Faculty Bibliography

BACKGROUND:As part of its 2020 Impact Goals, the American Heart Association developed the Life's Simple 7 metric for cardiovascular health promotion. The relationship between the Life's Simple 7 metric and incident chronic kidney disease (CKD) is unknown. METHODS AND RESULTS/RESULTS:We estimated the association between Life's Simple 7 and incident CKD in 14 832 Atherosclerosis Risk in Communities study participants. Ideal levels of Life's Simple 7 health factors were the following: nonsmoker or quit >1 year ago; body mass index <25 kg/m(2); ≥150 minutes/week of physical activity; healthy dietary pattern (high in fruits and vegetables, fish, and fiber-rich whole grains; low in sodium and sugar-sweetened beverages); total cholesterol <200 mg/dL; blood pressure <120/80 mm Hg; and fasting blood glucose <100 mg/dL. At baseline, mean age was 54 years, 55% were women, and 26% were African American. There were 2743 incident CKD cases over a median follow-up of 22 years. Smoking, body mass index, physical activity, blood pressure, and blood glucose were associated with CKD risk (all P<0.01), but diet and blood cholesterol were not. CKD risk was inversely related to the number of ideal health factors (P-trend<0.001). A model containing the Life's Simple 7 health factors was more predictive of CKD risk than the base model including only age, sex, race, and estimated glomerular filtration rate (Life's Simple 7 health factors area under the ROC curve: 0.73, 95% CI: 0.72, 0.74 versus base model area under the ROC curve: 0.68, 95% CI: 0.67, 0.69; P<0.001). CONCLUSIONS:The AHA's Life's Simple 7 metric, developed to measure and promote cardiovascular health, predicts a lower risk of CKD.

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.

BACKGROUND:The link of low estimated glomerular filtration rate (eGFR) and high proteinuria to cardiovascular disease (CVD) mortality is well known. However, its link to mortality due to other causes is less clear. METHODS:We studied 367,932 adults (20-93 years old) in the Korean Heart Study (baseline between 1996-2004 and follow-up until 2011) and assessed the associations of creatinine-based eGFR and dipstick proteinuria with mortality due to CVD (1,608 cases), cancer (4,035 cases), and other (non-CVD/non-cancer) causes (3,152 cases) after adjusting for potential confounders. RESULTS:Although cancer was overall the most common cause of mortality, in participants with chronic kidney disease (CKD), non-CVD/non-cancer mortality accounted for approximately half of cause of death (47.0%for eGFR <60 ml/min/1.73 m2 and 54.3% for proteinuria ≥1+). Lower eGFR (<60 vs. ≥60 ml/min/1.73 m2) was significantly associated with mortality due to CVD (adjusted hazard ratio 1.49 [95% CI, 1.24-1.78]) and non-CVD/non-cancer causes (1.78 [1.54-2.05]). The risk of cancer mortality only reached significance at eGFR <45 ml/min/1.73 m2 when eGFR 45-59 ml/min/1.73 m2 was set as a reference (1.62 [1.10-2.39]). High proteinuria (dipstick ≥1+ vs. negative/trace) was consistently associated with mortality due to CVD (1.93 [1.66-2.25]), cancer (1.49 [1.32-1.68]), and other causes (2.19 [1.96-2.45]). Examining finer mortality causes, low eGFR and high proteinuria were commonly associated with mortality due to coronary heart disease, any infectious disease, diabetes, and renal failure. In addition, proteinuria was also related to death from stroke, cancers of stomach, liver, pancreas, and lung, myeloma, pneumonia, and viral hepatitis. CONCLUSION/CONCLUSIONS:Low eGFR was associated with CVD and non-CVD/non-cancer mortality, whereas higher proteinuria was consistently related to mortality due to CVD, cancer, and other causes. These findings suggest the need for multidisciplinary prevention and management strategies in individuals with CKD, particularly when proteinuria is present.

BACKGROUND:Management trends in early chronic kidney disease (CKD) and their associations with clinical outcomes have not previously been reported. METHODS:We evaluated incident (Stage G3A) CKD patients from an integrated health care system in 2004-06, 2007-09 and 2010-12 to determine adjusted trends in screening (urinary protein quantification), treatment [prescription for angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and statin] and nephrology referral. For the same time periods, adjusted rates for mortality, progression to Stage G4 CKD and hospitalization for myocardial infarction or heart failure were calculated and compared across time periods. RESULTS:There were 728, 788 and 956 patients with incident CKD in 2004-06, 2007-09 and 2010-12, respectively. Adjusted rates of proteinuria quantification (31, 39 and 51 screens/100 person-years), statin prescription (53, 63 and 64 prescriptions/100 person-years) and nephrology referral (2, 3 and 5 referrals/100 person-years) all increased over time (P for trend <0.001 in all cases). ACEI/ARB prescription rates did not change (88, 83 and 80 prescriptions/100 person-years, P = 0.68). Adjusted death rates (7, 5 and 6 deaths/100 person-years), CKD progression (9, 10 and 7 progressors/100 person-years) and cardiovascular hospitalization (10, 8 and 9 hospitalizations per 100/person-years) did not change (P for trend >0.4 in all cases). CONCLUSION/CONCLUSIONS:In this integrated health care system, management of incident CKD over the past decade has intensified.

OBJECTIVES/OBJECTIVE:To examine qualitative responses regarding the use of placebo treatments in medical care in a sample of US patients.Survey studies suggest a deliberate clinical use of placebos by physicians, and prior research has found that although most US patients find placebo use acceptable, the rationale for these beliefs is largely unknown. SETTING/METHODS:Members of the Outpatient Clinic at the Kaiser Permanente Northern California interviewed research participants who had been seen for a chronic health problem at least once in the prior 6 months. PARTICIPANTS/METHODS:853 women (61%) and men, white (58%) and non-white participants aged 18-75 years. PRIMARY AND SECONDARY OUTCOMES/METHODS:Qualitative responses on perceptions of placebo use from one-time telephone surveys were analysed for common themes and associations with demographic variables. RESULTS:Prior results indicated that a majority of respondents felt it acceptable for doctors to recommend placebo treatments. Our study found that a lack of harm (n=291, 46.1%) and potential benefit (n=250, 39.6%) were the most common themes to justify acceptability of placebo use. Responses citing potential benefit were associated with higher education (r=0.787; p<0.024). Of the minority of respondents who judged it never acceptable for doctors to recommend placebo treatments, the most often referenced rationale was obligation of the doctor to do more (n=102, 48.3%). Additional themes emerged around the issue of whether a doctor was transparent about placebo use, including honesty, patient's right to know and power of the mind. Older age was associated with likelihood to cite overall physician, as opposed to treatment, related themes (r=0.753; p<0.002). CONCLUSIONS:Participants seem to appreciate and understand the lack of harm and potential benefit associated with placebo treatments, while valuing the role of the physician and the patient in its implementation.

OBJECTIVES/OBJECTIVE:To quantify the influence of abuse, particularly in childhood, with pain sensitivity and other adverse symptoms experienced by women with fibromyalgia (FM). METHODS:Subjects with FM completed a detailed abuse interview, dolorimetry, and questionnaire-based assessments of fatigue, cognitive self-appraisal, and depression. Student's t- and chi-square tests were used to analyse differences in FM symptoms between those with and without a history of childhood abuse. Linear regression was used to evaluate the relationship between abuse and symptom severity, adjusting for possible confounders. RESULTS:In 111 women with FM, physical abuse during childhood demonstrated a clinically modest, yet statistically significant, association with increased tenderness as measured by pain pressure thresholds (β=-0.25, p=0.011) and tender points (β=0.23, p=.022). Physical child abuse was also associated with cognitive language impairment after adjusting for depression (β=0.27, p=0.001). While emotional child abuse was associated with fatigue, the association did not persist after adjustment for depressive symptoms. CONCLUSIONS:Group differences are of small magnitude and might not directly impact clinical practice, however, the experience of child abuse is associated with FM symptom severity and may shape the biological development of interoception in ways that predispose to pain and polysymptomatic distress.

Matching methods are common in studies across many disciplines. However, there is limited evidence on how to optimally combine matching with subsequent analysis approaches to minimize bias and maximize efficiency for the quantity of interest. We conducted simulations to compare the performance of a wide variety of matching methods and analysis approaches in terms of bias, variance, and mean squared error (MSE). We then compared these approaches in an applied example of an employment training program. The results indicate that combining full matching with double robust analysis performed best in both the simulations and the applied example, particularly when combined with machine learning estimation methods. To reduce bias, current guidelines advise researchers to select the technique with the best post-matching covariate balance, but this work finds that such an approach does not always minimize mean squared error (MSE). These findings have important implications for future research utilizing matching. To minimize MSE, investigators should consider additional diagnostics, and use of simulations tailored to the study of interest to identify the optimal matching and analysis combination.