Figure S8. Two-way sensitivity analysis (cost-benefit model): symptomatic carrier proportion vs. lateral-flow GDH sensitivity

Transcription

1 Documents included: Figure S1. Simplified decision tree model for lateral-flow GDH-Tox/odPCR Figure S2. Prisma diagram of included studies Figure S3. Forest plots of included studies Figure S4. One-way sensitivity analysis (cost-effectiveness model): odpcr vs lateral-flow GDH/odPCR Figure S5. Net monetary benefit per-patient tested by willingness to pay for a true-positive diagnosis Figure S6. One-way sensitivity analysis (cost-benefit model): odpcr vs lateral-flow GDH/odPCR Figure S7. Categorization of costs in the cost-benefit model Figure S8. Two-way sensitivity analysis (cost-benefit model): symptomatic carrier proportion vs. lateral-flow GDH sensitivity Table S1. Transmission rate calculations Table S2. Monte Carlo Inputs Table S3. Studies included/excluded Table S4. Lateral flow GDH-Tox accuracy measures 1

2 Figure S1. Simplified decision tree model for lateral-flow GDH-Tox/odPCR CDI Lateral-flow concordant: GDH (+), Tox (+) or GDH (-), Tox (-) Lateral-flow concordant (+): GDH (+), Tox (+) True positive Lateral-flow concordant (-): GDH (-), Tox (-) False negative Lateral-flow discordant: GDH (+), Tox (-) or GDH (-), Tox (+) odpcr (+) True positive Lateral-flow GDH-Tox/odPCR Lateral-flow concordant: GDH (+), Tox (+) or GDH (-), Tox (-) odpcr (-) False negative Lateral-flow concordant (-): GDH (-), Tox (-) True negative Lateral-flow concordant (+): GDH (+), Tox (+) False positive no CDI Lateral-flow discordant: GDH (+), Tox (-) or GDH (-), Tox (+) odpcr (-) True negative odpcr (+) False positive Simplified decision tree model structure for one of the algorithms (lateral-flow GDH-Tox/odPCR). Other testing algorithms were represented in similar structures. Circles represent chance nodes where conditional probabilities are applied, and triangles represent terminal nodes where costs and effectiveness measures associated with each branch are calculated. Abbreviations: CDI, Clostridium difficile infection; odpcr, on demand PCR; lateral-flow GDH, lateral-flow test for glutamate dehydrogenase; lateral-flow Tox, lateral-flow test for Clostridium difficile toxin A/B. 2

3 Figure S2. Prisma diagram of included studies # of studies identified 38 full-text studies # studies excluded 33 full-text studies * 29 studies with toxigenic culture not the gold standard for all samples * 1 study with samples not serially collected # of studies included in quantitative synthesis 5 full-text studies * 3 studies with toxigenic culture not the gold standard for all samples & samples not serially collected 3

4 Figure S3. Forest plots of included studies odpcr Study Swindells, JCM 2010 Tenover JCM 2010 Batch PCR TP FP FN TN Sensitivity (95% CI) 1.00 [0.81, 1.00] 0.99 [0.97, 1.00] Specificity (95% CI) 0.99 [0.96, 1.00] 0.91 [0.89, 0.92] Sensitivity (95% CI) Specificity (95% CI) Study Swindells, JCM 2010 Barbut, BD, JCM 2009 Peterson, AJCP 2011 Barbut, EJCMID 2011 Peterson, AJCP 2011 Lateral-flow GDH TP FP FN TN Sensitivity (95% CI) 0.94 [0.73, 1.00] 0.94 [0.80, 0.99] 0.90 [0.81, 0.95] 0.87 [0.77, 0.93] 0.81 [0.72, 0.89] Specificity (95% CI) 0.99 [0.96, 1.00] 0.98 [0.95, 0.99] 0.90 [0.88, 0.92] 0.97 [0.96, 0.98] 0.94 [0.92, 0.95] Sensitivity (95% CI) Specificity (95% CI) Study Swindells, JCM 2010 Peterson, AJCP 2011 TP FP FN TN Direct tissue culture cytotoxicity Sensitivity (95% CI) 1.00 [0.81, 1.00] 0.79 [0.69, 0.87] Specificity (95% CI) 0.97 [0.92, 0.99] 0.89 [0.86, 0.91] Sensitivity (95% CI) Specificity (95% CI) Study Swindells, JCM 2010 Barbut, EJCMID 2011 Peterson, AJCP 2011 EIA toxin TP FP FN TN Sensitivity (95% CI) 0.83 [0.59, 0.96] 0.71 [0.60, 0.80] 0.55 [0.44, 0.65] Specificity (95% CI) 1.00 [0.97, 1.00] 1.00 [1.00, 1.00] 0.97 [0.96, 0.98] Sensitivity (95% CI) Specificity (95% CI) Study Peterson, AJCP 2011 Peterson, AJCP 2011 Peterson, AJCP 2011 Swindells, JCM 2010 Peterson, AJCP 2011 TP FP FN TN Sensitivity (95% CI) 0.52 [0.41, 0.63] 0.49 [0.38, 0.60] 0.49 [0.38, 0.60] 0.44 [0.22, 0.69] 0.44 [0.33, 0.55] Specificity (95% CI) 0.97 [0.95, 0.98] 0.97 [0.96, 0.98] 0.96 [0.95, 0.98] 1.00 [0.97, 1.00] 0.96 [0.94, 0.97] Sensitivity (95% CI) Specificity (95% CI) Accuracy data and forest plots of included diagnostic studies 1 5 from which model inputs were estimated (see Table 1). Measures are referenced against gold standard toxigenic culture performed on symptomatic patients. Abbreviations: odpcr, on demand polymerase chain reaction; EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; TP, true positive; FP, false positive; FN, false negative; TN, true negative. 4

5 Figure S4. One-way sensitivity analysis (cost-effectiveness model): odpcr vs lateral-flow GDH/odPCR Private room for isolation, additional cost ($0 to $138) Lateral-flow GDH sensitivity (0.74 to 0.89) Treatment per day ($4 to $43) Isolation required for positive test results, days (7 to 10) CDI prevalence (0.09 to 0.11) odpcr specificity (0.90 to 0.92) Isolation materials per day ($21 to $36) Number RN labor hours per day for isolation (0.4 to 0.6) Number days treatment required (10 to 14) Lab reagents, odpcr ($34 to $42) Cost RN labor per hour ($38 to $56) Lateral-flow GDH specificity (0.97 to 1.00) Low Range High Range $4000 $5000 $6000 $7000 $8000 $9000 $10000 $11000 ICER of odpcr relative to lateral-flow GDH/odPCR (cost per additional TP treated) Set of one-way sensitivity analyses for the most influential parameters on the incremental cost-effectiveness of stand-alone odpcr versus lateral-flow GDH/odPCR. The color of the bar represents the incremental cost-effectiveness ratio of stand-alone odpcr relative to lateral-flow GDH/odPCR when the variable is changed to its higher (green) or lower (blue) value. Inputs for this non-probabilistic analysis were the most likely values of the input probability distributions described in Table S2, explaining the slight difference between the base case in this figure and the incremental cost-effectiveness ratio in Table 3. Abbreviations: ICER, incremental cost-effectiveness ratio; GDH, glutamate dehydrogenase; odpcr, on demand polymerase chain reaction; CDI, Clostridium difficile infection. 5

6 Figure S5. Net monetary benefit per-patient tested by willingness to pay for a true-positive diagnosis Net monetary benefit was calculated as the extra cost of a missed case (transmission of disease, extended hospital stay, and eventual CDI diagnosis and treatment) for each true-positive diagnosis occurring in the given testing strategy, less the costs of initial testing, treatment, and isolation associated with the CDI testing strategy. The extra cost of an additional missed case was set to equal the willingness to pay along the x-axis. Colored lines represent different testing strategies (rapid algorithms are dashed), with shaded areas representing 5 th to 95 th percentiles from the corresponding Monte Carlo simulations. The incremental cost-effectiveness ratios (relative to the next best strategy) from Table 3 for the undominated strategies can be seen on the x-axis where minimal cost lines intersect ($1,600 and $6,900). Using our model, the most likely value for the extra cost of a missed case is represented by the black line ($13,848, median), with an uncertainty range shaded gray (5 th and 95 th percentiles). This figure is an alternative depiction of the cost-benefit analysis and correlates to Figure 1 in the manuscript. Abbreviations: GDH, glutamate dehydrogenase; EIA, enzyme immunoassay; Tox, Clostridium difficile toxin A/B; odpcr, on demand polymerase chain reaction. 6

7 Figure S6. One-way sensitivity analysis (cost-benefit model): odpcr vs lateral-flow GDH/odPCR Lateral-flow GDH sensitivity (0.74 to 0.89) Number of days before TP (5 to 9) Cost of hospital/day, non-isolation ($883 to $1804) Risk of transmission/day without isolation (0.19 to 0.62) CDI prevalence (0.09 to 0.11) Incremental isolation room cost/day ($0 to $138) odpcr specificity (0.90 to 0.92) Treatment per day ($4 to $43) Lab reagents, odpcr ($34 to $42) odpcr sensitivity (0.97 to 1.00) Isolation required for positive test results, days (7.0 to 10.0) Lateral-flow GDH specificity (0.88 to 0.92) Low range High range $20 $70 $120 $170 $220 $270 Savings per-patient tested for odpcr relative to Lateral-flow GDH/odPCR Set of one-way sensitivity analyses for the most influential parameters in the cost-benefit model. The color of the bar represents the savings per-patient associated with use of odpcr relative to lateral-flow GDH/odPCR when the variable is changed to its higher (green) or lower (blue) value. Inputs for this non-probabilistic analysis were the most likely values of the input probability distributions described in Table S2. Abbreviations: ICER, incremental cost-effectiveness ratio; GDH, glutamate dehydrogenase; odpcr, on demand polymerase chain reaction; CDI, Clostridium difficile infection.

8 Figure S7. Categorization of costs in the cost-benefit model Treat None Treat All EIA toxin Direct tissue culture cytotoxicity Batch PCR Lateral-flow GDH/odPCR Lateral-flow GDH-Tox/odPCR Stand alone odpcr Isolation room Isolation material Isolation labor CDI tx Transmission (missed cases) Extended stay Eventual diagnosis Laboratory labor Laboratory reagents $0 $200 $400 $600 $800 $1,000 $1,200 $1,400 $1,600 Average cost per-patient tested Categorization of costs: isolation (blue shades), treatment (purple), costs associated with missed cases (green shades), and laboratory testing (orange shades). Inputs for this nonprobabilistic analysis were the most likely values of the input probability distributions described in Table S2. Abbreviations: EIA, enzyme immunoassay; Tox or toxin, Clostridium difficile toxin A and/or B; GDH, glutamate dehydrogenase; CDI, Clostridium difficile infection. 8

9 Figure S8. Two-way sensitivity analysis (cost-benefit model): symptomatic carrier proportion vs. lateral-flow GDH sensitivity Symptomatic carrier proportion* Stand-alone odpcr preferred ($) Lateral-flow GDH/odPCR preferred ($) Lateral-flow GDH-Tox/odPCR preferred ($) Lateral-flow GDH sensitivity Economically preferred CDI testing strategy in the cost-benefit model with savings per-patient tested over the next-best option. In this figure, savings for lateral-flow GDH-Tox/odPCR and lateral-flow GDH/odPCR are relative to stand-alone odpcr, as there is significant uncertainty overlap between the two lateral-flow strategies. Three strategies are preferred at different magnitudes of lateral-flow GDH sensitivity and symptomatic carrier proportion: stand-alone odpcr (red), lateral-flow GDH/odPCR (blue), and lateral-flow GDH-Tox/odPCR (green). *The symptomatic carrier proportion refers to the proportion of patients with diarrhea who test positive according to the gold standard but are only carriers of Clostridium difficile and not experiencing diarrhea due to CDI. Abbreviations: CDI, Clostridium difficile infection; GDH, glutamate dehydrogenase; Tox, Clostridium difficile toxin A/B; odpcr, on demand polymerase chain reaction. 9

10 Table S1. Transmission rate calculations Number of new cases caused by a clinical case = Probability of disease after colonization (P) * New colonized without immunity (C-) Model Parameter Base Low High notes Probability of disease after colonization = P P = Φ/(Φ+k) P (Probability of disease after colonization) calculated Φ: (Clinical disease rate, per day) see Lanzas et al, 2011 k: (Discharge rate for susceptible and colonized, per day) see Lanzas et al, 2011 New colonized without immunity = C- (correct diagnosis, isolation) C- = (1 - ƒ)*β d S 0 /(p*ε + k d ) C-: (New colonized without immunity) calculated ƒ: (Fraction colonized patients that mount an immune response) see Lanzas et al, 2011 β d : (Transmission coefficient per-patient-day by diseased), isolation see Lanzas et al, 2011 S o : (# susceptible to colonization) # beds in ward p: (Probability of successful treatment) see Lanzas et al, 2011 ε: (Treatment rate, per day) see Lanzas et al, 2011 k d : (Discharge rate for diseased patients, per day) see Lanzas et al, 2011 Secondary cases per correct diagnosis (in isolation; P*C- ) calculated 10

11 Table S1. Transmission rate calculations, continued New colonized without immunity = C- (missed cases, no isolation) C- = (1 - ƒ)*β d S 0 /(p*ε + k d ) C-: (New colonized without immunity) calculated ƒ: (Fraction colonized patients that mount an immune response) see Lanzas et al, 2011 β d : (Transmission coefficient per-patient-day by diseased) times an isolated pt S o : (# susceptible to colonization) # beds in ward p: (Probability of successful treatment) see Lanzas et al, 2011 ε: (Treatment rate, per day) no treatment k d : (Correct diagnosis rate, per day) /(days till correct diagnosis) Secondary cases per missed case (while not in isolation; P*C-) calculated Secondary cases per correct diagnosis per day (in isolation) Secondary cases per missed case per day (while not in isolation) Notes: Based on the Lanzas et al. model for Clostridium difficile transmission. 6 The principal adjustments to the model to estimate transmission while not in isolation included increasing β d (transmission coefficient per-patient-day by diseased) ten-fold (model assumption), setting ε (treatment rate, per day) to zero, and changing k d (correct diagnosis rate, per day) to the inverse of the number of days before a correct diagnosis was assumed to be made (7 days, ranging from 5 to 9 days). Secondary cases per day were calculated by dividing total secondary cases per missed case by the following: 7 days (base), 5 days (low), 9 days (high). 11

12 Table S2. Monte Carlo Inputs Input Parameters Distribution Input Parameters Distribution CDI prevalence 4592, 467 beta (n,r) Reagents (per test): continued Laboratory: odpcr (includes capital costs & service) Sensivitity: odpcr (in odpcr) 37.7, 1.9 gamma (m,sd) odpcr 266, 263 beta (n,r) odpcr (in lateral-flow GDH/odPCR) 47.0, 2.4 gamma (m,sd) Lateral-flow GDH 104, 86 beta (n,r) odpcr (in lateral-flow GDH-Tox/odPCR) 54.7, 2.7 gamma (m,sd) Batch PCR 305, 266 beta (n,r) Isolation: EIA toxin 362, 175 beta (n,r) Isolation required for positive test (days) 8.5, 0.75 gamma (m,sd) Direct tissue culture cytotoxicity 186, 120 beta (n,r) Room: Specificity: Private room for isolation (additional cost) 0, 25, 138 tri (min,l,max) odpcr 2180, 1991 beta (n,r) Preemptive isolation before result (days): Lateral-flow GDH 1042, 935 beta (n,r) Batch PCR 1, 0.25 gamma (m,sd) Batch PCR 2984, 2812 beta (n,r) Direct tissue culture cytotoxicity 2, 0.25 gamma (m,sd) EIA toxin 3772, 3649 beta (n,r) EIA toxin 0.5, gamma (m,sd) Direct tissue culture cytotoxicity 1839, 1813 beta (n,r) Materials: Lateral-flow GDH-Tox rates a Isolation materials per isolation $39, $53, $66 tri (min,l,max) Concordance rate (CDI) 104, 69 beta (n,r) Isolation materials per day $21, $29, $36 tri (min,l,max) Concordance rate (no CDI) 1042, 959 beta (n,r) Sn of concordant results (CDI) 69, 52 beta (n,r) Sp of concordant results (no CDI) 959, 935 beta (n,r) 12

13 Table S2. Monte Carlo Inputs, continued Input Parameters Distribution Input Parameters Distribution Labor: Labor: Laboratory technician (per hour) $37, $43, $49 tri (min,l,max) Wage: Lab labor (minutes per test) Housekeeping (per hour) $15, $18, $22 tri (min,l,max) Batch PCR 2.8, 3.8, 4.7 tri (min,l,max) Nursing (per hour) $38, $47, $56 tri (min,l,max) Direct tissue culture Patient Access Manager (per hour) cytotoxicity 14.9, 20.0, 24.8 tri (min,l,max) $38, $47, $56 tri (min,l,max) EIA toxin 0.9, 1.3, 1.6 tri (min,l,max) Labor per isolation (hours) Lateral-flow GDH 4.2, 5.6, 7.0 tri (min,l,max) Patient Access Manager 0.4, 0.5, 0.6 tri (min,l,max) Lateral-flow GDH-Tox 4.2, 5.6, 7.0 tri (min,l,max) Housekeeping 0.4, 0.5, 0.6 tri (min,l,max) odpcr 3.8, 5.0, 6.3 tri (min,l,max) Labor per isolation day (hours) Clinician contact per Nursing positive result (min) 11.3, 15.0, 18.8 tri (min,l,max) 0.4, 0.5, 0.6 tri (min,l,max) Reagents (per test): Batch PCR $5, $0.25 gamma (m,sd) Direct tissue culture cytotoxicity $15, $0.75 gamma (m,sd) EIA toxin Lateral-flow GDH $10.3, $0.5 gamma (m,sd) Missed cases: Additional stay (days, without isolation) 5, 7, 9 tri (min,l,max) Hospital room cost (no isolation) $883, $1288, $1804 tri (min,l,max) Transmission, no isolation (new cases/day) 0.19, 0.45, 0.62 tri (min,l,max) Transmission, isolation (new cases/day) 0.02, 0.04, 0.08 tri (min,l,max) $12.3, $0.6 gamma (m,sd) Lateral-flow GDH-Tox $12.3, $0.6 gamma (m,sd) Treatment: Cost per day $4, $23, $43 tri (min,l,max) Duration of treatment (days) 10, 12, 14 tri (min,l,max) Note: Instrument costs for odpcr assumed to be $65,045 discounted over 5 years with the number of tests per year dependent on the algorithm used (odpcr, 10,000; lateral-flow GDH/odPCR, 1,780; lateral-flow GDH-Tox/odPCR, 1,060). Service costs for odpcr assumed to be $6,340 annually. These odpcr capital costs were included in odpcr reagent costs..abbreviations: CDI, Clostridium difficile infection; GDH, glutamate dehydrogenase; EIA, enzyme immunoassay; Tox or toxin, Clostridium difficile toxin A and/or B; Sn, sensitivity; Sp, specificity; tri, triangular distribution; gamma, gamma distribution; beta, beta distribution. 13

14 Table S3. Studies included/excluded Lateral flow GDH or GDH-Tox Article Results Reason for exclusion Peterson, AJCP (n=1000) Included Swindells, JCM (n=150) Included Bruins, EJCLIF Excluded Toxigenic culture not the gold standard for all samples. Samples not serially collected. Kawada, JIC Excluded Toxigenic culture not the gold standard for all samples. Larson, JCM Excluded Toxigenic culture not the gold standard for all samples. Reyes, DMID Excluded Toxigenic culture not the gold standard for all samples. Sharp, JCM Excluded Toxigenic culture not the gold standard for all samples. Culbreath, JCM Excluded Toxigenic culture not the gold standard for all samples. Quinn, JCM Excluded Toxigenic culture not the gold standard for all samples. Orellana-Miguel, EIMC Excluded Toxigenic culture not the gold standard for all samples. On demand PCR Article Results Reason for exclusion Tenover, JCM (n=2296) Swindells, JCM (n=150) Included Included Novak-Weakley JCM Excluded Toxigenic culture not the gold standard for all samples. Shin, ALM Excluded Toxigenic culture not the gold standard for all samples. Zidaric, JMM Excluded Toxigenic culture not the gold standard for all samples. Pancholi, JCM Excluded Toxigenic culture not the gold standard for all samples. Chapin, JMD, Excluded Toxigenic culture not the gold standard for all samples. Goldenberg, DMID Excluded Samples not serially collected. LaSala, APLM Excluded Toxigenic culture not the gold standard for all samples. Karre, JCM Excluded Toxigenic culture not the gold standard for all samples. Huang, JCM Excluded Toxigenic culture not the gold standard for all samples. Viala, JMM Excluded Toxigenic culture not the gold standard for all samples. Samples not serially collected. 14

15 Table S3. Studies included/excluded, continued Batch PCR Article Results Reason for exclusion Barbut, EJCMID (n=860) Included Peterson, AJCP (n=1000) Barbut, BD, JCM (n=290) Swindells, JCM (n=150) Included Included Included Kim, JMM Excluded Toxigenic culture not the gold standard for all samples. Sloan, JCM Excluded Toxigenic culture not the gold standard for all samples. dejong, EJCMID Excluded Toxigenic culture not the gold standard for all samples. Stamper, JCM Excluded Toxigenic culture not the gold standard for all samples. Larson, JCM Excluded Toxigenic culture not the gold standard for all samples. Kvach, JCM Excluded Toxigenic culture not the gold standard for all samples. Samples not serially collected. Cho, AJCP Excluded Toxigenic culture not the gold standard for all samples. Luo, JCM Excluded Toxigenic culture not the gold standard for all samples. deboer, JMM Excluded Toxigenic culture not the gold standard for all samples. Eastwood, JCM Excluded Toxigenic culture not the gold standard for all samples. Knetsch, JCM Excluded Toxigenic culture not the gold standard for all samples. 15

16 Table S3. Studies included/excluded, continued EIA toxin (multiplate reader) Article Results Reason for exclusion Peterson, AJCP (n=1000) Included Swindells, JCM (n=150) Included Sloan, JCM Excluded Toxigenic culture not the gold standard for all samples. Miendje, CL Excluded Toxigenic culture not the gold standard for all samples. Snell, JCM Excluded Toxigenic culture not the gold standard for all samples. Russman, EJCMID Excluded Toxigenic culture not the gold standard for all samples. Turgeon, JCM Excluded Toxigenic culture not the gold standard for all samples. Larson, JCM Excluded Toxigenic culture not the gold standard for all samples. Direct tissue culture cytotoxicity Article Results Reason for exclusion Barbut, EJCMID (n=860) Peterson, AJCP (n=1000) Swindells, JCM (n=150) Included Included Included Peterson, DMID Excluded Toxigenic culture not the gold standard for all samples. note: Toxigenic culture refers to direct (not pre-enriched with broth) culture of stool, identification of Clostridium difficile, and confirmation of toxin using a tissue culture cytotoxicity assay with neutralization by antitoxin/antibody. 16

17 Table S4. Lateral-flow GDH-Tox accuracy measures GDH+ EIA+ Direct TC+ (CDI, n=104) GDH+ GDH- EIA- EIA+ GDH- EIA- Direct TC - (no CDI, n=1042) GDH+ GDH+ GDH- GDH- EIA+ EIA- EIA+ EIA- Peterson, AJCP Swindells, JCM as % of all Direct TC+ Sum Sum % 32.7% 1.0% 16.3% as % of all Direct TC- 2.2% 7.7% 0.0% 87.1% as % of all Direct TC+ 95% CI as % of all Concordant samples 95% CI Direct TC + (CDI) Direct TC - (no CDI) Conc. Disc. Conc. Disc. 66.3% 33.7% as % of all Direct TC- 89.3% 7.7% [0.56, 0.75] 95% CI [0.90, 0.94] Conc.+ Conc.- Conc.+ Conc.- as % of all 75.4% 24.6% Concordant 2.5% 97.5% samples [0.64, 0.85] 95% CI 95% CI [0.96, 0.98] note: The model was constructed for lateral-flow GDH-Tox such that relevant inputs were the percentage of samples testing concordant for GDH and Tox in the CDI or non-cdi group and the percentage of these that were concordant positive for patients with CDI or concordant negative for patients without CDI. Abbreviations: Conc, concordant; Disc., discordant; TC, toxigenic culture; CDI, C. difficile infection. 17

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