Adaptation of the robust method to large distributions of reference values: program modifications and comparison of alternative computational methods.

The objective of this research was to compute reference limits using reference values from patients entering pharmaceutical development clinical trials by the nonparametric method and the robust method of Horn and Pesce, with and without outlier exclusion, and compare the methods with respect to influence on the limits. Reference limits were computed for 38 analytes with over 130,000 subjects contributing reference values. Subjects were partitioned into 10 demographic strata for limit computation. Limits were computed for both 95- and 98-percentile reference intervals by both methods. For each reference interval and method, the limits were calculated with and without outliers. Outliers were excluded by the Horn algorithm. Irrespective of method, reference limits were expanded with the 98-percentile interval, but some expansions were small. Outlier exclusion contracted limits with more influence on the upper limit. The robust method contracted the upper limit to a meaningful degree and slightly expanded the lower limit for many analytes. Outlier exclusion and computation by the robust method have an increasing influence on analytes with right-skewed distributions of reference values from large populations not screened to exclude common, stable diseases and environmental factors that might affect analyte variability. The method has advantages for computation of reference limits used in clinical trial analyses.

Health outcomes and cost of care among older adults with schizophrenia: a 10-year study using medical records across the continuum of care.

OBJECTIVES: The population of older patients with schizophrenia is increasing. This study describes health outcomes, utilization, and costs over 10 years in a sample of older patients with schizophrenia compared with older patients without schizophrenia. METHODS: An observational cohort study of 31,588 older adults (mean age: 70.44 years) receiving care from an urban public health system, including a community mental health center, during 1999-2008. Of these, 1,635 (5.2%) were diagnosed with schizophrenia and 757 (2.4%) had this diagnosis confirmed in the community mental health center. Patients' electronic medical records were merged with Medicare claims, Medicaid claims, the Minimum Dataset, and the Outcome and Assessment Information Set. Information on medication use was not available. MEASUREMENTS: Rates of comorbid conditions, healthcare utilization, costs, and mortality. RESULTS: Patients with schizophrenia had significantly higher rates of congestive heart failure (45.05% versus 38.84%), chronic obstructive pulmonary disease (52.71% versus 41.41%), and hypothyroidism (36.72% versus 26.73%) than the patients without schizophrenia (p <0.001). They had significantly lower rates of cancer (30.78% versus 43.18%) and significantly higher rates of dementia (64.46% versus 32.13%). The patients with schizophrenia had significantly higher mortality risk (hazard ratio: 1.25, 95% confidence interval: 1.07-1.47) than the patients without schizophrenia. They also had significantly higher rates of healthcare utilization. The mean costs for Medicare and Medicaid were significantly higher for the patients with schizophrenia than for the patients without schizophrenia. CONCLUSIONS: The management of older adult patients with schizophrenia is creating a serious burden for our healthcare system, requiring the development of integrated models of healthcare.

Inverse relationship between long-chain n-3 fatty acids and risk of sudden cardiac death in patients starting hemodialysis.

Experimental and clinical evidence suggests that long-chain n-3 fatty acids may protect against sudden cardiac death, the leading cause of mortality in hemodialysis patients. Here we investigated whether long-chain n-3 fatty acids have a protective relationship with sudden cardiac death in 100 patients who died of sudden cardiac death during the first year of starting hemodialysis and 300 patients who survived. Individuals were selected from a nationally representative cohort of over 1000 US hemodialysis units in 2004-2005. The odds of sudden cardiac death were calculated by quartile of long-chain n-3 fatty acid levels over the first year. There was a significant inverse relationship between long-chain n-3 fatty acids and the risk of sudden cardiac death even after adjusting for relevant comorbid conditions, biochemical values, and dietary fats. The odds of sudden cardiac death at 1 year for the second, third, and fourth quartile groups of long-chain n-3 fatty acids were 0.37, 0.22, and 0.20, respectively, compared with the lowest quartile. This significant inverse relationship was maintained even during the highest-risk first few months on hemodialysis. Thus, long-chain n-3 fatty acids are strongly and independently associated with a lower risk of sudden cardiac death in hemodialysis patients throughout the first year of hemodialysis.

Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma.

BACKGROUND: The objective of this study was to evaluate the effect of pericyte coverage (PC) of differentiated tumor microvessels on the prognosis of patients with clear cell renal cell carcinoma (CCRCC). METHODS: Samples from 2 cohorts of patients with CCRCC (101 Asian patients and 524 US patients) were prepared using 2 different histologic approaches: routine sectioning versus tissue microarray. Then, the samples were immunohistochemically doubled-stained for a pericyte marker (alpha smooth muscle actin [α-SMA]) and a differentiated vessel marker (cluster of differentiation 34 [CD34]), followed by multispectral image capturing and computerized image analyses to quantify the microvessel density (MVD) and the PC of differentiated vessels. The correlations of PC and the MVD:PC ratio with clinicopathologic characteristics were analyzed. RESULTS: There was an inverse correlation between differentiated MVD and PC. Higher PC correlated with more aggressive clinicopathologic characteristics of CCRCC in both cohorts, including more advanced T-classification, higher pathologic grades, and the occurrence of tumor necrosis. The MVD:PC ratio was an independent favorable prognostic factor for overall and recurrence-free survival in the Asian cohort and for recurrence-free survival in the US cohort. PC also was an independent prognostic factor, with higher PC predicting a poorer outcome. The combination of PC and MVD was better at distinguishing the outcome of patients with CCRCC. PC combined with differentiated MVD or with the MVD:PC ratio provided additional, independent prognostic information to the Leibovich risk model, and that information was used to generate improved risk models. CONCLUSIONS: The authors consistently observed that higher PC was correlated with more aggressive clinicopathologic characteristics. PC was an independent unfavorable prognostic factor. The authors concluded that pericytes should be considered for therapeutic targeting.

Low blood levels of long-chain n-3 polyunsaturated fatty acids in US hemodialysis patients: clinical implications.

BACKGROUND: Cardioprotective and other clinical benefits of long-chain n-3 polyunsaturated fatty acids (PUFA) are inversely related to dietary intake and hence blood content. We therefore investigated, in the first study of its kind, the blood content and distribution of these fatty acids in a large representative population of US hemodialysis patients. METHODS: Frozen sera were obtained from 400 individuals who were part of a large, contemporary, representative cohort of US incident hemodialysis patients. Long-chain n-3 PUFA were measured in total serum lipids and in the neutral and polar serum fractions using gas chromatography and solid phase extraction techniques. Mean long-chain n-3 PUFA levels were compared to levels in other dialysis and nondialysis populations from published reports. RESULTS: The study population was qualitatively similar to the overall US hemodialysis population in terms of major clinical characteristics. Long-chain n-3 PUFA were present in the serum polar fraction, with essentially none being detected in the neutral fraction (p < 0.0001 for polar vs. neutral fractions for all three long-chain n-3 PUFA). Mean serum long-chain n-3 PUFA levels (weight percent (±SD): total 1.55 ± 0.95, polar 3.99 ± 1.45) were low compared to nondialysis and most other non-US hemodialysis cohorts. CONCLUSIONS: While US hemodialysis patients have a blood distribution of long-chain n-3 PUFA that is similar to that in the general population, blood content is among the lowest recorded in the medical literature. This has implications for renal dietary recommendations and makes US patients an ideal group for testing the clinical effects of long-chain n-3 PUFA supplementation.

MCP-1 and IL-8 as pain biomarkers in fibromyalgia: a pilot study.

OBJECTIVE: Although fibromyalgia (FM) is traditionally a non-inflammatory condition, emerging data also suggest that FM has an immunologic component. Previous studies have reported that peripheral blood concentrations of two chemokines (i.e., interleukin-8 [IL-8] and monocyte chemotactic protein-1 [MCP-1]) were elevated in FM patients compared with normal controls. We sought to determine the longitudinal relationships of changes in the levels (picogram/mL) of IL-8 and MCP-1 with changes in the severity of FM-related pain. DESIGN: Secondary data analysis of a cohort of 16 FM subjects who provided blood samples at two time points: week 1 and week 12. Setting. Urban rheumatology clinic practices. PATIENTS: Individuals who met the American College of Rheumatology 1990 criteria for FM. OUTCOME MEASURES: Changes from week 1 to week 12 of the following variables: Brief Pain Inventory (BPI) pain severity and plasma concentrations of IL-8 and MCP-1. RESULTS: Change in BPI pain severity was significantly associated with changes in IL-8 and MCP-1 plasma concentrations. Specifically, for each unit increase in the change of BPI pain severity, IL-8 increased by 2.5 pg/mL (P = 0.03) and MCP-1 increased by 9.4 pg/mL (P = 0.006). None of the covariates (i.e., body mass index, medications, severity of depression, and overall FM burden) were significantly associated with either chemokines. CONCLUSION: Although preliminary, our findings raise the hypothesis that IL-8 and MCP-1 may be involved in the pathogenesis of FM. If replicated in a larger study, IL-8 and MCP-1 may assist in determining prognosis and in monitoring of treatment response.

Risk of Advanced Neoplasia Using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool.

Background: There is no validated, discriminating, and easy-to-apply tool for estimating risk of colorectal neoplasia. We studied whether the National Cancer Institute's (NCI's) Colorectal Cancer (CRC) Risk Assessment Tool, which estimates future CRC risk, could estimate current risk for advanced colorectal neoplasia among average-risk persons. Methods: This cross-sectional study involved individuals age 50 to 80 years undergoing first-time screening colonoscopy. We measured medical and family history, lifestyle information, and physical measures and calculated each person's future CRC risk using the NCI tool's logistic regression equation. We related quintiles of future CRC risk to the current risk of advanced neoplasia (sessile serrated polyp or tubular adenoma ≥ 1 cm, a polyp with villous histology or high-grade dysplasia, or CRC). All statistical tests were two-sided. Results: For 4457 (98.5%) with complete data (mean age = 57.2 years, SD = 6.6 years, 51.7% women), advanced neoplasia prevalence was 8.26%. Based on quintiles of five-year estimated absolute CRC risk, current risks of advanced neoplasia were 2.1% (95% confidence interval [CI] = 1.3% to 3.3%), 4.8% (95% CI = 3.5% to 6.4%), 6.4% (95% CI = 4.9% to 8.2%), 10.0% (95% CI = 8.1% to 12.1%), and 17.6% (95% CI = 15.5% to 20.6%; P < .001). For quintiles of estimated 10-year CRC risk, corresponding current risks for advanced neoplasia were 2.2% (95% CI = 1.4% to 3.5%), 4.8% (95% CI = 3.5% to 6.4%), 6.5% (95% CI = 5.0% to 8.3%), 9.3% (95% CI = 7.5% to 11.4%), and 18.4% (95% CI = 15.9% to 21.1%; P < .001). Among persons with an estimated five-year CRC risk above the median, current risk for advanced neoplasia was 12.8%, compared with 3.7% among those below the median (relative risk = 3.4, 95 CI = 2.7 to 4.4). Conclusions: The NCI's Risk Assessment Tool, which estimates future CRC risk, may be used to estimate current risk for advanced neoplasia, making it potentially useful for tailoring and improving CRC screening efficiency among average-risk persons.

Reference Limits for Outlier Analyses in Randomized Clinical Trials.

BACKGROUND: Reference limits used in clinical medicine to screen and manage patients are typically developed nonparametrically using reference values from a limited number of healthy subjects using a 95th percentile reference interval. We have evaluated alternative methods of computation and the resulting limits for use in the analyses of treatment-emergent outliers in clinical trials. METHODS: We developed a set of alternative reference limits for 38 laboratory analytes based on alternative statistical methods and assessed their relative performance in clinical trial analysis. Performance assessment was based on the clinical credibility of the limits, inferential statistical performance, consideration of incidences for the test drug and control (placebo) in cases where the drug was reasonably believed to be associated with a change in an analyte (positive cases), and in cases where prior analyses failed to demonstrate a change associated with the drug (negative cases). RESULTS: Based on consideration of these cases, no single method resulted in optimal limits for all cases considered. However, with the limits developed using clinical trial subjects' values at baseline as reference values, excluding outliers, the robust method and the 98th percentile interval appeared to produce optimal limits across the greatest number of cases considered. CONCLUSION: Although no single method of limit computation will result in optimal limits for all outlier analyses for all analytes across all clinical trials, the 98th percentile reference interval robust limits based on clinical trial reference values appeared superior to multiple alternatives considered for such analyses.

Atopy, cytokine production, and airway reactivity as predictors of pre-school asthma and airway responsiveness.

BACKGROUND: Childhood asthma is often characterized by recurrent wheezing, airway hyper-reactivity, atopy, and altered immune characteristics; however, our understanding of the development of these relationships from early in life remains unclear. The aim of our study was to evaluate whether atopy, cytokine production by peripheral blood mononuclear cells (PBMCs), and airway responsiveness, assessed in infants and toddlers, are associated with asthma and airway responsiveness at 4-years of age. METHODS: Infants with eczema (N = 116), enrolled prior to wheezing, were assessed at entry (mean age of 10.7 months), at 1-year follow-up (N = 112), and at 4-years of age (N = 94). Total serum IgE, specific IgE to allergens, and cytokines produced by stimulated PBMCs, were assessed at entry and 1-year follow-up. Spirometry was obtained at all 3-visits, while airway reactivity to methacholine was assessed at entry and 1-year follow-up, and bronchodilator (BD) responsiveness, as well as current asthma was assessed at 4-years of age. RESULTS: We found that pre-school children with asthma had lower spirometry and a greater BD-response. Serum IgE, particularly to egg and/or milk, and altered cytokine production by PBMCs at entry to the study were associated with asthma, lower spirometry, and greater airway responsiveness at 4-years of age. In addition, we found that airway responsiveness, as well as spirometry, tracked from infancy to 4-years of age. CONCLUSIONS: While spirometry and airway responsiveness track longitudinally from early in life, atopy and cytokine production by PBMCs are associated not only with an increased risk of pre-school asthma, but also lower spirometry and increased airway responsiveness.

Prevalence and correlates of pain and pain treatment in a western Kenya referral hospital.

BACKGROUND: Pain is often inadequately evaluated and treated in sub-Saharan Africa (SSA). OBJECTIVE: We sought to assess pain levels and pain treatment in 400 hospitalized patients at a national referral hospital in western Kenya, and to identify factors associated with pain and pain treatment. DESIGN: Using face-validated Kiswahili versions of two single-item pain assessment tools, the Numerical Rating Scale (NRS) and the Faces Pain Scale-Revised (FPS-R), we determined patients' pain levels. Additional data collected included patient demographics, prescribed analgesics, and administered analgesics. We calculated mean pain ratings and pain management index (PMI) scores. RESULTS: Averaged between the NRS and FPS-R, 80.5% of patients endorsed a nonzero level of pain and 30% of patients reported moderate to severe pain. Older patients, patients with HIV, and cancer patients had higher pain ratings. Sixty-six percent of patients had been prescribed analgesics at some point during their hospitalization, the majority of which were nonopioids. A majority of patients (66%) had undertreated pain (negative scores on the PMI). CONCLUSION: This study shows that hospitalized patients in Kenya are experiencing pain and that this pain is often undertreated.

Pulmonary diffusing capacity in healthy Caucasian children.

Previous studies of pulmonary diffusing capacity in children differed greatly in methodologies; numbers of subjects evaluated, and were performed prior to the latest ATS/ERS guidelines. The purpose of our study was to establish reference ranges for the diffusing capacity to carbon monoxide (DL(CO) ) and alveolar volume (V(A) ) in healthy Caucasian children using current international guidelines and contemporary equipment. Healthy children from the United States (N = 303) and from Australia (N = 176) performed acceptable measurements of single breath pulmonary diffusing capacity and alveolar volume according to current ATS/ERS guidelines. The natural log of DL(CO) and V(A) were associated with height, age and an age-sex interaction term, while DL(CO) /V(A) was related to height and the age-sex interaction term only. Adjustment of DL(CO) for hemoglobin (n = 303; USA data only) resulted is a small but significant decrease in DL(CO) of ∼1% but did not significantly alter the regression equations. In this dataset there was no influence of center for DL(CO) or DL(CO) /V(A) , while Australian children had a statistically smaller V(A) (mean difference 0.14 L after accounting for height, age and age-sex; P = 0.012). We report that diffusing capacity outcomes can be collated from multiple centers using similar equipment and collection protocols. Using collated data we have derived regression equations for pulmonary diffusing capacity outcomes in healthy Caucasian children aged 5-19 years.

Long-term hematopoietic stem cell damage in a murine model of the hematopoietic syndrome of the acute radiation syndrome.

Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is believed to be due to decreased self-renewal potential of radiation-damaged hematopoietic stem cells (HSC). Current literature has examined primarily sublethal doses of radiation and time points within a few months of exposure. In this study, the authors examined RBMD in mice surviving lethal doses of total body ionizing irradiation (TBI) in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS). Survivors were analyzed at various time points up to 19 mo post-TBI for hematopoietic function. The competitive bone marrow (BM) repopulating potential of 150 purified c-Kit+ Sca-1+ lineage- CD150+ cells (KSLCD150+) remained severely deficient throughout the study compared to KSLCD150+ cells from non-TBI age-matched controls. The minimal engraftment from these TBI HSCs is predominantly myeloid, with minimal production of lymphocytes both in vitro and in vivo. All classes of blood cells as well as BM cellularity were significantly decreased in TBI mice, especially at later time points as mice aged. Primitive BM hematopoietic cells (KSLCD150+) displayed significantly increased cell cycling in TBI mice at all time points, which may be a physiological attempt to maintain HSC numbers in the post-irradiation state. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to long-term HSC exhaustion and subsequent RBMD, exacerbated by the added insult of aging at later time points.