The influence of a range of apriori selected study-level and aggregated individual-level parameters on the observed effect estimate was investigated by means of meta-regressions. Table S5 summarizes the meta-regression analyses for all 51 results and is presented in the appendix. We observed that studies that used interviews to ascertain PPI exposure had on average lower effect estimates that studies that used medical records 1.17 (0.91, 1.51) vs. 1.89 (1.45, 2.45), p for interaction = 0.05 (Table 2). We also observed that studies that used adjusted effect estimates [1.76 (95% CI, 1.54, 2.00)] had higher pooled estimates than those that used unadjusted effect estimates [1.27 (95% CI, 0.93, 1.72)], p = 0.07. Publication bias. Figure 3 displays a contour-enhanced funnel plot with the corresponding fixed (FE) and random effect (RE) meta-analyses pooled estimates providing a weighted average of effect size across studies of 1.02 (95% CI, 1.01?.03) and 1.65 (95% CI, 1.47?.85) respectively. There was visual evidence of funnel asymmetry and Egger’s test for publication bias, P = 0.001. Hence, a novel regression based method was used to adjust for publication bias. The fitted regression line plotted in Figure 3 corresponds to the regression-based adjustment method. The adjusted estimate is obtained by extrapolating the line with a standard error of 0 (at the top of the funnel plot). This produced an adjusted average effect estimate (RE model) of 1.51 (95% CI, 1.26?.83). Residual confounding.
Comparison to Other Studies
Several systematic reviews [15,21?3,44,45] examining this association have been published previously; however, our review is the most comprehensive and is unique in its analytical approach and interpretation and thus adds substantially to the cumulative evidence. Table 3 summarizes the differences between our systematic and those recently published. First, our review identified the largest number of studies published to date. For example, our review has 36% more studies than the largest metaanalysis by Kowk et al [21] and 90% more studies that the recent FDA review published in February 2012. Second, our metaanalysis included adjusted effect estimates of the association between PPI and CDI. Third, we used meta-regression to explore sources of heterogeneity. None of the published analyses used this method. Fourth, we examined the effect of publication bias using a novel approach of contour-enhanced funnel plot [46]. The largest and most recent analysis by Kowk et al. [21] did not examine the effect of publication bias.
Table 1. Characteristics of the Included Studies.Source Multicenter Community Gen Pop Multicenter Community Gen Pop Multicenter Hospital Single Single Single Single Single Single GPRD Single GPRD Single Single Single Single Single Single Single Multicenter Hospital Single Single Single Single Single Multicenter Community Gen Pop & Hospital Single Single Single Hospital Hospital* Hospital Gen In-patient Gen In-patient Gen In-patient Hospital Med/CT surgical wards Hospital Gen In-patient Hospital Medical ICU Cohort Cohort , (P) Cohort Cohort , (R) Case control Case control Case control, (P) Hospital Gen In-patient Cohort, (R) Hospital Gen In-patient Cohort, (R) Med/Surgical Subspecialty Cohort , (R) Hospital Gen In-patient Cohort Hospital Gen In-patient Case-control Hospital Gen In-patient Case-control Hospital Gen In-patient Case-control, (P) Hospital Gen In-patient Case Control Hospital Gen In-patient Case-control NR Pts admitted for . 48 hr between study period were included In- pts with CDAD; Positive toxin result during or within m after the index admission Hospital Acquired CDAD; Adult Hospital Acquired CDAD Age $ 18 yr; LOS $3 d; Only first diagnosis Age: $18 yr; Minimum 7-d LOS; ABX exposure All pts admitted to BJH for more than 48 hours Adult In-patient LOS in ICU.24hr ; Diarrhea .24 hr and positive CD toxin between 2d to 2mo after discharge CD testing during 4m period; ABX within 40d prior to diarrhea Pharmacy database; ABX during study period; positive toxin in the infection control registry First positive CD toxin, VA health care system use for 1 yr before or after the index CDAD In-patient Age:$18 yr; CDAD Age . 18 yr Hospital Gen In-patient Case-control Age $18 Yr; Inpt for $3 d Community Gen Pop Case-control Hospital Gen In-patient Case-control Community Gen Pop Case-control Hospital Gen In-patient Case-control Age . 65 yr; Gen medical/ elderly care wards Age $18 yr ; At least 2 yrs of records in the GPRD prior to index date; first occurrence of CDAD Afro-American/ Hispanic pts admitted with diarrhea positive CD All pts with first prescription oral Vancomycin; No previous admission 1yr before index date Hospital LTCF pts Case-control Positive CD toxin; documented diagnosis/ ABX for CDAD Hospital Gen In-patient Case-control Age $18yr ; In-patient Hospital Gen In-patient Case-control Age .18 Hospital Gen In-patient Case-control Age .18 Hospital Hem-oncology pts Case-control Adult; In-patient . 3d Abd-surgery pts Case-Control Positive CD within 30 d after surgery; diarrhea Case-control Age: $18 yr; Durham residence; Community onset CDAD Case-control Age: $18 yr; Community onset CDADAcid Suppression Therapy PPI exposure 3mo prior to test PPI exposure 3mo prior to test PPI: exposure within 10d before surgery Acid suppressive therapy PPI pre or during admission PPI: post admission PPI: 3d before testing or 7d within the last month; before hospitalization PPI PPI: up to 16wk before diarrhea PPI: 90d prior to the index date PPI: 3m before diarrhea PPI: 90d prior to the index date PPI: at least 3d before CDAD PPI: preceding 2mo PPI PPI : at least 3d before diarrhea ; 3d in hospital if no diarrhea PPI: 6wk before diagnosis PPI: 6wk prior to onset of CDAD Daily PPI PPI Days: 18.7621.5 PPI PPI PPI PPI PPI PPI: Concurrent with CDAD Treatment PPI: 60d before index date PPI: In the past 3mo PPI: 3m prior to study entry
