Effect size as a tool to identify subpopulations with improved clinical outcomes in metastatic colorectal cancer.

252 Background: ASCO defined meaningful trial endpoints in colorectal cancer (CRC) to include OS HR ≤0.67 (Ellis, JCO 2014). This measure is limited in identifying treatment benefit for subgroups from heterogeneous populations. Effect size (Glass’s Δ) calculates the absolute difference in median clinical outcomes normalized to the control group standard deviation. We hypothesized that durable effect sizes ≥2 would be useful in predicting which trials possess subgroup populations of clinical significance despite a HR > 0.67. Methods: Prospective phase II-III trials in metastatic CRC from the ASCO Meeting Library (2016-2019) were cataloged by clinical outcomes of PFS and OS. Effect size was calculated from trials reporting confidence intervals and compared with absolute difference in clinical outcome, hazard ratio and therapeutic intervention. Trials with an indeterminant HR, yet effect size > 2 were reviewed in subgroup analyses. Results: 385 abstracts were reviewed with 99 clinical analyses available for effect size calculation. Absolute difference in PFS correlated with effect size (R = 0.64) and was inversely proportional to HR (R = -0.63). The absolute difference in OS correlated with effect size (R = 0.69) and was inversely proportional to HR (R = -0.57). When stratified by clinically significant HR (defined ≤0.67), median effect size for PFS was 13.7±13.3 (SD) which was significantly different from HR > 0.67 with median effect size 1.0±3.8 (p < 0.001). Median effect size for OS when stratified by HR ≤0.67 was 3.7±2.5 which was significantly different when compared to endpoints with HR > 0.67 with median effect size 0.9±1.4 (p < 0.003). Subgroup populations with survival benefit included combination checkpoint blockade durvalumab/tremelimumab vs supportive care with effect size 3.1 (HR 0.72; NCT02870920). First-line PFS benefit was predicted in KRAS wildtype liver-limited CRC treated with FOLFOX+cetuximab vs FOLFOX+bevacizumab by effect size of 3.2 (HR 0.80; NCT01836653). Conclusions: Effect size holds potential as a measure to delineate improved clinical outcomes from heterogeneous populations and could identify those trials for which further subgroup analysis should be explored.

SYSTOLIC FUNCTION AND DYSSYNCHRONY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

Echographic evaluation of systolic function plays an important role in examination of the patients with acute myocardial infarction (AMI). Recent developments in real-time 3D echocardiography (RT3DE) allow us to evaluate additional parameters such as the dyssynchrony.The aim of this study was to evaluate the relationship between myocardium dyssynchrony and systolic function and to assess the prognostic value of dyssynchrony and its influence on the development of arrhythmias and fatal event in post AMI period.Methods: Study population consisted of 82 (mean age 52±21) patients with AMI and 65 age and gender matched persons with similar cardiovascular risk factors, but without AMI (control group). Standard deviation of the time to the regional LV minimum systolic volume for all 16 segments Tmsv4 16-SD index was used for the assessment of dyssynchrony. The follow-up period was 6 months afterAMI.Results: Tmsv 16-SD values were significantly higher in patients with MI compared control group (6.8 ± 2.7% vs 2.9 ± 1.6 % respectively, р<0,001). Moderate negative correlation was observed between Tmsv 16-SD and Cardiac Index (CI) (r =-0.58, p<0.008). No significant correlations were found between Tmsv 16-SD and mean arterial pressure and herat rate. Tmsv 16-SD was significantly lower in patients with pulmonary hypertension (maximum systolic pressure in lung artery (SPLA) – 55.0±5.58 mm Hg) as compared to patients without pulmonary hypertension (maximum SPLA – 33.0±5.76 mmHg); 4.9±0.75 vs 6.1±1.88 respectively, р=0.03. Significant positive correlation was observed between Tmsv 16-SD and end-diastolic volume (EDV) (r=0.63; р<0.05) and negative with ejection fraction (EF) (r=-0.73; p<0.05).28 patients (34%) of the MI group had the increase Tmsv 16-SD and normal values of EDV and EF. According to ROC analysis ROC Tmsv 16-SD>6.1 was associated with arrhythmic complications in post IM period (sensitivity 83.3%, specificity 87.5%, AUC=0.865, p<0.0001). Tmsv 16SD>6.1 correlates with increasing likelihood of fatal event (sensitivity 87.5%, specificity 71.6%, AUC=0.81, p<0.0001)Conclusions: Tmsv 16-SD is increased in patients with MI. In 34% of MI patients the increase of Tmsv 16-SD was observed in combination normal values of EF and EDV which allow us to consider Tmsv 16-SD as an additional indicator describing pathological changes in myocardium. Tmsv16-SD is correlated with hemodynamic indicators such as CI and SPLA. High Tmsv 16-SD is associated with increased level of arrhythmic complications and fatal events.

Intralaboratory Performance Requirements Necessary to Pass Proficiency Testing: CAP-1990 vs CLIA-1967 (March 14, 1990) Formats Compared

The pre-1990 College of American Pathologists' (CAP) Proficiency Testing (PT) program used a two samples per analyte/four challenges per year format with performance or pass-fail grading criteria determined by the program. On Jan. 1, 1991, the Clinical Laboratory Improvement Act of 1967 (CLIA-67) final rules (March 14, 1990) mandated a revised PT format of five samples per analyte/four challenges per year, with the regulations specifying minimum performance criteria. Extending our previous analysis, we compare the maximum permissible intralaboratory imprecision at low bias compatible with passing external PT in the former CAP and current CLIA-67 formats. If a laboratory is able to reduce its internal coefficient of variation (CV) to less than 44% of the PT criterion for each analyte, its overall chance of adverse action for any of the 27 routine chemistry analytes specified in CLIA-67 will be less than 1% in a two-year (eight PT challenges or events) period. Consideration of actual interlaboratory CVs from CAP surveys suggest that a reduction of this magnitude may be difficult for the analytes total cholesterol and blood urea nitrogen, where intralaboratory imprecision comparable with the group standard deviation (SD) from 1990 CAP surveys would yield individual adverse action (PT failure) rates of 5% and 1%, respectively. Five other analytes have CLIA-67 performance limits dangerously close to CAP interlaboratory CVs.