Separating signal from noise: the challenge of identifying useful biomarkers in sepsis

Abstract Sepsis diagnosis remains based largely on clinical presentation despite significant advances in the understanding of underlying pathophysiology and host-pathogen interactions. The systematic review article by Zonneveld and colleagues in the previous issue of Critical Care describes another potential avenue of study for using biomarkers for sepsis diagnosis and prognostication. Soluble leukocyte adhesion molecules and their associated sheddase enzymes vary in detectable levels and activity in patients in relation to immunologic status, age, and systemic inflammation, including in the setting of sepsis. Unfortunately, studies of these molecules as diagnostic or prognostic aids (or both) in sepsis have thus far been disappointing. Zonneveld and colleagues propose two potential avenues to enhance the performance characteristics of soluble adhesion molecules and their sheddases in sepsis diagnosis and prognosis: (a) identifying age-adjusted normal values for soluble leukocyte adhesion molecules and their sheddases and (b) investigating simultaneous measurement of both soluble adhesion molecules and sheddases in integrated sepsis evaluation schema. This commentary discusses the proposed solutions of Zonneveld and colleagues in more detail and outlines additional considerations that should be addressed in order to develop robust and valid diagnostic and prognostic tools for clinicians managing patients with sepsis.Peer Reviewe

Assessing response bias from missing quality of life data: The Heckman method

BACKGROUND: The objective of this study was to demonstrate the use of the Heckman two-step method to assess and correct for bias due to missing health related quality of life (HRQL) surveys in a clinical study of acute coronary syndrome (ACS) patients. METHODS: We analyzed data from 2,733 veterans with a confirmed diagnosis of acute coronary syndromes (ACS), including either acute myocardial infarction or unstable angina. HRQL outcomes were assessed by the Short-Form 36 (SF-36) health status survey which was mailed to all patients who were alive 7 months following ACS discharge. We created multivariable models of 7-month post-ACS physical and mental health status using data only from the 1,660 survey respondents. Then, using the Heckman method, we modeled survey non-response and incorporated this into our initial models to assess and correct for potential bias. We used logistic and ordinary least squares regression to estimate the multivariable selection models. RESULTS: We found that our model of 7-month mental health status was biased due to survey non-response, while the model for physical health status was not. A history of alcohol or substance abuse was no longer significantly associated with mental health status after controlling for bias due to non-response. Furthermore, the magnitude of the parameter estimates for several of the other predictor variables in the MCS model changed after accounting for bias due to survey non-response. CONCLUSION: Recognition and correction of bias due to survey non-response changed the factors that we concluded were associated with HRQL seven months following hospital admission for ACS as well as the magnitude of some associations. We conclude that the Heckman two-step method may be a valuable tool in the assessment and correction of selection bias in clinical studies of HRQL

Depression predicts revascularization procedures for 5 years after coronary angiography.

OBJECTIVE:Depression has been reported to increase cardiac event rates and functional impairment in patients with coronary disease. This article describes the impact of depression on subsequent healthcare utilization for such patients. METHODS:One hundred ninety-eight health maintenance organization patients with stable coronary disease were interviewed after elective angiography using a structured psychiatric diagnostic scale. Cardiac events, hospitalizations, procedures, and costs were monitored for the next 5 years through automated data. Subjects were classified at the time of angiography by modified DSM-IV criteria into those with major, minor, and no depression. RESULTS:In univariate analyses, the no depression group (N = 136) was most likely to receive coronary artery bypass grafting (CABG) (61% vs. 36% in the major depression group vs. 27% in the minor depression group, p =.001), and the major depression group (N = 25) was most likely to receive percutaneous transluminal coronary angioplasty (PTCA) (44% vs. 14% in the minor depression group vs. 24% in the no depression group). The minor depression group (N = 37) was least likely to be hospitalized for cardiac reasons during follow-up (54% vs. 80% in the major depression group vs. 80% in the no depression group, p =.005). Five-year rates of myocardial infarction and death did not differ significantly between groups. Proportional hazard models showed that those in the depression groups differed in time from catheterization to CABG (chi2(2) = 11.9, p =.003) and time to PCTA (chi2(2) = 7.74, p =.02) after controlling for relevant covariates. Median regression showed that patients with no depression had higher costs during the first year but tended to have lower costs in years 2 through 5 than patients with minor or major depression. CONCLUSIONS:Depression status at angiography is associated with the need for revascularization and total healthcare costs for the following year

Testing the performance of the ENRICHD Social Support Instrument in cardiac patients

BACKGROUND: Previous investigations suggest an important role of social support in the outcomes of patients treated for ischemic heart disease. The ENRICHD Social Support Instrument (ESSI) is a 7-item self-report survey that assesses social support. Validity and reliability of the ESSI, however, has not been formally tested in patients undergoing percutaneous coronary intervention (PCI). METHODS: The ESSI, along with the Short Form-36 (SF-36), was sequentially administered to a cohort of 271 patients undergoing PCI. The test-retest reliability was examined with an intra-class correlation coefficient by comparing scores among 174 patients who completed both instruments 5 and 6 months after their procedure. Internal reliability was assessed using Cronbach's alpha at the time of patients' baseline procedure. The concurrent validity of the ESSI was assessed by comparing scores between depressed (MHI-5 score < 44) vs. non-depressed patients. The correlation between the ESSI and the SF-36 Social Functioning sub-scale, an accepted measure of social functioning, was also examined. RESULTS: Test-retest reliability showed no significant differences in mean scores among ESSI questionnaires administered 1 month apart (27.8+/-1.4 vs 27.8+/-1.5, p = 0.98). The intra-class correlation coefficient was 0.94 and Cronbach's alpha was 0.88. Mean ESSI scores were significantly lower among depressed vs. non-depressed patients (24.6+/-1.7 vs 27+/-1.4, p < 0.018) and a positive albeit modest correlation with social functioning was seen (r = 0.19, p = 0.002). CONCLUSION: The ESSI appears to be a valid and reliable measure of social support in patients undergoing treatment for coronary artery disease. It may prove to be a valuable method of controlling for patient variability in outcomes studies where the outcomes are related to patients' social support

Investigation of 89 candidate gene variants for effects on all-cause mortality following acute coronary syndrome

BACKGROUND: Many candidate genes have been reported to be risk factors for acute coronary syndrome (ACS), but their impact on clinical prognosis following ACS is unknown. METHODS: We examined the association of putative genetic risk factors with 3-year post-ACS mortality in 811 ACS survivors at university-affiliated hospitals in Kansas City, Missouri. Through a systematic literature search, we first identified genetic variants reported as susceptibility factors for atherosclerosis or ACS. Restricting our analysis to whites, so as to avoid confounding from racial admixture, we genotyped ACS cases for 89 genetic variants in 72 genes, and performed individual Kaplan-Meier survival analyses. We then performed Cox regression to create multivariate risk prediction models that further minimized potential confounding. RESULTS: Of 89 variants tested, 16 were potentially associated with mortality (P < 0.1 for all), of which 6 were significantly associated (P < 0.05) with mortality following ACS. While these findings are not more than what would be expected by chance (P = 0.28), even after Bonferroni correction and adjustment for traditional cardiac risk factors, the IRS1 972Arg variant association (P = 0.001) retained borderline statistical significance (P < 0.1). CONCLUSION: With the possible exception of IRS1, we conclude that multiple candidate genes were not associated with post-ACS mortality in our patient cohort. Because of power limitations, the 16 gene variants with P values < 0.1 may warrant further study. Our data do not support the hypothesis that the remaining 73 genes have substantial, clinically significant association with mortality after an ACS

Factors influencing patient willingness to participate in genetic research after a myocardial infarction

Abstract Background Achieving 'personalized medicine' requires enrolling representative cohorts into genetic studies, but patient self-selection may introduce bias. We sought to identify characteristics associated with genetic consent in a myocardial infarction (MI) registry. Methods We assessed correlates of participation in the genetic sub-study of TRIUMPH, a prospective MI registry (n = 4,340) from 24 US hospitals between April 2005 and December 2008. Factors examined included extensive socio-demographics factors, clinical variables, and study site. Predictors of consent were identified using hierarchical modified Poisson regression, adjusting for study site. Variation in consent rates across hospitals were quantified by the median rate ratio (MRR). Results Most subjects consented to donation of their genetic material (n = 3,484; 80%). Participation rates varied greatly between sites, from 40% to 100%. After adjustment for confounding factors, the MRR for hospital was 1.22 (95% confidence interval (CI) 1.11 to 1.29). The only patient-level factors associated with consent were race (RR 0.93 for African Americans versus whites, 95% CI 0.88 to 0.99) and body mass index (RR 1.03 for BMI &#8805; 25, 95% CI 1.01 to 1.06). Conclusion Among patients with an MI there were notable differences in genetic consent by study site, but little association with patient-level factors. This suggests that variation in the way information is presented during recruitment, or other site factors, strongly influence patients' decision to participate in genetic studies.Peer Reviewe

Patterns and predictors of fast food consumption with acute myocardial infarction

Computational Infrastructure & Informatics Poster SessionBackground: Fast food is affordable and convenient, yet high in calories, saturated fat and sodium. The prevalence of fast food intake at the time of acute myocardial infarction (AMI) and patterns of fast food intake in recovery are unknown. Moreover, the association between dietary counseling at hospital discharge and fast food intake after MI has not been described. Methods: We assessed baseline, 1 and 6-month fast food intake in 2494 patients in TRIUMPH, a 26-center, prospective registry of AMI patients. Fast food intake was divided into frequent (≥ weekly) vs. infrequent (< weekly) consumption. Multivariable regression was used to identify predictors of frequent fast food intake at 6-months, adjusted for baseline fast food consumption, sociodemographics and clinical factors. Results: Frequent fast food intake was common at the time of AMI (36%), but decreased substantially after AMI to 17% at 1-month and 20% at 6-months (p-value <0.0001). Patient characteristics independently associated with frequent fast food intake at 6-months included white race, male gender, health literacy, financial difficulty, dyslipidemia and diabetes. College education, heart failure and coronary revascularization during AMI admission were inversely associated with 6-month fast food consumption. Importantly, dietary counseling at discharge was not associated with lower 6-month fast food intake. Conclusion: Fast food consumption declined substantially after AMI. Certain populations, including patients with financial difficulty and lower health literacy continued to eat fast food frequently after their event. Although several patient groups are at risk for persistent high fast food intake, current dietary counseling efforts appear ineffective at altering behavior and new counseling strategies are needed