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Table 3 Relative risk estimations for breast cancer among insulin treatment groups and the evaluation of bias and power of the studies

From: Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

Author, year Exposure of interest Exposure comparison group Cases/controls*** or cases/person-years**** in exposure group (number) Cases/controls*** or cases/person-years****in comparison group (number) Risk Ratio** 95 % CI Risk of bias Power
Any insulin-no insulin: hazard ratio
Carstensen et al., 2012 [43] Insulin users No insulin users 248/102,500 2,118/627,100 0.96 0.84, 1.09 Moderate Adequate
Ferrara et al., 2011 [48] Insulin users No insulin users NR NR 1.0 0.9, 1.2 Moderate Adequate
Neumann et al., 2012 [60] Insulin users No insulin users NR/NR* NR/NR* 0.86 0.81, 0.91 High Adequate
Onitilo et al., 2014 [61] Insulin users No insulin users NR/NR* NR/NR* 0.84 0.58, 1.23 High Too low
Any insulin-no insulin: odds ratio
Bodmer et al., 2010a [41] Insulin users No insulin users 43/131 262/1,022 NE NE High Too low
Cleveland et al., 2012 [45] Insulin users No insulin users 20/16 50/49 1.15 0.40, 3.40 High Too low
Any insulin-NIAD: hazard ratio
Currie et al., 2009a [6] Insulin users Metformin only NR/12,640* NR/34,847* 1.07 0.79, 1.44 Moderate Too low
Redaniel et al., 2012a [62] Insulin and NIAD users Sulfonylurea only users 33/8,233.8 93/27,308.2 1.23 0.63, 2.38 Low Too low
Redaniel et al., 2012b [62] Insulin only users Sulfonylurea only users 8/2,247.3 93/27,308.2 1.67 0.70, 3.99 Low Too low
Vallarino et al., 2013****** [67] Pioglitzone users, not using insulin Insulin users, not using pioglitazone 181/29,721 113/13,680 0.85 0.67, 1.08 High Low
Any insulin-NIAD: odds ratio
Hsieh et al., 2012 [53] Insulin only users Metformin only users 5/NR 19/NR 1.63 0.60, 4.40 High Too low
Koro et al., 2007a [54] Insulin and NIAD users TZD users 13/52 83/449 0.71 0.36, 1.37 High Too low
Koro et al., 2007b [54] Insulin only users TZD users 9/62 83/449 1.27 0.61, 2.67 High Too low
Glargine-no glargine: hazard ratio
Bordeleau et al., 2014***** [42] Glargine users Standard care, not using glargine 28/11,620* 28/12,845* 1.15 0.67, 1.97 Low Too low
Home and Lagarenne, 2009***** [52] Glargine users Any anti-diabetic drug, NPH in 20 studies 4/4,711 6/4,524 0.62 0.17, 2.18 Moderate Too low
Rosenstock et al., 2009 [63] Glargine users NPH users 3/2,144 5/2,096 0.90 0.64, 1.26 Low Too low
Chang et al., 2011***** [44] Glargine users, not using int-/long-acting HI Non-glargine int/long-acting HI users 6/6,558.8* 65/47,724.6* 0.53 0.21, 1.31 Moderate Too low
Colhoun et al., 2009a [5] Glargine plus non-glargine insulin users Non-glargine insulin users 0/NR 29/9,667* NE NE High Too low
Colhoun et al., 2009b***** [5] Glargine only users Non-glargine insulin users 6/1,200* 29/9,667* 1.47 0.59, 3.64 High Too low
Currie et al., 2009b***** [6] Glargine users Non-glargine insulin users 10/2,245* 38/8,102* 0.86 0.42, 1.75 Moderate Too low
Fagot et al., 2013a***** [47] Glargine users Other int-/long-acting insulin only users 114/42,129* 40/14,082* 1.08 0.72, 1.62 High Too low
Habel et al., 2013a**** * [51] Glargine users NPH insulin users 52/10,614.8 217/60,868.1 1.3 1.0, 1.8 Moderate Too low
Habel et al., 2013b [51] Glargine only users NPH insulin users 33/6,402.4 217/60,868.1 1.3 0.9, 2.0 Moderate Too low
Habel et al., 2013c [51] Glargine and NPH insulin users NPH insulin users 19/4,212.5 217/60,868.1 1.3 0.8, 2.0 Moderate Too low
Kostev et al., 2012a***** [55] Glargine users NPH insulin users NR NR 0.93 0.68, 1.27 High Too low
Lind et al., 2012a***** [56] Glargine users Non-glargine users 19/7,019.4 96/48,889.6* 1.54 0.90, 2.67 Moderate Too low
Morden et al., 2011a [59] Glargine plus non-glargine insulin users Non-glargine insulin users 102/18,889* 333/65,294* 1.08 0.86, 1.36 High Low
Morden et al., 2011b***** [59] Glargine only users Non-glargine insulin users 118/21,071* 333/65,294* 1.03 0.83, 1.29 High Low
Ruiter et al., 2012a***** [64] Glargine only users Human insulin only users 11/6,875* NR; IR=2.28* 1.65 1.10, 2.47 Moderate Too low
Sturmer et al., 2013a **** [65] Glargine users NPH users 103/26,277 19/5,885 1.07 0.65, 1.75 Moderate Too low
Suissa et al., 2011a***** [66] Glargine users Non-glargine insulin users 18/6,094 60/12,262 0.8 0.3, 2.1 Moderate Too low
Pooled hazard ratio Glargine No glargine    1.04 0.91, 1.17   
Glargine-no glargine: incidence rate ratio
Ljung et al., 2011a [57] Glargine plus non-glargine insulin users Non-glargine insulin users 59/25,033 283/101,419 1.04 0.77, 1.41 High Low
Ljung et al., 2011b [57] Glargine only users Non-glargine insulin users 31/7,302 283/101,419 1.58 1.09, 2.29 High Too low
Glargine-no glargine: odds ratio
Grimaldi-Bensouda et al., 2013a [49] Glargine users Non-glargine users 78/287 697/2,763* 1.04 0.76, 1.44 Low Borderline
Grimaldi-Bensouda et al., 2013b [49] Glargine users Non-glargine insulin users 74/203 70/207 0.96 0.61, 1.53 Low Too low
Grimaldi-Bensouda et al., 2013c [49] Glargine users Human insulin users NR NR 1.29 0.78, 2.13 Low NE
Grimaldi-Bensouda et al., 2013d [49] Glargine users Aspart users NR NR 1.10 0.64, 1.89 Low NE
Grimaldi-Bensouda et al., 2013e [49] Glargine users Lispro users NR NR 0.85 0.48, 1.50 Low NE
Mannucci et al., 2010a [58] Glargine users Non-glargine insulin users NR NR NE NE High Too low
Determir-no determir: hazard ratio
Fagot et al., 2013b [47] Determir users Other int-/long-acting insulin only users 38/12,806* 116/43,131* 1.08 0.72, 1.62 High Too low
Kostev et al., 2012b [55] Detemir users NPH insulin users NR/789 NR/4,206 1.17 0.66, 2.06 High Too low
Determir-no determir: incidence rate ratio
Dejgaard et al., 2009a [46] Determir users NPH users 1/2,252 0/1,420 NE NE Low Too low
Dejgaard et al., 2009b [46] Determir users Glargine users 1/917 3/628 NR NR Low Too low
Aspart-no aspart: odds ratio
Grimaldi-Bensouda et al., 2013f [55] Aspart users Non-aspart users 54/241 721/2,809* 0.95 0.64, 1.40 Low Borderline
Lispro-no lispro: odds ratio
Grimaldi-Bensouda et al., 2013g [49] Lispro users Non-lispro users 46/133 729/2,917* 1.23 0.79, 1.92 Low Borderline
Human insulin-no human insulin: hazard ratio
Fagot et al., 2013c [47] Basal human insulin users Other int-/long-acting insulin only users 15/5,813* 139/50,948* 1.03 0.56, 1.88 High Too low
Gu et al., 2013 [50] Human insulin users No insulin users 4/6,188* 14/10,435* 0.33 0.10, 1.13 Moderate Too low
Ruiter et al., 2012b [64] Non-glargine insulin users Human insulin only users 31/15,578* NR; IR=2.28* 0.99 0.81, 1.20 Moderate Too low
Human insulin-no human insulin: odds ratio
Grimaldi-Bensouda et al., 2013h [49] Human insulin users Non-human insulin users 59/260 716/2,790* 0.81 0.55, 1.20 Low Borderline
  1. Bold values are significantly different. *Calculated using data provided (if not indicated directly these were taken from the table in the paper). **Risk estimates are adjusted for covariates as stated in Additional file 1: Table S3. Covariates used in the various analyses are the same within one study. ***Case–control studies. ****Cohort studies or randomized clinical trials. *****Included in meta-analysis. ******The exposure of interest is the exposure comparison group in this analysis. Studies are first ordered by type of exposure and then by type of risk estimate. Note: Hiesh 2012 is a cohort study but provided odds ratio estimates in the paper. Names of exposure groups are defined by the authors of the study. Several papers showed multiple risk estimates for the same exposure with different analytical approaches. For each study and exposure, the results from the least biased or best performed analyses are shown; showing hazard ratios, incidence rate ratios or odds ratios as applicable. Different exposure comparisons within one study are indicated by a,b,c etc. We choose to include the risk estimate that gave (in order of importance): 1) estimates for incident users was preferred over estimates for prevalent users; 2) as-treated analysis (during study period/follow up) was preferred over intention-to-treat analysis (during fixed period/at baseline); 3) estimates with the longest latency period were preferred. Estimates from statistical models adjusted for covariates were preferred over crude estimate. NR not reported, NE not estimated, HI human insulin, TZD Thiazolidinedione, NIAD non-insulin anti-diabetic drug, NPH Neutral Protamine Hagedorn, Int intermediate.
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