160	AD	I-IV	Serum	28123597
2017.Leng, Q. [75]	USA	126/118	NSCLC	I-IV	Plasma	29340099
2017.Ibrahim, F. K. [76]	Egypt	15/15	LC	NA	EBC	NA
2017.Bagheri, A. [77]	Iran	17/17	NSCLC	I-IV	Sputum, Lung tissue	29090068
2016.Zhu, W. [78]	China	112/104	NSCLC	I-II	Serum	27093275
2016.Zaporozhchenko, I.A. [79]	Russia	75/50	SCC, AD	II-IV	Plasma	27768748
2016.Wang, X. [80]	China	59/59	NSCLC	I-IV	Plasma	27499953
2016.Su, Y^b. [81]	USA	57/62	NSCLC	I	Sputum	27777637
2016.Su, Y^a. [82]	USA	117/174	NSCLC	I	Sputum	27176474
2016.Razzak, R. [83]	Canada	43/10	NSCLC	I-II	Sputum	27122989
2016.Jia, Y. C. [84]	China	35/30	NSCLC, SCLC	NA	Plasma	NA
2016.Chen, J. L. [85]	China	30/30	NSCLC	I-II	EBC, Serum	NA
2015.Zhao, W. [86]	China	80/60	NSCLC	NA	Serum	26628958
2015.Yang, J. S. [87]	China	152/300	NSCLC	I-IV	Serum	25501703
2015.Yan, H. J. [88]	China	300/300	NSCLC	I-IV	PB	25765717
2015.Xing L. [89]	USA	203/227	LC	I-II	Sputum	25593345
2015.Wang, R. J. [90]	China	70/70	NSCLC	NA	Serum	25755772
2015.Wang, P. [91]	China	142/111	NSCLC	I-II	Serum	25639977
2015.Su, J. [92]	USA	56/73	NSCLC	NA	Sputum	26309391
2015.Li, W. [93]	China	11/11	NSCLC, SCC	NA	Plasma	26237047
2015.Fan, L. [94]	China	164/112	NSCLC	I-III	Serum	26695145
2015.Dou, H. [95]	China	120/360	NSCLC	I-IV	Plasma	26309587
2014.Zhu, W. Y. [96]	China	36/44	NSCLC	I	Serum	24945821
2014.Li, N. [97]	USA	35/40	NSCLC	NA	Sputum	24281335
2014.Geng, Q. [98]	China	151/85	NSCLC, SCC, AD	I-II	Plasma	25421010
2013.Zeng, X. L. [99]	China	64/26	NSCLC	I-IV	PBMCs	24286416
2013.Tang, D. [100]	China	96/92	NSCLC, SCC, AD	I-III	Plasma	23462458
2013.Mozzoni, P. [101]	Italy	54/46	NSCLC	I-III	Plasma, EBC	24102090
2013.Anjuman, N. [102]	USA	43/47	NSCLC	I	Sputum	24053570
2013.Abd El Fattah, A. A. [103]	Egypt	65/37	LC	NA	Serum	23559272
2012.Wang, B. [104]	China	31/39	LC	I-IV	Serum	22638884
2011.Wei, J^b. [105]	China	77/36	NSCLC	I-IV	Plasma	21627863
2011.Wei, J^a. [106]	China	63/30	NSCLC	I-IV	Plasma	23483517
2011.Shen J^b. [107]	USA	58/29	NSCLC, SCC, AD	III-IV	Sputum	21116241
2011.Shen J^a. [108]	USA	108/113	NSCLC	I-IV	Sputum, Plasma	21864403
2011.Li, Y. [109]	China	20/10	NSCLC	I-IV	PB	22866162
2011.Jeong, H. C. [110]	Korea	35/30	NSCLC	I-IV	Blood	21468581
2010.Yu, L. [111]	USA	64/58	NSCLC, AD	I-IV	Sputum	21351266
2010.Xing, L. [112]	USA	67/55	SCC	III-IV	Sputum	20526284
2010.Xie, Y. [113]	USA	23/17	NSCLC	I-IV	Sputum	19446359

^a,b: Different articles by the same author initials in the same year. *: The stage of clinical diagnosis in the CASE group, in which stage I-IV represents patients who are not classified as stage I-II or III-IV, including II-III, I-III, I-IV. NA: not available.

Tumor type: AD: Adenocarcinoma; SCC: Squamous cell carcinoma; SCLC: Small cell lung carcinoma; NSCLC: Non-Small Cell Lung Carcinoma; LC: lung cancer.

Sample sources: EBC: exhaled breath condensate; PB: Peripheral blood; PBMCs: Peripheral blood mononuclear cells; BALF: bronchoalveolar lavage; PLF: Pleural lavage fluid.

Table 2. Detailed assessment of overall diagnostic value of 20 single-miRNAs in NSCLC.

miRNA-type	No. of research (Case/Control)	Sen [95% CI]	Spe [95% CI]	PLR [95% CI]	NLR [95% CI]	AUC [95% CI]	DOR [95% CI]
miR-21	23 (1641/1503)	0.70 [0.64–0.76]	0.77 [0.73–0.81]	3.1 [2.6–3.6]	0.39 [0.32–0.46]	0.81 [0.77–0.84]	8 [6–11]
miR-210	11 (670/645)	0.71 [0.57–0.82]	0.81 [0.70–0.88]	3.7 [2.6–5.3]	0.36 [0.26–0.51]	0.83 [0.79–0.86]	10 [7–15]
miR-145	11 (762/626)	0.73 [0.57–0.84]	0.75 [0.66–0.82]	2.9 [2.1–4.0]	0.36 [0.22–0.58]	0.80 [0.76–0.83]	8 [4–16]
miR-155	10 (697/555)	0.77 [0.63–0.87]	0.84 [0.72–0.91]	4.8 [2.6–8.9]	0.27 [0.16–0.46]	0.88 [0.85–0.91]	18 [7–47]
miR-486	10 (491/404)	0.75 [0.71–0.78]	0.76 [0.68–0.82]	3.1 [2.3–4.2]	0.33 [0.28–0.39]	0.77 [0.73–0.80]	9 [6–14]
miR-17	9 (1339/1170)	0.78 [0.63–0.88]	0.86 [0.77–0.92]	5.7 [3.1–10.3]	0.26 [0.15–0.46]	0.90 [0.87–0.92]	22 [8–60]
miR-126	8 (531/430)	0.70 [0.51–0.84]	0.85 [0.76–0.91]	4.6 [2.8–7.6]	0.36 [0.21–0.62]	0.86 [0.83–0.89]	13 [5–31]
miR-223	7 (605/419)	0.78 [0.73–0.83]	0.81 [0.72–0.87]	4.0 [2.7–6.0]	0.27 [0.21–0.35]	0.85 [0.82–0.88]	15 [8–27]
miR-31	7 (873/819)	0.73 [0.63–0.81]	0.78 [0.74–0.81]	3.3 [2.8–3.8]	0.35 [0.25–0.48]	0.80 [0.77–0.84]	9 [6–14]
miR-20	7 (329/239)	0.68 [0.47–0.84]	0.88 [0.72–0.95]	5.6 [2.6–12.2]	0.36 [0.21–0.62]	0.86 [0.83–0.89]	15 [6–37]
miR-182	6 (444/227)	0.57 [0.43–0.70]	0.79 [0.61–0.90]	2.7 [1.5–4.9]	0.54 [0.42–0.70]	0.72 [0.68–0.76]	5 [2–10]
miR-146	6 (306/247)	0.58 [0.36–0.76]	0.86 [0.62–0.96]	4.0 [1.6–10.0]	0.49 [0.33–0.74]	0.78 [0.75–0.82]	8 [3–22]
miR-205	6 (332/270)	0.57 [0.43–0.69]	0.78 [0.53–0.92]	2.6 [1.2–5.7]	0.55 [0.44–0.69]	0.68 [0.64–0.72]	5 [2–11]
miR-19	6 (470/363)	0.81 [0.70–0.89]	0.66 [0.53–0.77]	2.4 [1.7–3.4]	0.29 [0.18–0.45]	0.81 [0.77–0.84]	8 [4–16]
miR-221	6 (283/176)	0.52 [0.28–0.74]	0.75 [0.60–0.86]	2.1 [1.2–3.8]	0.64 [0.39–1.04]	0.73 [0.68–0.76]	3 [1–9]
miR-200	5 (200/154)	0.58 [0.48–0.67]	0.74 [0.60–0.84]	2.2 [1.5–3.4]	0.57 [0.46–0.70]	0.69 [0.64–0.73]	4 [2–7]
Let-7	5 (297/486)	0.67 [0.57–0.75]	0.74 [0.65–0.81]	2.5 [1.7–3.9]	0.45 [0.32–0.65]	0.76 [0.72–0.80]	6 [3–12]
miR-125	4 (466/456)	0.67 [0.57–0.75]	0.66 [0.57–0.73]	1.9 [1.6–2.3]	0.51 [0.41–0.62]	0.71 [0.67–0.75]	4 [3–5]
miR-7	4 (168/86)	0.66 [0.44–0.83]	0.86 [0.66–0.95]	4.8 [2.1–10.6]	0.39 [0.23–0.66]	0.85 [0.81–0.88]	12 [5–28]
miR-10	4 (351/345)	0.79 [0.72–0.85]	0.88 [0.73–0.96]	6.8 [2.6–17.8]	0.24 [0.16–0.34]	0.85 [0.82–0.88]	29 [8–103]

Sen: sensitivity; Spe: specificity; PLR: positive likelihood ratio; NLR: negative likelihood ratio; AUC: area under curve; DOR: diagnostic odds ratio; CI: confidence interval.

Figure 3. The diagnostic value of several single-miRNAs in NSCLC between different sample sources. (a–d) The difference in diagnostic power of a certain miRNA between respiratory-based and blood-based samples for NSCLC (a–b) and early NSCLC (c–d) through comparison of sensitivity (a, c) and specificity (b, d). Colour in dark gray refers to respiratory-based samples while colour in light gray refers to blood-based samples.

Table 3. The overall diagnostic value of single miRNAs in early NSCLC.

miRNA-type	No. of research (Case/Control)	Sen [95% CI]	Spe [95% CI]	PLR [95% CI]	NLR [95% CI]	AUC [95% CI]	DOR [95% CI]
miR-21	10 (703/606)	0.74 [0.62–0.83]	0.76 [0.68–0.82]	3.1 [2.4–3.9]	0.35 [0.25–0.49]	0.81 [0.78–0.84]	9 [6–13]
miR-145	4 (342/260)	0.59 [0.34–0.80]	0.86 [0.68–0.95]	4.2 [2.0–8.8]	0.48 [0.28–0.82]	0.83 [0.79–0.86]	9 [3–23]
miR-126	4 (170/160)	0.56 [0.30–0.79]	0.81 [0.70–0.89]	2.9 [1.9–4.5]	0.55 [0.32–0.95]	0.80 [0.77–0.84]	5 [2–13]
miR-210	4 (251/298)	0.64 [0.46–0.78]	0.83 [0.76–0.88]	3.8 [2.6–5.5]	0.44 [0.28–0.68]	0.84 [0.81–0.87]	9 [4–18]
miR-146	4 (144/89)	0.49 [0.25–0.75]	0.93 [0.79–0.98]	7.3 [2.6–20.2]	0.54 [0.33–0.90]	0.89 [0.86–0.92]	13 [4–43]

Sen: sensitivity; Spe: specificity; PLR: positive likelihood ratio; NLR: negative likelihood ratio; AUC: area under curve; DOR: diagnostic odds ratio; CI: confidence interval.

Figure 4. Containment relationship of analyzed single-miRNAs as different combined groups for NSCLC. The colour of each miRNA depends on their AUC value shown in Table 2. Panel-1contains three miRNAs (miR-21, -31, -210), Model-1 contains 20 miRNAs and Model-2 contains 14 miRNAs.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.