Nicholas M. Pajewski

Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial

IMPORTANCE The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain. OBJECTIVE To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015. INTERVENTIONS Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319). MAIN OUTCOMES AND MEASURES The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome. RESULTS Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]). CONCLUSIONS AND RELEVANCE Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01206062.

Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity

Background: Anthropometric-based classification schemes for excess adiposity do not include direct assessment of obesity-related comorbidity and functional status and thus have limited clinical utility. We examined the ability of the Edmonton obesity staging system, a 5-point ordinal classification system that considers comorbidity and functional status, in predicting mortality in a nationally representative US sample. Methods: We analyzed data from the National Health and Human Nutrition Examination Surveys (NHANES) III (1988–1994) and the NHANES 1999–2004, with mortality follow-up through to the end of 2006. Adults (age ≥ 20 yr) with overweight or obesity who had been randomized to the morning session at the mobile examination centre were scored according to the Edmonton obesity staging system. We examined the relationship between staging system scores and mortality, and Cox proportional hazards models were adjusted for the presence of the metabolic syndrome or hypertriglyceridemic waist. Results: Over 75% of the cohort with overweight or obesity were given scores of 1 or 2. Scores of 4 could not be reliably assigned because specific data elements were lacking. Survival curves clearly diverged when stratified by scores of 0–3, but not when stratified by obesity class alone. Within the data from the NHANES 1988–1994, scores of 2 (hazard ratio [HR] 1.57; 95% confidence interval [CI] 1.16 to 2.13) and 3 (HR 2.69; 95% CI 1.98 to 3.67) were associated with increased mortality compared with scores of 0 or 1, even after adjustment for body mass index and the metabolic syndrome. We found similar results after adjusting for hypertriglyceridemic waist (i.e., waist circumference ≥ 90 cm and a triglyceride level ≥ 2 mmol/L for men; the corresponding values for women were ≥ 85 cm and ≥ 1.5 mmol/L), as well as in a cohort eligible for bariatric surgery. Interpretation: The Edmonton obesity staging system independently predicted increased mortality even after adjustment for contemporary methods of classifying adiposity. The Edmonton obesity staging system may offer improved clinical utility in assessing obesity-related risk and prioritizing treatment.

Beyond Missing Heritability: Prediction of Complex Traits

Despite rapid advances in genomic technology, our ability to account for phenotypic variation using genetic information remains limited for many traits. This has unfortunately resulted in limited application of genetic data towards preventive and personalized medicine, one of the primary impetuses of genome-wide association studies. Recently, a large proportion of the “missing heritability” for human height was statistically explained by modeling thousands of single nucleotide polymorphisms concurrently. However, it is currently unclear how gains in explained genetic variance will translate to the prediction of yet-to-be observed phenotypes. Using data from the Framingham Heart Study, we explore the genomic prediction of human height in training and validation samples while varying the statistical approach used, the number of SNPs included in the model, the validation scheme, and the number of subjects used to train the model. In our training datasets, we are able to explain a large proportion of the variation in height (h2 up to 0.83, R2 up to 0.96). However, the proportion of variance accounted for in validation samples is much smaller (ranging from 0.15 to 0.36 depending on the degree of familial information used in the training dataset). While such R2 values vastly exceed what has been previously reported using a reduced number of pre-selected markers (<0.10), given the heritability of the trait (∼0.80), substantial room for improvement remains.

Prevalence of the Female Athlete Triad in High School Athletes and Sedentary Students

Objective:To determine the prevalence of the female athlete triad (low energy availability, menstrual dysfunction, and low bone mineral density) in high school varsity athletes in a variety of sports compared with sedentary students/control subjects. Design:Prospective study. Setting:Academic medical center in the Midwest. Participants:Eighty varsity athletes and 80 sedentary students/control subjects volunteered for this study. Intervention:Subjects completed questionnaires, had their blood drawn, and underwent bone mineral density testing. Main Outcome Measures:Each participant completed screening questionnaires assessing eating behavior, menstrual status, and physical activity. Each subject completed a 3-day food diary. Serum hormonal, thyroid-stimulating hormone, and prolactin levels were determined. Bone mineral density and body composition were measured by dual-energy x-ray absorptiometry. Results:Low energy availability was present in similar numbers of athletes (36%) and sedentary/control subjects (39%; P = 0.74). Athletes had more menstrual abnormalities (54%) compared with sedentary students/control subjects (21%) (P < 0.001). Dual-energy x-ray absorptiometry revealed that 16% of the athletes and 30% of the sedentary/control subjects had low bone mineral density (P = 0.03). Risk factors for reduced bone mineral density include sedentary control student, low body mass index, and increased caffeine consumption. Conclusions:A substantial number of high school athletes (78%) and a surprising number of sedentary students (65%) have 1 or more components of the triad. Given the high prevalence of triad characteristics in both groups, education in the formative elementary school years has the potential to prevent several of the components in both groups, therefore improving health and averting long-term complications.

A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap

In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non–Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10−06) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohns disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.

Use of self-reported height and weight biases the body mass index-mortality association

Background:Many large-scale epidemiological data sources used to evaluate the body mass index (BMI: kg/m2) mortality association have relied on BMI derived from self-reported height and weight. Although measured BMI (BMIM) and self-reported BMI (BMISR) correlate highly, self-reports are systematically biased.Objective:To rigorously examine how self-reporting bias influences the association between BMI and mortality rate.Subjects:Samples representing the US non-institutionalized civilian population.Design and Methods:National Health and Nutrition Examination Survey data (NHANES II: 1976–80; NHANES III: 1988–94) contain BMIM and BMISR. We applied Cox regression to estimate mortality hazard ratios (HRs) for BMIM and BMISR categories, respectively, and compared results. We similarly analyzed subgroups of ostensibly healthy never-smokers.Results:Misclassification by BMISR among the underweight and obesity ranged from 30–40% despite high correlations between BMIM and BMISR (r>0.9). The reporting bias was moderately correlated with BMIM (r>0.35), but not BMISR (r<0.15). Analyses using BMISR failed to detect six of eight significant mortality HRs detected by BMIM. Significantly biased HRs were detected in the NHANES II full data set (χ2=12.49; P=0.01) and healthy subgroup (χ2=9.93; P=0.04), but not in the NHANES III full data set (χ2=5.63; P=0.23) or healthy subgroup (χ2=1.52; P=0.82).Conclusions:BMISR should not be treated as interchangeable with BMIM in BMI mortality analyses. Bias and inconsistency introduced by using BMISR in place of BMIM in BMI mortality estimation and hypothesis tests may account for important discrepancies in published findings.

Vaso-occlusive Painful Events in Sickle Cell Disease: Impact on Child Well-Being

This study describes how painful events affect the health‐related quality of life (HRQL) of children with sickle cell disease (SCD) and determines the responsiveness of a generic HRQL measure in SCD. Our hypotheses were twofold: (1) HRQL is significantly impaired at presentation to the emergency department for a painful event and (2) PedsQL 4.0 Acute Version Generic Core Scales is responsive to change in the evolution of a painful event.

Impact of family income and sickle cell disease on the health-related quality of life of children

PurposeThe objective of this study was to determine the impact of family income and sickle cell disease on the health-related quality of life (HRQL) of children.MethodsThis was a cross-sectional study of children with and without sickle cell disease. Participants completed the PedsQL™ generic core scales parent-proxy or child self-report questionnaire during a routine clinic visit. HRQL was the primary outcome measured. Family income and sickle cell disease were the primary independent variables of interest.ResultsA total of 104 children with sickle cell disease and 74 without disease participated in the study. After adjusting for family income, patient age, and the presence of co-morbidities, children with severe sickle cell disease had increased odds of worse overall HRQL (parent-proxy HRQL report odds ratio [OR] 4.0) and physical HRQL (parent-proxy report OR 5.67, child self-report OR 3.33) compared to children without sickle cell disease.ConclusionsChildren with sickle cell disease have significantly impaired HRQL, even after considering the potential detrimental effect of family income on HRQL. Targeted interventions to improve these children’s HRQL are warranted.

Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in The Systolic Blood Pressure Intervention Trial

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans. Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2,571 African Americans from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary or carotid artery revascularization) and CKD (eGFR under 60 ml/min/1.73m2 and/or UACR over 30 mg/g). African American SPRINT participants were 45.3% female with mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mmHg, eGFR 76.3 (77.1) ml/min/1.73m2, UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08–1.73) and log UACR estimated slope [β] 0.33) and negatively associated with eGFR (β −3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82–1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not prevalent CVD in African American with a UACR under 1000 mg/g.

Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants

Flavin-containing monooxygenases (FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single-nucleotide polymorphism (SNP) frequencies were determined in 202 Hispanics (Mexican descent), 201 African Americans, and 200 non-Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non-Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by non-Latino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (-2650C>G, -2543T>A, and -2177G>C) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non-Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the African-American study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [15,167G>A (E158K)], H5B [-2650C>G, 15,167G>A (E158K), 21,375C>T (N285N), 21,443A>G (E308G)], and H6 [15,167G>A (E158K), 21,375C>T (N285N)] was 28% in Hispanics, 23% in non-Latino whites, and 24% in African Americans.