Prevalence of Nonalcoholic Steatohepatitis and Associated Fibrosis Stages Among US Adults Using Imaging-Based vs Biomarker-Based Noninvasive Tests.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease worldwide. Therapies are under development for nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, such that the prevalence of NASH with liver fibrosis, which is likely to require treatment, may be of interest to healthcare decision makers. Noninvasive tests are used in initial screening for NASH, as well as in observational studies of NASH prevalence. However, existing evidence does not address how estimated prevalence varies with different noninvasive tests. This analysis estimated the prevalence of NASH among US adults and assessed variation with different noninvasive tests. Methods: A cross-sectional analysis was conducted using the 2017-March 2020 National Health and Nutrition Examination Survey cycle. Participants with presumed NAFLD (steatosis and without alternative causes of liver disease) were identified, among whom NASH was predicted based on FAST score, Fibrosis-4 (FIB-4), and AST-to-Platelet Ratio Index (APRI) cutoffs across 11 scenarios. Among NASH participants, fibrosis stages were explored based on distribution across the spectrum of liver-stiffness measurements. Results: Among participants with complete data for the analysis (N=6969), prevalence of presumed NAFLD was 25.6%. Within presumed NAFLD, prediction of NASH using imaging-based NIT cutoffs yielded estimated prevalence of 1.3%-4.8% (3.3 million-12.2 million) based on FAST score cutoffs from 0.35-0.67. Using biomarker-based NIT cutoffs yielded estimated prevalence of 0.4%-12.3% (1.0 million-14.5 million) based on FIB-4 cutoffs from 0.90-2.67, and 0.1%-1.9% (0.2-5.0 million) based on APRI cutoffs from 0.50-1.50. Conclusion: Prevalence of NASH among US adults was estimated to range from 1.3% to 4.8% when predicted using imaging-based noninvasive test values for participants with presumed NAFLD, generally aligning with estimates in the literature of prevalence of biopsy-confirmed NASH. Use of biomarker-based noninvasive test values for prediction of NASH yielded a wider range of estimates with FIB-4, and a considerably lower range of estimates with APRI.

Prevalence and Overlap of Cardiac, Renal, and Metabolic Conditions in US Adults, 1999-2020.

Importance: Individually, cardiac, renal, and metabolic (CRM) conditions are common and leading causes of death, disability, and health care-associated costs. However, the frequency with which CRM conditions coexist has not been comprehensively characterized to date. Objective: To examine the prevalence and overlap of CRM conditions among US adults currently and over time. Design, Setting, and Participants: To establish prevalence of CRM conditions, nationally representative, serial cross-sectional data included in the January 2015 through March 2020 National Health and Nutrition Examination Survey (NHANES) were evaluated in this cohort study. To assess temporal trends in CRM overlap, NHANES data between 1999-2002 and 2015-2020 were compared. Data on 11 607 nonpregnant US adults (≥20 years) were included. Data analysis occurred between November 10, 2020, and November 23, 2022. Main Outcomes and Measures: Proportion of participants with CRM conditions, overall and stratified by age, defined as cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes (T2D), or all 3. Results: From 2015 through March 2020, of 11 607 US adults included in the analysis (mean [SE] age, 48.5 [0.4] years; 51.0% women), 26.3% had at least 1 CRM condition, 8.0% had at least 2 CRM conditions, and 1.5% had 3 CRM conditions. Overall, CKD plus T2D was the most common CRM dyad (3.2%), followed by CVD plus T2D (1.7%) and CVD plus CKD (1.6%). Participants with higher CRM comorbidity burden were more likely to be older and male. Among participants aged 65 years or older, 33.6% had 1 CRM condition, 17.1% had 2 CRM conditions, and 5.0% had 3 CRM conditions. Within this subset, CKD plus T2D (7.3%) was most common, followed by CVD plus CKD (6.0%) and CVD plus T2D (3.8%). The CRM comorbidity burden was disproportionately high among participants reporting non-Hispanic Black race or ethnicity, unemployment, low socioeconomic status, and no high school degree. Among participants with 3 CRM conditions, nearly one-third (30.5%) did not report statin use, and only 4.8% and 3.0% used glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, respectively. Between 1999 and 2020, the proportion of US adults with multiple CRM conditions increased significantly (from 5.3% to 8.0%; P < .001 for trend), as did the proportion having all 3 CRM conditions (0.7% to 1.5%; P < .001 for trend). Conclusions and Relevance: This cohort study found that CRM multimorbidity is increasingly common and undertreated among US adults, highlighting the importance of collaborative and comprehensive management strategies.

Association between posttreatment α-fetoprotein reduction and outcomes in real-world US patients with advanced hepatocellular carcinoma.

BACKGROUND: Clinical trials suggest α-fetoprotein (AFP) reduction may be prognostic among patients with advanced hepatocellular carcinoma. However, the association of AFP reduction with outcomes in real-world settings is unclear. METHODS: Patients with advanced hepatocellular carcinoma between January 1, 2011, and June 30, 2021, first-line tyrosine kinase inhibitor, and baseline and posttreatment AFP values (closest to 8 ± 2 weeks after first-line initiation) were included. AFP reduction was defined as ≥20% decrease from baseline vs <20% or no decrease. Real-world overall survival and progression-free survival (rwPFS) were defined as time from posttreatment AFP measurement to death, and the first progression event or death, respectively. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazards models adjusted for potential confounders and baseline AFP. Effect modification by baseline AFP and hepatocellular carcinoma risk factors was assessed. RESULTS: Among 533 patients, median baseline AFP was higher in those with AFP reduction than those without (N = 166, 210 µg/L vs N = 367, 150 µg/L). There was a 35% decrease in hazard of death for patients with reduction vs without (aHR = 0.65; 95% CI, 0.52-0.81; median, 10.3 vs 5.9 months). Results were similar for rwPFS (aHR = 0.66; 95% CI, 0.54-0.81; median, 4.6 vs 2.6 months). AFP reduction was associated with better outcomes among patients with baseline AFP ≥400 µg/L or with history of hepatitis B virus, hepatitis C virus, or alcohol use. Only the interaction between baseline AFP and reduction in association with rwPFS was statistically significant. CONCLUSIONS: For certain etiologies, posttreatment AFP change may be more important than baseline AFP for prognosis. Further work should characterize the prognostic implications of longitudinal AFP changes during treatment. PLAIN LANGUAGE SUMMARY: The prognostic value of the change in α-fetoprotein (AFP) concentration after treatment initiation is less established, particularly in real-world settings. Longitudinal data from a large nationwide cohort of patients with advanced hepatocellular carcinoma (HCC) treated with first-line tyrosine kinase inhibitor in routine practice revealed that ≥20% reduction in posttreatment AFP levels was associated with better real-world overall survival and progression-free survival after adjusting for baseline AFP levels and other factors. The results also suggested that the associations may be stronger among patients with a history of HCC risk factors (e.g., hepatitis C virus, alcohol) or with higher baseline AFP levels.

Feasibility of Large-Scale Implementation of an Electronic Patient-Reported Outcome Remote Monitoring System for Patients on Active Treatment at a Community Cancer Center.

PURPOSE: The use of digital symptom monitoring with patient-reported outcomes (PROs) has been shown to improve patient outcomes. The evidence of benefit has been largely derived from research studies. The feasibility of adopting this technology in the real-world setting is unknown. METHODS: We report on the clinical implementation of a proprietary electronic patient-reported outcome (ePRO)-based digital symptom monitoring platform at the Highlands Oncology Group practice, a large community oncology practice. We present here our experience with patient enrollment, engagement, and retention; reasons for discontinued use; proportion of reports generating alerts and containing severe symptoms; and the responses to alerts including nursing telephone consultations and urgent office visits. RESULTS: Over an approximately 17-month period, 923 patients were successfully enrolled. Patients enrolled from June 20, 2020, through November 30, 2021, with follow-up through February 28, 2022. Retention rates at 3, 6, 9, and 12 months were 94%, 88%, 73%, and 67%, respectively, with greater retention at 12 months in patients age 65 years or older. Few patients discontinued use for reasons related to the platform (n = 47; 5%). Of the 25,311 ePRO reports submitted, 49% (n = 12,334) exceeded the predefined alert thresholds and 8% (n = 1,920) included severe symptoms. The nursing team responded within 24 hours by telephone to 31.2% (n = 3,910) of all reports with alerts. Of reports with severe symptoms, 72.7% (n = 1,395) received a call. Only 6.4% (n = 249) of phone calls required an office evaluation within 72 hours of the report. CONCLUSION: This single-center experience indicates that an ePRO-based digital symptom monitoring platform can be effectively implemented at a large scale with a high level of long-term patient engagement. Most reports could be effectively resolved by nurses, and physician intervention was infrequently required.

Analysis of a Real-World Progression Variable and Related Endpoints for Patients with Five Different Cancer Types.

INTRODUCTION: We previously demonstrated that real-world progression (rwP) can be ascertained from unstructured electronic health record (EHR)-derived documents using a novel abstraction approach for patients with advanced non-small cell lung cancer (base case). The objective of this methodological study was to assess the reliability, clinical relevance, and the need for disease-specific adjustments of this abstraction approach in five additional solid tumor types. METHODS: Patients with metastatic breast cancer (mBC), advanced melanoma (aMel), small cell lung cancer (SCLC), metastatic renal cell carcinoma (mRCC), and advanced gastric/esophageal cancer (aGEC) were selected from a real-world database. Disease-specific additions to the base case were implemented as needed. The resulting abstraction approach was applied to each disease cohort to capture rwP events and dates. To provide comprehensive clinical context, real-world progression-free survival (rwPFS) and time to progression (rwTTP) were compared to real-world overall survival (rwOS), time to next treatment (rwTTNT), and time to treatment discontinuation (rwTTD). Endpoint estimates were assessed using the Kaplan-Meier method. Correlations between real-world endpoints and rwOS were calculated using Spearman's ρ. RESULTS: Additions to the base-case rwP abstraction approach were required for mBC, aMel, and SCLC. Inter-abstractor agreement for rwP occurrence, irrespective of date, ranged from 88% to 97%. Occurrence of clinically relevant downstream events (new antineoplastic systemic therapy start, antineoplastic systemic therapy end, or death relative to the rwP event) ranged from 59% (aMel) to 72% (mBC). Median rwPFS ranged from 3.7 (aMel) to 7.7 (mBC) months, and median rwTTP ranged from 4.6 (aMel) to 8.3 (mRCC) months. Correlations between rwOS and rwPFS ranged from 0.52 (aMel) to 0.82 (SCLC). The correlation between rwOS and rwTTD was often lower relative to other comparisons (range 0.40-0.62). CONCLUSION: Derivation of a rwP variable from EHR documentation is feasible and reliable across the five solid tumors. Endpoint analyses show that rwP produces clinically meaningful information.

Validation analysis of a composite real-world mortality endpoint for patients with cancer in the United States.

OBJECTIVE: We expanded the previous assessment of a mortality variable suited for real-world evidence-focused oncology research. DATA SOURCE: We used a nationwide electronic health record (EHR)-derived de-identified database. DATA COLLECTION: We included patients with at least 1 of 18 cancer types between January 1, 2011 and December 31, 2017. Patient-level structured data (EHRs, obituaries, and Social Security Death Index) and unstructured EHR data (abstracted) were linked to generate a composite mortality variable. STUDY DESIGN: We benchmarked sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and ±15-day agreement against the National Death Index (NDI). Real-world overall survival (rwOS) was estimated using the Kaplan-Meier method. We performed sensitivity analyses using a smaller patient cohort that underwent next-generation sequencing testing. PRINCIPAL FINDINGS: Compared with the NDI across 18 cancer types (overall N = 160 436): sensitivity, 83.9%-91.5% (17/18 cancer types had sensitivity ≥85.0%); specificity, 93.5%-99.7%; PPV, 96.3%-98.3%; NPV, 75.0%-98.7%; ±15-day agreement, 95.6%-97.6%; and median rwOS estimates ranging from 2.8% to 12.7% greater. Sensitivity analysis results (n = 17 540) were consistent with the main analysis. CONCLUSIONS: Across all cancer types analyzed, this composite mortality variable showed high sensitivity, specificity, PPV, NPV, and ±15-day agreement, and yielded median rwOS values modestly overestimated when compared to NDI-based results.

Concordance of real-world versus conventional progression-free survival from a phase 3 trial of endocrine therapy as first-line treatment for metastatic breast cancer.

There is growing interest in leveraging real-world data to complement knowledge gained from randomized clinical trials and inform the design of prospective randomized studies in oncology. The present study compared clinical outcomes in women with metastatic breast cancer who received letrozole as first-line monotherapy in oncology practices across the United States versus patients in the letrozole-alone cohort of the PALOMA-2 phase 3 trial. The real-world cohort (N = 107) was derived from de-identified patient data from the Flatiron Health electronic health record database. The clinical trial cohort (N = 222) comprised postmenopausal women in the letrozole-alone arm of PALOMA-2. Patients in the real-world cohort received letrozole monotherapy per labeling and clinical judgment; patients in PALOMA-2 received letrozole 2.5 mg/d, continuous. Real-world survival and response rates were based on evidence of disease burden curated from clinician notes, radiologic reports, and pathology reports available in the electronic health record. Progression-free survival and objective response rate in PALOMA-2 were based on Response Evaluation Criteria in Solid Tumors v1.1. Concordance of survival and response rates were retrospectively assessed using inverse probability of treatment weighting-adjusted Cox regression analysis. Inverse probability of treatment weighting-adjusted Cox regression results showed similar median progression-free survival in the real-world and PALOMA-2 cohorts (18.4 and 16.6 months, respectively): the hazard ratio using real-world data as reference was 1.04 (95% CI, 0.69-1.56). No significant difference was observed in response rates: 41.8% in the real-world cohort vs 39.4% in the PALOMA-2 cohort (odds ratio using real-world data as reference: 0.91 [95% CI, 0.57-1.44]). These findings indicate that data abstracted from electronic health records with proper quality controls can yield meaningful information on clinical outcomes. These data increase confidence in the use of real-world assessments of progression and response as efficacy endpoints. Trial registration NCT01740427; Funding: Pfizer.

Associations of Insulin Resistance and Glycemia With Liver Enzymes in Hispanic/Latino Youths: Results From the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth).

BACKGROUND: Associations of insulin resistance and hyperglycemia with a panel of liver enzymes have not been well studied in a young, heterogenous Hispanic/Latino population. We aimed to assess the associations of insulin resistance and glycemia with nonalcoholic fatty liver disease (NAFLD), as measured by liver enzymes and the pediatric NAFLD fibrosis index (PNFI), and whether these associations are modified by body mass index and mediated by inflammation or endothelial dysfunction. MATERIALS AND METHODS: We conducted a cross-sectional study of 1317 boys and girls aged 8 to 16 years from the Hispanic Community Children's Health Study/Study of Latino Youth. We used Poisson regression to assess the associations of fasting glucose, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) with elevated alanine aminotransferase (ALT) (>25 U/L in boys, >22 U/L in girls), aspartate aminotransferase (AST) (≥37 U/L), gamma-glutamyl transpeptidase (GGT) (≥17 U/L), and PNFI (≥9; a function of age, waist circumference, and triglyceride level). RESULTS: HOMA-IR was associated with elevated ALT, AST, GGT, and PNFI [prevalence ratios (95% confidence intervals) for each 1-unit increase in the natural log of HOMA-IR: 1.99 (1.40-2.81), 2.15 (1.12-4.12), 1.70 (1.26-2.30), and 1.98 (1.43-2.74), respectively]. Associations were observed in overweight/obese children, but not in normal weight children (P-interaction=0.04 for AST and P-interaction=0.07 for GGT). After further adjustment for adiponectin, high-sensitivity C-reactive protein, e-selectin, and PAI-1, associations of HOMA-IR with liver enzymes and PNFI were attenuated, but remained statistically significant for AST and PNFI. CONCLUSION: Insulin resistance was associated with NAFLD in overweight/obese Hispanic/Latino youth, and this association may be partially mediated by inflammation and endothelial dysfunction.

Metabolic Syndrome in Hispanic Youth: Results from the Hispanic Community Children's Health Study/Study of Latino Youth.

BACKGROUND: Metabolic syndrome (MetS), a cluster of cardiovascular risk factors, is being diagnosed in youth. Specific diagnostic criteria used to define MetS influence prevalence estimates and populations considered at risk for cardiovascular disease. The National Cholesterol Education Program's Adult Treatment Panel III (ATP), the World Health Organization (WHO), and the International Diabetes Federation (IDF) provide three MetS definitions used in medical research. This study examined concordance among these definitions in 1137 children 10-16 years of age, who participated in the Hispanic Community Children's Health Study/Study of Latino Youth. METHODS: Prevalence of MetS and of individual components was estimated using SAS. Mplus was used to test a single-factor model of MetS components (triglycerides, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, waist circumference, and fasting glucose). RESULTS: The ATP definition identified most MetS cases in 10-15 (N = 19, 4.7%) and 16-year-old girls (N = 3, 7.3%). The IDF definition identified most cases of MetS in 10-15 (N = 16, 3.1%) and 16-year-old boys (N = 2, 2.8%). Fewest cases of MetS were identified with the WHO definition across age and sex groups. CONCLUSION: Only one participant was classified as having MetS across all three definitions. Confirmatory factor analysis indicated fasting glucose and systolic blood pressure did not reliably cluster with other risk factors that define MetS in Hispanic/Latino adolescents. We conclude that prevalence estimates of MetS in youth are unstable across current criteria, calling into question the accuracy of defining and diagnosing MetS in youth.

Associations of hyperglycemia and insulin resistance with biomarkers of endothelial dysfunction in Hispanic/Latino youths: Results from the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth).

AIMS: We hypothesized that Hispanic/Latino youth at high risk for diabetes would have elevated biomarkers of endothelial dysfunction. METHODS: Among 1316 children 8-16years old from the Study of Latino Youth (SOL Youth), we used Poisson regression to obtain prevalence ratios (PRs) and 95% CIs for the cross-sectional association of quartiles of fasting glucose, HbA1c, and insulin resistance with E-selectin and plasminogen activator inhibitor-1 (PAI-1) levels above the median (≥48.1 and ≥2.02ng/mL, respectively). RESULTS: Levels of E-selectin and PAI-1 were higher in children who were obese or had higher levels of hs-CRP (p<0.05). Insulin resistance was independently associated with higher levels of PAI-1 (adjusted PR and 95% CI for the highest versus lowest quartile (Q4 vs Q1): 2.25 [1.64, 3.09]). We found stronger evidence of associations of insulin resistance with higher levels of PAI-1 among boys as compared with girls (p-interaction = 0.10). CONCLUSIONS: Insulin resistance was associated with endothelial dysfunction, as measured by higher levels of PAI-1, in Hispanic/Latino youth. These biomarkers may be useful in risk stratification and prediction of diabetes and cardiovascular disease in high-risk youth.

Diabetes, hyperglycemia, and the burden of functional disability among older adults in a community-based study.

BACKGROUND: There is a need for continued surveillance of diabetes-related functional disability. In the present study, we examined associations between diabetes, hyperglycemia, and the burden of functional disability in a community-based population. METHODS: A cross-sectional analysis was conducted of 5035 participants who attended Visit 5 (2011-13) of the Atherosclerosis Risk in Communities study. Functional disability was dichotomously defined by any self-reported difficulty performing 12 tasks essential to independent living grouped into four functional domains. Associations of diagnosed diabetes (via self-report) and undiagnosed diabetes and prediabetes (via HbA1c) with functional disability were evaluated using Poisson regression. RESULTS: Participants had a mean age of 75 years, 42 % were male, 22 % were Black, and 31 % had diagnosed diabetes. Those with diagnosed diabetes had a significantly greater burden of functional disability than those without diabetes, even after adjustment for demographics, health behaviors, and comorbidities: prevalence ratios (95 % confidence intervals) were 1.24 (1.15, 1.34) for lower extremity mobility, 1.14 (1.07, 1.21) for general physical activities, 1.33 (1.16, 1.52) for instrumental activities of daily living (ADL), and 1.46 (1.24, 1.73) for ADL (all P < 0.05). The associations of undiagnosed diabetes and prediabetes with disability were not statistically significant (all P > 0.05). CONCLUSIONS: Among older adults, the burden of functional disability associated with diabetes was not entirely explained by known risk factors, including comorbidities. Hyperglycemia below the threshold for the diagnosis of diabetes was not associated with disability. Research into effective strategies for the prevention of functional disability among older adults with diabetes is needed.

Short-term Variability of Vitamin D-Related Biomarkers.

BACKGROUND: Quantifying the variability of biomarkers is important, as high within-person variability can lead to misclassification of individuals. Short-term variability of important markers of vitamin D metabolism is relatively unknown. METHODS: A repeatability study was conducted in 160 Atherosclerosis Risk in Communities study participants (60% female, 28% black, mean age 76 years). Fasting serum was drawn at 2 time points, a median of 6 (range 3-13) weeks apart. Vitamin D binding protein (VDBP) and 25-hydroxyvitamin D [25(OH)D] were measured by LC-MS, fibroblast growth factor (FGF23) and parathyroid hormone (PTH) by enzyme-linked immunoassay, and calcium and phosphorus by Roche Cobas 6000. Free and bioavailable 25(OH)D were calculated. We calculated the within-person CV (CVW), intraclass correlation coefficient (ICC), Spearman rank correlation coefficient (r), and percent reclassified. RESULTS: The CVW was lowest for calcium (2.0%), albumin (3.6%), 25(OH)D (6.9%), VDBP (7.0%) and phosphorus (7.6%); intermediate for free 25(OH)D (9.0%) and bioavailable 25(OH)D (9.9%); and highest for PTH (16.7%) and FGF23 (17.8%). Reclassification was highest for PTH, VDBP, and phosphorus (all 7.5%). The ICC and r were highest (≥0.80) for 25(OH)D, free 25(OH)D, bioavailable 25(OH)D and PTH, but somewhat lower (approximately 0.60-0.75) for the other biomarkers. CONCLUSIONS: Six-week short-term variability, as assessed by CVW, was quite low for VDBP, calcium and phosphorus, but fairly high for FGF23 and PTH. As such, multiple measurements of FGF23 and PTH may be needed to minimize misclassification. These results provide insight into the extent of potential misclassification of vitamin D markers in research and clinical settings.

Sex Differences in Cardiometabolic Risk Factors among Hispanic/Latino Youth.

OBJECTIVE: To determine the prevalence of obesity and cardiometabolic risk in US Hispanic/Latino youth and examine whether there are disparities by sex in cardiometabolic risk factors. STUDY DESIGN: Study of Latino Youth is a population-based cross-sectional study of 1466 Hispanic/Latino youth (8-16 years old) who were recruited from 4 urban US communities (Bronx, NY, Chicago, IL, Miami, FL, and San Diego, CA) in 2012-2014. The majority of children were US-born (78%) and from low-income and immigrant families. Cardiometabolic risk factors were defined by the use of national age- and sex-specific guidelines. RESULTS: The prevalence of obesity was 26.5%. The prevalence of class II-III obesity, diabetes, and dyslipidemia was high (9.7%, 16.5%, and 23.3%, respectively). The prevalence of cardiometabolic risk factors increased with severity of obesity in both boys and girls. Boys had a greater prevalence of diabetes and of elevated blood pressure than girls (20.9% vs 11.8% and 8.5% vs 3.3%). In multivariable analyses, younger boys were more likely to have obesity class II-III than girls (OR 3.59; 95% CI 1.44-8.97). Boys were more likely to have prediabetes than girls (OR 2.02; 95% CI 1.35-3.02), and the association was stronger at older ages. CONCLUSIONS: The prevalence of cardiometabolic risk factors was high in this sample of Hispanic youth. Boys had a more adverse cardiometabolic profile compared with girls that may put them at higher risk of diabetes and cardiovascular disease later in life. Reasons for this disparity and the long-term clinical implications remain to be elucidated.

Iterative Outlier Removal: A Method for Identifying Outliers in Laboratory Recalibration Studies.

BACKGROUND: Extreme values that arise for any reason, including those through nonlaboratory measurement procedure-related processes (inadequate mixing, evaporation, mislabeling), lead to outliers and inflate errors in recalibration studies. We present an approach termed iterative outlier removal (IOR) for identifying such outliers. METHODS: We previously identified substantial laboratory drift in uric acid measurements in the Atherosclerosis Risk in Communities (ARIC) Study over time. Serum uric acid was originally measured in 1990-1992 on a Coulter DACOS instrument using an uricase-based measurement procedure. To recalibrate previous measured concentrations to a newer enzymatic colorimetric measurement procedure, uric acid was remeasured in 200 participants from stored plasma in 2011-2013 on a Beckman Olympus 480 autoanalyzer. To conduct IOR, we excluded data points >3 SDs from the mean difference. We continued this process using the resulting data until no outliers remained. RESULTS: IOR detected more outliers and yielded greater precision in simulation. The original mean difference (SD) in uric acid was 1.25 (0.62) mg/dL. After 4 iterations, 9 outliers were excluded, and the mean difference (SD) was 1.23 (0.45) mg/dL. Conducting only one round of outlier removal (standard approach) would have excluded 4 outliers [mean difference (SD) = 1.22 (0.51) mg/dL]. Applying the recalibration (derived from Deming regression) from each approach to the original measurements, the prevalence of hyperuricemia (>7 mg/dL) was 28.5% before IOR and 8.5% after IOR. CONCLUSIONS: IOR is a useful method for removal of extreme outliers irrelevant to recalibrating laboratory measurements, and identifies more extraneous outliers than the standard approach.

Association of Childhood Economic Hardship with Adult Height and Adult Adiposity among Hispanics/Latinos. The HCHS/SOL Socio-Cultural Ancillary Study.

The study examined the association of childhood and current economic hardship with anthropometric indices in Hispanic/Latino adults, using data from the HCHS/SOL Socio-cultural ancillary study (N = 5,084), a community-based study of Hispanic/Latinos living in four urban areas (Bronx, NY, Chicago, IL, Miami, FL, and San Diego, CA). Childhood economic hardship was defined as having experienced a period of time when one's family had trouble paying for basic needs (e.g., food, housing), and when this economic hardship occurred: between 0-12, 13-18 years old, or throughout both of those times. Current economic hardship was defined as experiencing trouble paying for basic needs during the past 12 months. Anthropometry included height, body mass index (BMI), waist circumference (WC), and percentage body fat (%BF). Complex survey linear regression models were used to test the associations of childhood economic hardship with adult anthropometric indices, adjusting for potential confounders (e.g., age, sex, Hispanic background). Childhood economic hardship varied by Hispanic background, place of birth, and adult socio-economic status. Childhood economic hardship during both periods, childhood and adolescence, was associated with shorter height. Childhood economic hardship was associated with greater adiposity among US born individuals only. Current economic hardship was significantly associated with all three measures of adiposity (BMI, WC, %BF). These findings suggest that previous periods of childhood economic hardship appear to influence adult height more than adiposity, whereas current economic hardship may be a better determinant of adult adiposity in Hispanics.

Racial Differences in and Prognostic Value of Biomarkers of Hyperglycemia.

OBJECTIVE: We compared levels and associations of traditional (fasting glucose, HbA1c) and nontraditional (fructosamine, glycated albumin, and 1,5-anhydroglucitol [1,5-AG]) biomarkers of hyperglycemia with incident cardiovascular disease (CVD), incident end-stage renal disease (ESRD), and prevalent retinopathy in black and white adults. RESEARCH DESIGN AND METHODS: We included 10,373 participants without (8,096 white, 2,277 black) and 727 with diagnosed diabetes (425 white, 302 black) from the Atherosclerosis Risk in Communities (ARIC) Study. We used Cox proportional hazards models to compare hazards ratios of CVD and ESRD among blacks and whites from baseline (1990-1992) through 2012. We compared the odds ratios (from logistic regression) of retinopathy among blacks and whites. We tested for the interaction of each biomarker with race. RESULTS: Median values of biomarkers were higher among blacks versus whites (all P < 0.001). Relative risks for each biomarker with incident CVD and ESRD, and odds ratios for each biomarker with prevalent retinopathy, were similar by race (all P values for interaction by race >0.10). CONCLUSIONS: The prognostic value of HbA1c, fructosamine, glycated albumin, and 1,5-AG with incident CVD, incident ESRD, and prevalent retinopathy were similar by race. Our results support similar interpretation of HbA1c and nontraditional biomarkers of hyperglycemia among black and whites with respect to long-term complications.

Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality.

BACKGROUND: Single measurements of elevated high-sensitivity C-reactive protein (hs-CRP) are associated with increased risk of diabetes, cardiovascular disease, and mortality. Large increases or sustained elevations in hs-CRP may be associated with even greater risk of these outcomes. The objective of this study was to characterize the association of 6-year change in hs-CRP with incident diabetes, incident cardiovascular events (heart disease, stroke, and heart failure), and mortality. METHODS: We included 10,160 ARIC participants with hs-CRP measured at visits 2 (1990-1992) and 4 (1996-1998). Change in hs-CRP was categorized as sustained low/moderate (<3 mg/L at both visits), decreased (≥3 mg/L at visit 2 and <3 mg/L at visit 4), increased (<3 mg/L at visit 2 and ≥3 mg/L at visit 4), and sustained elevated (≥3 mg/L at both visits). Cox proportional hazards models were used to assess the association of 6-year change in hs-CRP with incident diabetes, cardiovascular events, and death during ~15 years after visit 4. RESULTS: Compared with persons with sustained low/moderate hs-CRP, those with increased or sustained elevated hs-CRP had an increased risk of incident diabetes (hazard ratios [95% CIs] 1.56 [1.38-1.76] and 1.39 [1.25-1.56], respectively), whereas those with deceased hs-CRP did not. Persons with sustained elevated hs-CRP had an increased risk of coronary heart disease, ischemic stroke, heart failure, and mortality (hazard ratios [95% CIs] 1.51 [1.23-1.85], 1.70 [1.32-2.20], 1.60 [1.35-1.89], and 1.52 [1.37-1.69], respectively) compared with those with sustained low/moderate hs-CRP. Associations for sustained elevated hs-CRP were greater than for those with increased hs-CRP over 6 years. CONCLUSIONS: Large increases or sustained elevations in hs-CRP over a 6-year period were associated with a subsequent increased risk of diabetes, and persons with sustained elevations in hs-CRP were at the highest risk for cardiovascular disease and mortality. Two measurements of hs-CRP are better than one for characterizing risk, and large increases are particularly prognostic.

Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults.

OBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period. DESIGN: Retrospective analysis of a cohort study. SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania. PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897). MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06). RESULTS: At baseline, mean age was 76.3±3.6, and 18.5% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3% for IGF-I, 59.7% for IGFBP-1, -13.4% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7% for IGF-I, 25.6% for IGFBP-1, -6.4% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up. CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.