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

Integrating Quality of Life and Survival Outcomes in Cardiovascular Clinical Trials.

Background Survival and health status (eg, symptoms and quality of life) are key outcomes in clinical trials of heart failure treatment. However, health status can only be recorded on survivors, potentially biasing treatment effect estimates when there is differential survival across treatment groups. Joint modeling of survival and health status can address this bias. Methods and Results We analyzed patient-level data from the PARTNER 1B trial (Placement of Aortic Transcatheter Valves) of transcatheter aortic valve replacement versus standard care. Health status was quantified with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 1, 6, and 12 months. We compared hazard ratios for survival and mean differences in KCCQ scores at 12 months using several models: the original growth curve model for KCCQ scores (ignoring death), separate Bayesian models for survival and KCCQ scores, and a Bayesian joint longitudinal-survival model fit to either 12 or 30 months of survival follow-up. The benefit of transcatheter aortic valve replacement on 12-month KCCQ scores was greatest in the joint-model fit to all survival data (mean difference, 33.7 points; 95% credible intervals [CrI], 24.2-42.4), followed by the joint-model fit to 12 months of survival follow-up (32.3 points; 95% CrI, 22.5-41.5), a Bayesian model without integrating death (30.4 points; 95% CrI, 21.4-39.3), and the original growth curve model (26.0 points; 95% CI, 18.7-33.3). At 12 months, the survival benefit of transcatheter aortic valve replacement was also greater in the joint model (hazard ratio, 0.50; 95% CrI, 0.32-0.73) than in the nonjoint Bayesian model (0.54; 95% CrI, 0.37-0.75) or the original Kaplan-Meier estimate (0.55; 95% CI, 0.40-0.74). Conclusions In patients with severe symptomatic aortic stenosis and prohibitive surgical risk, the estimated benefits of transcatheter aortic valve replacement on survival and health status compared with standard care were greater in joint Bayesian models than other approaches

Incorporating development of a patient-reported outcome instrument in a clinical drug development program: examples from a heart failure program.

BackgroundPatient-reported outcome (PRO) measures can be used to support label claims if they adhere to US Food & Drug Administration guidance. The process of developing a new PRO measure is expensive and time-consuming. We report the results of qualitative studies to develop new PRO measures for use in clinical trials of omecamtiv mecarbil (a selective, small molecule activator of cardiac myosin) for patients with heart failure (HF), as well as the lessons learned from the development process.MethodsConcept elicitation focus groups and individual interviews were conducted with patients with HF to identify concepts for the instrument. Cognitive interviews with HF patients were used to confirm that no essential concepts were missing and to assess patient comprehension of the instrument and items.ResultsDuring concept elicitation, the most frequently reported HF symptoms were shortness of breath, tiredness, fluid retention, fatigue, dizziness/light-headedness, swelling, weight fluctuation, and trouble sleeping. Two measures were developed based on the concepts: the Heart Failure Symptom Diary (HF-SD) and the Heart Failure Impact Scale (HFIS). Findings from cognitive interviews suggested that the items in the HF-SD and HFIS were relevant and well understood by patients. Multiple iterations of concept elicitation and cognitive interviews were needed based on FDA request for a broader patient population in the qualitative study. Lessons learned from the omecamtiv mecarbil PRO/clinical development program are discussed, including challenges of qualitative studies, patient recruitment, expected and actual timelines, cost, and engagement with various stakeholders.ConclusionDevelopment of a new PRO measure to support a label claim requires significant investment and early planning, as demonstrated by the omecamtiv mecarbil program

The Influence of Race on Health Status Outcomes One Year After an Acute Coronary Syndrome

ObjectivesThe goal of this study was to compare health status (symptoms, function, and quality of life) outcomes of whites and blacks one year after an acute coronary syndrome (ACS).BackgroundAlthough racial differences in the use of angiography and revascularization after ACS are known to exist, differences in health status outcomes have not been described.MethodsWe conducted a prospective registry of 1,159 consecutive ACS patients treated between February 1, 2000 and October 31, 2001. One-year health status was quantified with the Seattle Angina Questionnaire (SAQ) and Short Form-12 Physical Component Score (SF-12 PCS). Multivariable models were used to adjust for racial differences in sociodemographic, clinical, and treatment characteristics.ResultsMortality rates were similar among the 196 black and 963 white patients (7.1% vs. 7.0%, p = 0.93); 81 died during follow-up, and 199 (17%) could not be interviewed. At one year, blacks had a higher prevalence of angina (43.4% vs. 27.1%), worse quality of life (SAQ score = 70.6 ± 28.3 vs. 83.9 ± 20.8), and poorer physical function (SF-12 PCS = 36.8 ± 12.3 vs. 43.2 ± 11.4; p < 0.0001 for all). Multivariable models, including hospital treatments, revealed a trend for more angina (odds ratio 1.46 [95% confidence interval 0.91 to 2.34]) and significantly worse quality of life (mean difference = −7.7 ± 2.4, p = 0.002) and physical function (−3.6 ± 1.3, p = 0.005).ConclusionsBlacks have more angina, worse quality of life, and worse physical function one year after an ACS than do whites. Closer surveillance of black ACS patients is needed to determine whether additional treatment can improve their outcomes

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