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

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

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

Development and Content Validity Testing of a Patient-Reported Treatment Acceptance Measure for Use in Patients Receiving Treatment via Subcutaneous Injection

AbstractBackgroundNew therapies in development for lowering low-density lipoprotein cholesterol, such as alirocumab, require administration by subcutaneous injections. There is a need to assess the acceptance of such treatments and their mode of administration.ObjectivesTo develop a novel patient-reported outcome measure, the Injection-Treatment Acceptance Questionnaire (I-TAQ), and assess its content validity using qualitative methods.MethodsConcepts generated from a literature and instrument review informed the initial drafting of 17 items in the I-TAQ, with item wording adapted from three existing instruments. Three rounds of qualitative interviews were conducted with 29 US-English speaking patients at high cardiovascular risk. Concept elicitation questioning was used to explore patients’ treatment experiences followed by cognitive debriefing of the I-TAQ using “think-aloud” methods. Verbatim transcripts were analyzed using thematic analysis.ResultsQualitative analysis of concept elicitation data identified the following relevant concepts: perceived efficacy, side effects, self-efficacy, convenience, and overall acceptance. Seven (24%) patients discussed an initial fear of needles, but described this as subsiding with no impact on adherence. Five items were added after round one interviews, three of which were retained after round two testing in which two further items were added, forming the conceptually comprehensive 22-item I-TAQ. Patients demonstrated good understanding of item wording, instructions, response scales, and recall period.ConclusionsSuccessive rounds of in-depth interviews resulted in a treatment acceptance measure with strong content validity. Pending demonstration of its psychometric properties, the I-TAQ may prove to be a valuable measure of patients’ perspectives toward being treated with low-density lipoprotein cholesterol–lowering therapies requiring subcutaneous injections