Does anemia contribute to end-organ dysfunction in ICU patients Statistical Analysis

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1 Does anemia contribute to end-organ dysfunction in ICU patients Statistical Analysis Xue Han, MPH and Matt Shotwell, PhD Department of Biostatistics Vanderbilt University School of Medicine November 7, 2014 Contents 1 Analysis 1: Transitional Model to model next day s effect Outcome1: Daily Delirium Descriptive Statistics Multinomial logistic regression with Normal as the reference level for outcome variable Delirium Outcome2: Daily troponin (greater than 0.1) as an index of cardiac dysfunction Descriptive Statistics Outcome3: Daily renal SOFA score Descriptive Statistics Logistic regression, Daily renal SOFA 2(Y/N) Proportional odds logistic regression regression, Ordinal response (0-4) Outcome4: Daily resp SOFA score ( 2) Descriptive Statistics Logistic regression, Daily RESP SOFA 2(Y/N) Proportional odds logistic regression, Ordinal response (0-4) Proportional odds logistic regression, Ordinal response (0-4),without three way interaction Proportional odds logistic regression, Ordinal response (0-4),Sensitivity Analysis Proportional odds logistic regression, Ordinal response (0-4),Sensitivity Analysis2, without three way interaction Proportional odds logistic regression, Ordinal response (0-4),Marginal Model Proportional odds logistic regression, Ordinal response (0-4),Marginal Model with hgb.icu and resp.sofa interaction Tomorrow resp.sofa Tomorrow resp.sofa Tomorrow resp.sofa Outcome5: Daily Ventilator (Y/N) as a measure of success of extubation Descriptive Statistics Proportional odds logistic regression, Ordinal response (0-4),Marginal Model Logistic regression (Daily Ventilation (Y/N)) Analysis2: Hb during ICU stay and predicted outcomes Outcome1: ICU mortality Descriptive Statistics Logistic regression for ICU.mortality (Y/N) Time dependent covariate survival analysis for Time to ICU.mortality

2 2.2 Outcome2: Cardiac dysfunction(tropnin greater than 0.1) Correlated time dependent covariate survival analysis for Time to Tropnin greater than Outcome3: Renal dysfunction Outcome: Time to renal dysfunction Survival analysis with correlated time dependent covariate Outcome4: Time to resolution of delirium Outcome5: Time to successful extubation

3 1 Analysis 1: Transitional Model to model next day s effect 1.1 Outcome1: Daily Delirium Descriptive Statistics Table 1: Descriptive by Icu.status 3 N Normal Discharged Delirious Comatose Deceased Combined Test Statistic N = 1976 N = 697 N = 1994 N = 1917 N = 127 N = 6711 icu.status.today 6711 χ 2 8 = 4326, P < Normal 73% (1451) 66% ( 462) 11% ( 217) 5% ( 88) 9% ( 11) 33% (2229) Delirious 21% ( 410) 28% ( 193) 61% (1210) 20% ( 380) 22% ( 28) 33% (2221) Comatose 6% ( 115) 6% ( 42) 28% ( 567) 76% (1449) 69% ( 88) 34% (2261) Age at enrollment F 4,6706 = 18, P < ICU type 6711 Surgical 28% ( 552) 35% ( 242) 42% ( 844) 38% ( 736) 19% ( 24) 36% (2398) χ 2 4 = 112, P < APACHE APS at enrollment F 4,6706 = 43, P < Charlson score F 4,6706 = 8, P < Framingham stroke risk score F 4,6706 = 24, P < Lowest mean arterial pressure, current 24h F 4,6699 = 51, P < Was patient in ICU today? ICU 100% (1976) 100% ( 697) 100% (1994) 100% (1917) 100% ( 127) 100% (6711) Study day F 4,6706 = 35, P < Septic in the current 24h? 6703 Septic today 60% (1182) 49% ( 344) 67% (1330) 70% (1337) 73% ( 91) 64% (4284) χ 2 4 = 117, P < sevsepsis.l Severely septic today 47% ( 926) 34% ( 240) 65% (1302) 69% (1323) 71% ( 89) 58% (3880) χ 2 4 = 406, P < Lowest hemoglobin, current 24h F 4,5832 = 4.4, P = a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test

4 1.1.2 Multinomial logistic regression with Normal as the reference level for outcome variable Delirium 4 Level Discharged vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal icu.status.todaydelirious icu.status.todaycomatose age.enroll icu.typesurgical apache.aps charlson.score stroke.risk map.low.icu study.day sepsis.l24septic today hgb.icu study.day:hgb.icu icu.status.todaydelirious:age.enroll icu.status.todaycomatose:age.enroll icu.status.todaydelirious:icu.typesurgical icu.status.todaycomatose:icu.typesurgical icu.status.todaydelirious:apache.aps icu.status.todaycomatose:apache.aps icu.status.todaydelirious:charlson.score icu.status.todaycomatose:charlson.score icu.status.todaydelirious:stroke.risk icu.status.todaycomatose:stroke.risk icu.status.todaydelirious:map.low.icu icu.status.todaycomatose:map.low.icu icu.status.todaydelirious:study.day icu.status.todaycomatose:study.day icu.status.todaydelirious:sepsis.l24septic today icu.status.todaycomatose:sepsis.l24septic today icu.status.todaydelirious:hgb.icu icu.status.todaycomatose:hgb.icu icu.status.todaydelirious:study.day:hgb.icu icu.status.todaycomatose:study.day:hgb.icu

5 5 Level Delirious vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal icu.status.todaydelirious icu.status.todaycomatose age.enroll icu.typesurgical apache.aps charlson.score stroke.risk map.low.icu study.day sepsis.l24septic today hgb.icu study.day:hgb.icu icu.status.todaydelirious:age.enroll icu.status.todaycomatose:age.enroll icu.status.todaydelirious:icu.typesurgical icu.status.todaycomatose:icu.typesurgical icu.status.todaydelirious:apache.aps icu.status.todaycomatose:apache.aps icu.status.todaydelirious:charlson.score icu.status.todaycomatose:charlson.score icu.status.todaydelirious:stroke.risk icu.status.todaycomatose:stroke.risk icu.status.todaydelirious:map.low.icu icu.status.todaycomatose:map.low.icu icu.status.todaydelirious:study.day icu.status.todaycomatose:study.day icu.status.todaydelirious:sepsis.l24septic today icu.status.todaycomatose:sepsis.l24septic today icu.status.todaydelirious:hgb.icu icu.status.todaycomatose:hgb.icu icu.status.todaydelirious:study.day:hgb.icu icu.status.todaycomatose:study.day:hgb.icu Level Comatose vs. Level Normal betahat se pval RRR RRR.lo RRR.up

6 6 icu.status.todaynormal icu.status.todaydelirious icu.status.todaycomatose age.enroll icu.typesurgical apache.aps charlson.score stroke.risk map.low.icu study.day sepsis.l24septic today hgb.icu study.day:hgb.icu icu.status.todaydelirious:age.enroll icu.status.todaycomatose:age.enroll icu.status.todaydelirious:icu.typesurgical icu.status.todaycomatose:icu.typesurgical icu.status.todaydelirious:apache.aps icu.status.todaycomatose:apache.aps icu.status.todaydelirious:charlson.score icu.status.todaycomatose:charlson.score icu.status.todaydelirious:stroke.risk icu.status.todaycomatose:stroke.risk icu.status.todaydelirious:map.low.icu icu.status.todaycomatose:map.low.icu icu.status.todaydelirious:study.day icu.status.todaycomatose:study.day icu.status.todaydelirious:sepsis.l24septic today icu.status.todaycomatose:sepsis.l24septic today icu.status.todaydelirious:hgb.icu icu.status.todaycomatose:hgb.icu icu.status.todaydelirious:study.day:hgb.icu icu.status.todaycomatose:study.day:hgb.icu Level Deceased vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal icu.status.todaydelirious icu.status.todaycomatose

7 7 age.enroll icu.typesurgical apache.aps charlson.score stroke.risk map.low.icu study.day sepsis.l24septic today hgb.icu study.day:hgb.icu icu.status.todaydelirious:age.enroll icu.status.todaycomatose:age.enroll icu.status.todaydelirious:icu.typesurgical icu.status.todaycomatose:icu.typesurgical icu.status.todaydelirious:apache.aps icu.status.todaycomatose:apache.aps icu.status.todaydelirious:charlson.score icu.status.todaycomatose:charlson.score icu.status.todaydelirious:stroke.risk icu.status.todaycomatose:stroke.risk icu.status.todaydelirious:map.low.icu icu.status.todaycomatose:map.low.icu icu.status.todaydelirious:study.day icu.status.todaycomatose:study.day icu.status.todaydelirious:sepsis.l24septic today icu.status.todaycomatose:sepsis.l24septic today icu.status.todaydelirious:hgb.icu icu.status.todaycomatose:hgb.icu icu.status.todaydelirious:study.day:hgb.icu icu.status.todaycomatose:study.day:hgb.icu Level Withdrawn vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal icu.status.todaydelirious icu.status.todaycomatose age.enroll icu.typesurgical apache.aps

8 8 charlson.score stroke.risk map.low.icu study.day sepsis.l24septic today hgb.icu study.day:hgb.icu icu.status.todaydelirious:age.enroll icu.status.todaycomatose:age.enroll icu.status.todaydelirious:icu.typesurgical icu.status.todaycomatose:icu.typesurgical icu.status.todaydelirious:apache.aps icu.status.todaycomatose:apache.aps icu.status.todaydelirious:charlson.score icu.status.todaycomatose:charlson.score icu.status.todaydelirious:stroke.risk icu.status.todaycomatose:stroke.risk icu.status.todaydelirious:map.low.icu icu.status.todaycomatose:map.low.icu icu.status.todaydelirious:study.day icu.status.todaycomatose:study.day icu.status.todaydelirious:sepsis.l24septic today icu.status.todaycomatose:sepsis.l24septic today icu.status.todaydelirious:hgb.icu icu.status.todaycomatose:hgb.icu icu.status.todaydelirious:study.day:hgb.icu icu.status.todaycomatose:study.day:hgb.icu

9 1.2 Outcome2: Daily troponin (greater than 0.1) as an index of cardiac dysfunction Descriptive Statistics Table 2: Descriptive by Troponin (greater than 0.1) 9 N No Yes Combined Test Statistic N = 5710 N = 137 N = 5847 tro.imp.cat 6704 χ 2 1 = 369, P < Yes 5% ( 271) 43% ( 59) 6% ( 330) Highest troponin, current 24h (missing = <0.1) F 1,5840 = 80, P < trop.tomo F 1,5845 = 431, P < Age at enrollment F 1,5845 = 3.6, P = ICU type 6711 Surgical 36% (2067) 36% ( 49) 36% (2116) χ 2 1 = 0.01, P = APACHE APS at enrollment F 1,5845 = 3.5, P = Charlson score F 1,5845 = 4.8, P = Framingham stroke risk score F 1,5845 = 8.1, P = Lowest mean arterial pressure, current 24h F 1,5840 = 18, P < Was patient in ICU today? ICU 100% (5710) 100% ( 137) 100% (5847) Septic in the current 24h? 6703 Septic today 65% (3732) 65% ( 89) 65% (3821) χ 2 1 = 0.01, P = sevsepsis.l Severely septic today 60% (3443) 60% ( 82) 60% (3525) χ 2 1 = 0.01, P = Lowest hemoglobin, current 24h F 1,5157 = 2.1, P = a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test Table 3: Outcome:Tropnin ( 0.1).. P-values less than 0.05 are in red. tro.imp.cat=yes ( 6.862, ) age.enroll ( 0.980, 1.027) icu.type=surgical ( 0.607, 1.641) apache.aps ( 0.986, 1.046) charlson.score ( 0.953, 1.177) stroke.risk ( 1.011, 1.117) map.low.icu ( 0.965, 1.002) study.day ( 0.839, 1.443) sepsis.l24=septic today ( 0.584, 1.565) hgb.icu ( 0.850, 1.345) study.day * hgb.icu ( 0.957, 1.014) tro.imp.cat=yes * age.enroll ( 0.944, 1.023) tro.imp.cat=yes * icu.type=surgical ( 0.999, 5.229) tro.imp.cat=yes * apache.aps ( 0.933, 1.030) 0.439

10 Table 3: (continued) tro.imp.cat=yes * charlson.score ( 0.768, 1.105) tro.imp.cat=yes * stroke.risk ( 0.836, 0.995) tro.imp.cat=yes * map.low.icu ( 0.957, 1.021) tro.imp.cat=yes * study.day ( 0.248, 0.908) tro.imp.cat=yes * sepsis.l24=septic today ( 0.738, 3.859) tro.imp.cat=yes * hgb.icu ( 0.617, 1.229) tro.imp.cat=yes * study.day * hgb.icu ( 1.017, 1.163) Outcome3: Daily renal SOFA score Descriptive Statistics Table 4: Descriptive by next day s Renal SOFA score 2 10 N No Yes Combined Test Statistic N = 4319 N = 1528 N = 5847 sofa.renal.cat 6704 χ 2 1 = 4270, P < Yes 4% ( 185) 90% (1380) 27% (1565) SOFA renal component score % (2971) 1% ( 11) 51% (2982) χ 2 4 = 4375, P < % (1161) 9% ( 134) 22% (1295) 2 4% ( 172) 48% ( 726) 15% ( 898) 3 0% ( 6) 21% ( 317) 6% ( 323) 4 0% ( 7) 22% ( 337) 6% ( 344) renal.tomo % (3061) 0% ( 0) 52% (3061) χ 2 4 = 5847, P < % (1258) 0% ( 0) 22% (1258) 2 0% ( 0) 58% ( 886) 15% ( 886) 3 0% ( 0) 20% ( 303) 5% ( 303) 4 0% ( 0) 22% ( 339) 6% ( 339) Age at enrollment F 1,5845 = 22, P < ICU type 6711 Surgical 39% (1668) 29% ( 448) 36% (2116) χ 2 1 = 42, P < APACHE APS at enrollment F 1,5845 = 158, P < Charlson score F 1,5845 = 307, P < Framingham stroke risk score F 1,5845 = 20, P < Lowest mean arterial pressure, current 24h F 1,5840 = 213, P < Was patient in ICU today? ICU 100% (4319) 100% (1528) 100% (5847) Septic in the current 24h? 6703 Septic today 65% (2823) 65% ( 998) 65% (3821) χ 2 1 = 0, P = sevsepsis.l Severely septic today 59% (2533) 65% ( 992) 60% (3525) χ 2 1 = 19, P < Lowest hemoglobin, current 24h F 1,5157 = 34, P < a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test

11 Table 5: Descriptive by next day s Renal SOFA score (0-4) 11 N Combined Test Statistic N = 3061 N = 1258 N = 886 N = 303 N = 339 N = 5847 sofa.renal.cat 6704 χ 2 4 = 4379, P < Yes 0% ( 12) 14% ( 173) 85% ( 756) 98% ( 295) 97% ( 329) 27% (1565) SOFA renal component score % (2820) 12% ( 151) 1% ( 7) 1% ( 2) 1% ( 2) 51% (2982) χ 2 16 = 11626, P < % ( 227) 74% ( 934) 14% ( 122) 2% ( 5) 2% ( 7) 22% (1295) 2 0% ( 7) 13% ( 165) 73% ( 642) 22% ( 66) 5% ( 18) 15% ( 898) 3 0% ( 2) 0% ( 4) 10% ( 88) 59% ( 179) 15% ( 50) 6% ( 323) 4 0% ( 3) 0% ( 4) 3% ( 26) 17% ( 50) 77% ( 261) 6% ( 344) Age at enrollment F 4,5842 = 22, P < ICU type 6711 Surgical 40% (1215) 36% ( 453) 35% ( 310) 22% ( 68) 21% ( 70) 36% (2116) χ 2 4 = 77, P < APACHE APS at enrollment F 4,5842 = 52, P < Charlson score F 4,5842 = 93, P < Framingham stroke risk score F 4,5842 = 19, P < Lowest mean arterial pressure, current 24h F 4,5837 = 84, P < Was patient in ICU today? ICU 100% (3061) 100% (1258) 100% ( 886) 100% ( 303) 100% ( 339) 100% (5847) Septic in the current 24h? 6703 Septic today 66% (2032) 63% ( 791) 67% ( 589) 61% ( 184) 67% ( 225) 65% (3821) χ 2 4 = 8.4, P = sevsepsis.l Severely septic today 58% (1781) 60% ( 752) 66% ( 583) 61% ( 184) 67% ( 225) 60% (3525) χ 2 4 = 23, P < Lowest hemoglobin, current 24h F 4,5154 = 11, P < a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test

12 1.3.2 Logistic regression, Daily renal SOFA 2(Y/N) Table 6: Outcome:Daily renal SOFA =2.. P-values less than 0.05 are in red. 12 sofa.renal.cat=yes 3e ( 1.184, ) age.enroll 9e ( 0.992, 1.026) icu.type=surgical -3e ( 0.509, 1.073) apache.aps 2e ( 1.001, 1.047) charlson.score 1e ( 1.019, 1.189) stroke.risk -3e ( 0.930, 1.010) map.low.icu -4e ( 0.950, 0.977) <0.001 study.day 1e ( 0.848, 1.202) sepsis.l24=septic today 1e ( 0.694, 1.471) hgb.icu -4e ( 0.806, 1.153) study.day * hgb.icu -1e ( 0.981, 1.017) sofa.renal.cat=yes * age.enroll 7e ( 0.978, 1.024) sofa.renal.cat=yes * icu.type=surgical 5e ( 0.634, 1.741) sofa.renal.cat=yes * apache.aps -1e ( 0.957, 1.015) sofa.renal.cat=yes * charlson.score 1e ( 0.905, 1.130) sofa.renal.cat=yes * stroke.risk 4e ( 0.985, 1.097) sofa.renal.cat=yes * map.low.icu 4e ( 1.020, 1.059) <0.001 sofa.renal.cat=yes * study.day -9e ( 0.717, 1.159) sofa.renal.cat=yes * sepsis.l24=septic today 3e ( 0.820, 2.254) sofa.renal.cat=yes * hgb.icu -7e ( 0.738, 1.185) sofa.renal.cat=yes * study.day * hgb.icu 1e ( 0.987, 1.038) Proportional odds logistic regression regression, Ordinal response (0-4) Table 7: Outcome:Daily renal SOFA (0-4).. P-values less than 0.05 are in red. sofa.renal (11.321, ) <0.001 age.enroll ( 0.999, 1.020) icu.type=surgical ( 0.676, 1.079) apache.aps ( 1.008, 1.037) charlson.score ( 1.009, 1.119) stroke.risk ( 0.964, 1.014) map.low.icu ( 0.965, 0.983) <0.001 study.day ( 0.872, 1.086) sepsis.l24=septic today ( 0.823, 1.319) hgb.icu ( 0.879, 1.093) study.day * hgb.icu ( 0.991, 1.014) 0.722

13 Table 7: (continued) sofa.renal * age.enroll ( 0.991, 1.003) sofa.renal * icu.type=surgical ( 0.860, 1.149) sofa.renal * apache.aps ( 0.981, 0.997) sofa.renal * charlson.score ( 0.960, 1.019) sofa.renal * stroke.risk ( 0.990, 1.019) sofa.renal * map.low.icu ( 1.004, 1.015) <0.001 sofa.renal * study.day ( 0.924, 1.047) sofa.renal * sepsis.l24=septic today ( 0.866, 1.146) sofa.renal * hgb.icu ( 0.932, 1.059) sofa.renal * study.day * hgb.icu ( 0.996, 1.009) Outcome4: Daily resp SOFA score ( 2) Descriptive Statistics Table 8: Descriptive by next day s RESP SOFA score ( 2) 13 N No Yes Combined Test Statistic N = 276 N = 5571 N = 5847 sofa.resp.cat 6704 χ 2 1 = 2576, P < Yes 39% ( 107) 99% (5510) 96% (5617) SOFA respiratory component score % ( 0) 0% ( 9) 0% ( 9) χ 2 4 = 2717, P < % ( 169) 1% ( 47) 4% ( 216) 2 34% ( 95) 51% (2852) 50% (2947) 3 4% ( 12) 45% (2505) 43% (2517) 4 0% ( 0) 3% ( 153) 3% ( 153) resp.tomo % ( 8) 0% ( 0) 0% ( 8) χ 2 4 = 5847, P < % ( 268) 0% ( 0) 5% ( 268) 2 0% ( 0) 57% (3152) 54% (3152) 3 0% ( 0) 41% (2285) 39% (2285) 4 0% ( 0) 2% ( 134) 2% ( 134) Age at enrollment F 1,5845 = 0.13, P = ICU type 6711 Surgical 23% ( 64) 37% (2052) 36% (2116) χ 2 1 = 21, P < APACHE APS at enrollment F 1,5845 = 33, P < Charlson score F 1,5845 = 0.71, P = Framingham stroke risk score F 1,5845 = 2.4, P = Lowest mean arterial pressure, current 24h F 1,5840 = 9.6, P = Was patient in ICU today? ICU 100% ( 276) 100% (5571) 100% (5847) Septic in the current 24h? 6703 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. χ 2 1 = 157, P < N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test

14 Table 8: (continued) N No Yes Combined Test Statistic N = 276 N = 5571 N = 5847 Septic today 30% ( 84) 67% (3737) 65% (3821) sevsepsis.l Severely septic today 22% ( 61) 62% (3464) 60% (3525) χ 2 1 = 177, P < Lowest hemoglobin, current 24h F 1,5157 = 38, P < a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test Table 9: Descriptive by next day s RESP SOFA score (0-4) 14 N Combined Test Statistic N = 8 N = 268 N = 3152 N = 2285 N = 134 N = 5847 sofa.resp.cat 6704 χ 2 4 = 2633, P < Yes 88% ( 7) 37% ( 100) 99% (3102) 100% (2275) 99% ( 133) 96% (5617) SOFA respiratory component score % ( 0) 0% ( 0) 0% ( 7) 0% ( 2) 0% ( 0) 0% ( 9) χ 2 16 = 5156, P < % ( 1) 63% ( 168) 1% ( 40) 0% ( 6) 1% ( 1) 4% ( 216) 2 38% ( 3) 34% ( 92) 76% (2404) 19% ( 435) 10% ( 13) 50% (2947) 3 50% ( 4) 3% ( 8) 22% ( 685) 76% (1744) 57% ( 76) 43% (2517) 4 0% ( 0) 0% ( 0) 0% ( 13) 4% ( 96) 33% ( 44) 3% ( 153) renal.tomo % ( 6) 44% ( 119) 55% (1718) 51% (1158) 45% ( 60) 52% (3061) χ 2 16 = 101, P < % ( 0) 16% ( 44) 20% ( 644) 23% ( 534) 27% ( 36) 22% (1258) 2 25% ( 2) 15% ( 40) 14% ( 441) 17% ( 380) 17% ( 23) 15% ( 886) 3 0% ( 0) 7% ( 19) 6% ( 182) 4% ( 95) 5% ( 7) 5% ( 303) 4 0% ( 0) 17% ( 46) 5% ( 167) 5% ( 118) 6% ( 8) 6% ( 339) Age at enrollment F 4,5842 = 11, P < ICU type 6711 Surgical 75% ( 6) 22% ( 58) 37% (1177) 37% ( 841) 25% ( 34) 36% (2116) χ 2 4 = 39, P < APACHE APS at enrollment F 4,5842 = 11, P < Charlson score F 4,5842 = 6.4, P < Framingham stroke risk score F 4,5842 = 11, P < Lowest mean arterial pressure, current 24h F 4,5837 = 8.9, P < Was patient in ICU today? ICU 100% ( 8) 100% ( 268) 100% (3152) 100% (2285) 100% ( 134) 100% (5847) Septic in the current 24h? 6703 Septic today 75% ( 6) 29% ( 78) 64% (2024) 71% (1611) 76% ( 102) 65% (3821) χ 2 4 = 192, P < sevsepsis.l Severely septic today 62% ( 5) 21% ( 56) 60% (1876) 66% (1505) 62% ( 83) 60% (3525) χ 2 4 = 205, P < Lowest hemoglobin, current 24h F 4,5154 = 12, P < a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test Logistic regression, Daily RESP SOFA 2(Y/N)

15 Table 10: Outcome:Daily resp SOFA =2.P-values less than 0.05 are in red. 15 sofa.resp.catyes ( , ) <0.001 age.enroll ( 0.955, 1.041) icu.typesurgical ( 1.022, 6.859) apache.aps ( 0.991, 1.088) charlson.score ( 0.801, 1.107) stroke.risk ( 0.952, 1.130) map.low.icu ( 0.956, 1.004) study.day ( 0.482, 1.373) sepsis.l24septic today ( 0.826, 4.261) hgb.icu ( 0.554, 1.329) study.day:hgb.icu ( 0.963, 1.068) sofa.resp.catyes:age.enroll ( 0.954, 1.050) sofa.resp.catyes:icu.typesurgical ( 0.150, 1.233) sofa.resp.catyes:apache ( 0.930, 1.035) sofa.resp.catyes:charlson.score ( 0.801, 1.155) sofa.resp.catyes:stroke.risk ( 0.893, 1.085) sofa.resp.catyes:map.low.icu ( 0.975, 1.034) sofa.resp.catyes:study.day ( 0.730, 2.243) sofa.resp.catyes:sepsis.l24septic today ( 0.611, 3.908) sofa.resp.catyes:hgb.icu ( 0.632, 1.624) sofa.resp.catyes:study.day:hgb.icu ( 0.928, 1.036) Proportional odds logistic regression, Ordinal response (0-4) Table 11: Outcome:Daily resp SOFA (0-4).. P-values less than 0.05 are in red. sofa.resp ( 2.842, ) <0.001 age.enroll ( 0.964, 1.013) icu.type=surgical ( 3.157, 9.969) <0.001 apache.aps ( 1.000, 1.064) charlson.score ( 0.852, 1.091) stroke.risk ( 1.042, 1.173) <0.001 map.low.icu ( 0.958, 0.998) study.day ( 0.753, 1.283) sepsis.l24=septic today ( 2.562, 8.005) <0.001 hgb.icu ( 0.557, 0.949) study.day * hgb.icu ( 0.970, 1.024) sofa.resp * age.enroll ( 0.995, 1.014) sofa.resp * icu.type=surgical ( 0.408, 0.635) <0.001 sofa.resp * apache.aps ( 0.974, 0.997) sofa.resp * charlson.score ( 0.942, 1.039) 0.662

16 Table 11: (continued) sofa.resp * stroke.risk ( 0.940, 0.983) <0.001 sofa.resp * map.low.icu ( 0.998, 1.013) sofa.resp * study.day ( 0.894, 1.099) sofa.resp * sepsis.l24=septic today ( 0.499, 0.775) <0.001 sofa.resp * hgb.icu ( 1.000, 1.218) sofa.resp * study.day * hgb.icu ( 0.992, 1.013) Proportional odds logistic regression, Ordinal response (0-4),without three way interaction Table 12: Outcome:Daily resp SOFA (0-4).. P-values less than 0.05 are in red. 16 sofa.resp ( 3.029, ) <0.001 age.enroll ( 0.964, 1.013) icu.type=surgical ( 3.148, 9.935) <0.001 apache.aps ( 1.000, 1.064) charlson.score ( 0.852, 1.091) stroke.risk ( 1.043, 1.174) <0.001 map.low.icu ( 0.958, 0.998) study.day ( 0.854, 0.994) sepsis.l24=septic today ( 2.561, 8.000) <0.001 hgb.icu ( 0.573, 0.840) <0.001 sofa.resp * age.enroll ( 0.996, 1.014) sofa.resp * icu.type=surgical ( 0.409, 0.636) <0.001 sofa.resp * apache.aps ( 0.974, 0.997) sofa.resp * charlson.score ( 0.942, 1.039) sofa.resp * stroke.risk ( 0.939, 0.983) <0.001 sofa.resp * map.low.icu ( 0.998, 1.013) sofa.resp * study.day ( 1.001, 1.033) sofa.resp * sepsis.l24=septic today ( 0.499, 0.775) <0.001 sofa.resp * hgb.icu ( 1.051, 1.202) <0.001 study.day * hgb.icu ( 0.997, 1.010) Proportional odds logistic regression, Ordinal response (0-4),Sensitivity Analysis

17 Table 13: Outcome:Daily resp SOFA (0-4).. P-values less than 0.05 are in red. 17 sofa.resp ( 3.508, ) <0.001 age.enroll ( 0.966, 1.019) icu.type=surgical ( 3.240, ) <0.001 apache.aps ( 0.994, 1.060) charlson.score ( 0.898, 1.169) stroke.risk ( 1.020, 1.156) map.low.icu ( 0.956, 0.997) study.day ( 0.696, 1.353) sepsis.l24=septic today ( 2.624, 8.658) <0.001 hgb.icu ( 0.587, 1.095) study.day * hgb.icu ( 0.966, 1.032) sofa.resp * age.enroll ( 0.993, 1.013) sofa.resp * icu.type=surgical ( 0.396, 0.632) <0.001 sofa.resp * apache.aps ( 0.975, 1.000) sofa.resp * charlson.score ( 0.920, 1.022) sofa.resp * stroke.risk ( 0.945, 0.991) sofa.resp * map.low.icu ( 0.998, 1.014) sofa.resp * study.day ( 0.878, 1.141) sofa.resp * sepsis.l24=septic today ( 0.487, 0.773) <0.001 sofa.resp * hgb.icu ( 0.947, 1.195) sofa.resp * study.day * hgb.icu ( 0.989, 1.015) Proportional odds logistic regression, Ordinal response (0-4),Sensitivity Analysis2, without three way interaction Table 14: Outcome:Daily resp SOFA (0-4).. P-values less than 0.05 are in red. sofa.resp ( 4.315, ) <0.001 age.enroll ( 0.966, 1.018) icu.type=surgical ( 3.237, ) <0.001 apache.aps ( 0.993, 1.060) charlson.score ( 0.898, 1.169) stroke.risk ( 1.021, 1.156) map.low.icu ( 0.956, 0.997) study.day ( 0.852, 1.024) sepsis.l24=septic today ( 2.617, 8.625) <0.001 hgb.icu ( 0.624, 0.980) sofa.resp * age.enroll ( 0.993, 1.013) sofa.resp * icu.type=surgical ( 0.397, 0.633) <0.001 sofa.resp * apache.aps ( 0.975, 1.000) 0.056

18 Table 14: (continued) sofa.resp * charlson.score ( 0.920, 1.022) sofa.resp * stroke.risk ( 0.945, 0.990) sofa.resp * map.low.icu ( 0.998, 1.014) sofa.resp * study.day ( 1.000, 1.034) sofa.resp * sepsis.l24=septic today ( 0.488, 0.774) <0.001 sofa.resp * hgb.icu ( 0.993, 1.164) study.day * hgb.icu ( 0.994, 1.011) Proportional odds logistic regression, Ordinal response (0-4),Marginal Model Table 15: Outcome:Daily resp SOFA (0-4).. P-values less than 0.05 are in red. 18 sofa.resp= ( , ) <0.001 sofa.resp= ( , ) <0.001 sofa.resp= ( , ) <0.001 age.enroll ( 0.994, 1.006) icu.type=surgical ( 0.875, 1.141) apache.aps ( 0.987, 1.003) charlson.score ( 0.913, 0.972) <0.001 stroke.risk ( 0.983, 1.012) map.low.icu ( 0.986, 0.996) <0.001 study.day ( 0.917, 1.037) sepsis.l24=septic today ( 1.207, 1.589) <0.001 hgb.icu ( 0.898, 1.015) study.day * hgb.icu ( 0.996, 1.008) Proportional odds logistic regression, Ordinal response (0-4),Marginal Model with hgb.icu and resp.sofa interaction Table 16: Outcome:Daily resp SOFA (0-4).. P-values less than 0.05 are in red. sofa.resp= ( , ) <0.001 sofa.resp= ( , ) <0.001 sofa.resp= ( , ) <0.001 hgb.icu ( 0.728, 1.118) age.enroll ( 0.995, 1.007) 0.866

19 Table 16: (continued) icu.type=surgical ( 0.871, 1.135) apache.aps ( 0.986, 1.002) charlson.score ( 0.909, 0.968) <0.001 stroke.risk ( 0.984, 1.012) map.low.icu ( 0.987, 0.997) study.day ( 0.898, 1.017) sepsis.l24=septic today ( 1.209, 1.593) <0.001 sofa.resp=2 * hgb.icu ( 0.762, 1.181) sofa.resp=3 * hgb.icu ( 0.880, 1.354) sofa.resp=4 * hgb.icu ( 0.997, 1.831) hgb.icu * study.day ( 0.998, 1.011)

20 20

21 1.4.9 Tomorrow resp.sofa 2 Today level 34 Today level P(y>=2) 0.6 Today level 1 1 Today level 2 2 Today level 3 3 Today level Today level Lowest hemoglobin, current 24h ted to:age.enroll=61.76 icu.type=medical apache.aps=22 charlson.score=2 stroke.risk=10 map.low.icu=62 study.day=6 sepsis.l24=septic today

22 22

23 Tomorrow resp.sofa 3 Today level Today level P(y>=3) Today level 1 1 Today level 2 2 Today level 3 3 Today level Today level 2 Today level Lowest hemoglobin, current 24h ted to:age.enroll=61.76 icu.type=medical apache.aps=22 charlson.score=2 stroke.risk=10 map.low.icu=62 study.day=6 sepsis.l24=septic today

24 24

25 Tomorrow resp.sofa Today level 1 1 Today level 2 2 Today level 3 3 Today level P(y>=4) 0.4 Today level Today level 3 Today level Lowest hemoglobin, current 24h ted to:age.enroll=61.76 icu.type=medical apache.aps=22 charlson.score=2 stroke.risk=10 map.low.icu=62 study.day=6 sepsis.l24=septic today

26 1.5 Outcome5: Daily Ventilator (Y/N) as a measure of success of extubation Descriptive Statistics Proportional odds logistic regression, Ordinal response (0-4),Marginal Model Table 17: Descriptive by ventilator (Y/N) 26 N No Yes Combined Test Statistic N = 1580 N = 4269 N = 5849 on.vent.l χ 2 1 = 3661, P < Yes 25% ( 399) 98% (4198) 79% (4597) Age at enrollment F 1,5847 = 8.7, P = ICU type 6711 Surgical 32% ( 500) 38% (1616) 36% (2116) χ 2 1 = 19, P < APACHE APS at enrollment F 1,5847 = 110, P < Charlson score F 1,5847 = 16, P < Framingham stroke risk score F 1,5847 = 0.06, P = Lowest mean arterial pressure, current 24h F 1,5842 = 83, P < Was patient in ICU today? ICU 100% (1580) 100% (4269) 100% (5849) Septic in the current 24h? 6703 Septic today 54% ( 858) 69% (2963) 65% (3821) χ 2 1 = 116, P < sevsepsis.l Severely septic today 37% ( 587) 69% (2938) 60% (3525) χ 2 1 = 483, P < Lowest hemoglobin, current 24h F 1,5157 = 29, P < a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test Logistic regression (Daily Ventilation (Y/N)) Table 18: Outcome:Daily ventilation (Y/N).. P-values less than 0.05 are in red. on.vent.l24=yes 9e e+04 ( , ) <0.001 age.enroll 4e e+00 ( 0.977, 1.031) icu.type=surgical 7e e+00 ( 1.123, 3.430) apache.aps 1e e+00 ( 0.978, 1.043) charlson.score 2e e+00 ( 0.906, 1.154) stroke.risk -7e e+00 ( 0.938, 1.052) map.low.icu -3e e+00 ( 0.979, 1.016) study.day 2e e+00 ( 0.939, 1.579) sepsis.l24=septic today 6e e+00 ( 1.016, 3.119) hgb.icu 3e e+00 ( 0.989, 1.703) study.day * hgb.icu -2e e+00 ( 0.952, 1.004) 0.093

27 Table 18: (continued) on.vent.l24=yes * age.enroll 4e e+00 ( 0.975, 1.033) on.vent.l24=yes * icu.type=surgical -9e e-01 ( 0.224, 0.750) on.vent.l24=yes * apache.aps 2e e+00 ( 0.966, 1.036) on.vent.l24=yes * charlson.score -8e e-01 ( 0.812, 1.054) on.vent.l24=yes * stroke.risk -1e e+00 ( 0.926, 1.049) on.vent.l24=yes * map.low.icu -3e e+00 ( 0.953, 0.993) on.vent.l24=yes * study.day -6e e-01 ( 0.709, 1.262) on.vent.l24=yes * sepsis.l24=septic today -2e e-01 ( 0.452, 1.520) on.vent.l24=yes * hgb.icu -2e e-01 ( 0.584, 1.045) on.vent.l24=yes * study.day * hgb.icu 1e e+00 ( 0.982, 1.042)

28 2 Analysis2: Hb during ICU stay and predicted outcomes 2.1 Outcome1: ICU mortality Descriptive Statistics Table 19: Descriptive by Mortality (Y/N) unique subject) N No Yes Combined Test Statistic N = 685 N = 128 N = 813 Age at enrollment F 1,811 = 4.3, P = ICU type 813 Surgical 35% (238) 19% ( 24) 32% (262) χ 2 1 = 13, P < APACHE APS at enrollment F 1,811 = 22, P < Charlson score F 1,811 = 6.5, P = Framingham stroke risk score F 1,811 = 1.9, P = lowest.hgb.icu F 1,801 = 4.8, P = auc.hgb.icu F 1,811 = 0.57, P = mean.sofa F 1,811 = 134, P < duration.sepsis F 1,811 = 12, P < max.sofa.renal % (285) 15% ( 19) 37% (304) χ 2 4 = 44, P < % (163) 23% ( 30) 24% (193) 2 19% (132) 37% ( 47) 22% (179) 3 6% ( 39) 12% ( 16) 7% ( 55) 4 10% ( 66) 12% ( 16) 10% ( 82) a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Wilcoxon test; 2 Pearson test Logistic regression for ICU.mortality (Y/N) Two different functional forms of hemoglobin during ICU was considered in the below analysis (two different models) Table 20: Outcome:Mortality.. P-values less than 0.05 are in red. lowest.hgb.icu (0.857, 1.157) age.enroll (1.019, 1.065) <0.001 icu.type=surgical (0.217, 0.633) <0.001 apache.aps (0.964, 1.024) charlson.score (0.892, 1.090) stroke.risk (0.907, 1.000) mean.sofa (1.401, 1.670) <0.001 duration.sepsis (0.982, 1.063) Table 21: Outcome:Mortality.. P-values less than 0.05 are in red. auc.hgb.icu (0.991, 1.004) age.enroll (1.020, 1.065) <0.001 icu.type=surgical (0.223, 0.655) <0.001 apache.aps (0.964, 1.024) charlson.score (0.897, 1.094) stroke.risk (0.905, 0.998) mean.sofa (1.407, 1.674) <0.001 duration.sepsis (0.978, 1.114)

29 2.1.3 Time dependent covariate survival analysis for Time to ICU.mortality Variable hgb.icu, daily.sofa, severe sepsis were time variang covariates. charlson.score,stroke.risk did not change over time. Age.enroll, icu.type, apache.aps, Call: coxph(formula = Surv(time1, time2, mortality.censor) ~ hgb.icu + age.enroll + icu.type + apache.aps + charlson.score + stroke.risk + daily.sofa + sevsepsis.l24 + cluster(id), data = brain.dailyobs) coef exp(coef) se(coef) robust se z p hgb.icu e-01 age.enroll e-02 icu.typesurgical e-03 apache.aps e-01 charlson.score e-02 stroke.risk e-02 daily.sofa e-11 sevsepsis.l24severely septic today e-01 Likelihood ratio test=78.3 on 8 df, p=1.05e-13 n= 5848, number of events= 84 (876 observations deleted due to missingness) For every unit increase of hgb.icu, the hazard of mortality in ICU increased by 6.4%. Given the p value equals to 0.4, no evidence to conclude hgb.icu has statistically significant effect on ICU.mortality after controlling for all other covariates. The robust standard error is used due to repeated measurement of hgb.icu on each subject. 29

30 2.2 Outcome2: Cardiac dysfunction(tropnin greater than 0.1) Correlated time dependent covariate survival analysis for Time to Tropnin greater than 0.1 Variable hgb.icu, daily.sofa, severe sepsis were time variang covariates. charlson.score,stroke.risk did not change over time. Call: coxph(formula = Surv(time1, time2, tropnin.censor) ~ hgb.icu + age.enroll + icu.type + apache.aps + charlson.score + stroke.risk + daily.sofa + sevsepsis.l24 + cluster(id), data = brain.dailyobs) Age.enroll, icu.type, apache.aps, coef exp(coef) se(coef) robust se z p hgb.icu age.enroll icu.typesurgical apache.aps charlson.score stroke.risk daily.sofa sevsepsis.l24severely septic today Likelihood ratio test=33.4 on 8 df, p= n= 5848, number of events= 129 (876 observations deleted due to missingness) 30

31 2.3 Outcome3: Renal dysfunction Outcome: Time to renal dysfunction Survival analysis with correlated time dependent covariate Variable hgb.icu, daily.sofa, severe sepsis were time variang covariates. charlson.score,stroke.risk did not change over time. Call: coxph(formula = Surv(time1, time2, renal.censor) ~ hgb.icu + age.enroll + icu.type + apache.aps + charlson.score + stroke.risk + daily.sofa + sevsepsis.l24 + cluster(id), data = brain.dailyobs) Age.enroll, icu.type, apache.aps, coef exp(coef) se(coef) robust se z p hgb.icu age.enroll icu.typesurgical apache.aps charlson.score stroke.risk daily.sofa sevsepsis.l24severely septic today Likelihood ratio test=508 on 8 df, p=0 n= 5848, number of events= 557 (876 observations deleted due to missingness) 2.4 Outcome4: Time to resolution of delirium To be continue 2.5 Outcome5: Time to successful extubation To be continue 31