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1.  The SEARCH for Diabetes in Youth Study: Rationale, Findings, and Future Directions 
Diabetes Care  2014;37(12):3336-3344.
The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support from the National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U.S. and represents the largest, most diverse study of diabetes among U.S. youth. An active registry of youth diagnosed with diabetes at age <20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. Many youth with diabetes, particularly those from low-resourced racial/ethnic minority populations, are not meeting recommended guidelines for diabetes care. Markers of micro- and macrovascular complications are evident in youth with either diabetes type, highlighting the seriousness of diabetes in this contemporary cohort. This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions.
PMCID: PMC4237981  PMID: 25414389
2.  Timing of Complementary Food Introduction and Age at Diagnosis of Type 1 Diabetes: the SEARCH Nutrition Ancillary STUDY (SNAS) 
European journal of clinical nutrition  2014;68(11):1258-1260.
The association between timing of complementary food introduction and age at diagnosis of type 1 diabetes was investigated among 1077 children in the SEARCH for Diabetes in Youth study. Age at diagnosis was 5-month earlier for children introduced to sugar-sweetened beverages (SSB) in the first 12 months of life compared to those who were not (9.0 ± 0.2 vs. 9.5 ± 0.1; p=0.02), independent of HLA-risk status. Analyses stratified by HLA-risk status found that children with a high risk HLA genotype had an earlier age at diagnosis if they were introduced to fruit juice in the first year of life (mean age of diagnosis=9.3 ± 0.1, 9.1 ± 0.1 and 9.6 ± 0.2 for introduction at ≤ 6 months, between 7 and 11 months, and ≤12 months, respectively; p=0.04). Introduction of SSB in the first year of life may accelerate onset of type 1 diabetes independent of HLA-risk status.
PMCID: PMC4414319  PMID: 25117987
infant diet; type 1 diabetes; autoimmunity; islet autoantibodies; age factors; diabetes mellitus genetics; genetic susceptibility to disease; HLA-DQ antigens; disease progression
3.  Correlates of Treatment Patterns Among Youth With Type 2 Diabetes 
Diabetes Care  2013;37(1):64-72.
To describe treatment regimens in youth with type 2 diabetes and examine associations between regimens, demographic and clinical characteristics, and glycemic control.
This report includes 474 youth with a clinical diagnosis of type 2 diabetes who completed a SEARCH for Diabetes in Youth study visit. Diabetes treatment regimen was categorized as lifestyle alone, metformin monotherapy, any oral hypoglycemic agent (OHA) other than metformin or two or more OHAs, insulin monotherapy, and insulin plus any OHA(s). Association of treatment with demographic and clinical characteristics (fasting C-peptide [FCP], diabetes duration, and self-monitoring of blood glucose [SMBG]), and A1C was assessed by χ2 and ANOVA. Multiple linear regression models were used to evaluate independent associations of treatment regimens and A1C, adjusting for demographics, diabetes duration, FCP, and SMBG.
Over 50% of participants reported treatment with metformin alone or lifestyle. Of the autoantibody-negative youth, 40% were on metformin alone, while 33% were on insulin-containing regimens. Participants on metformin alone had a lower A1C (7.0 ± 2.0%, 53 ± 22 mmol/mol) than those on insulin alone (9.2 ± 2.7%, 77 ± 30 mmol/mol) or insulin plus OHA (8.6 ± 2.6%, 70 ± 28 mmol/mol) (P < 0.001). These differences remained significant after adjustment (7.5 ± 0.3%, 58 ± 3 mmol/mol; 9.1 ± 0.4%, 76 ± 4 mmol/mol; and 8.6 ± 0.4%, 70 ± 4 mmol/mol) (P < 0.001) and were more striking in those with diabetes for ≥2 years (7.9 ± 2.8, 9.9 ± 2.8, and 9.8 ± 2.6%). Over one-half of those on insulin-containing therapies still experience treatment failure (A1C ≥8%, 64 mmol/mol).
Approximately half of youth with type 2 diabetes were managed with lifestyle or metformin alone and had better glycemic control than individuals using other therapies. Those with longer diabetes duration in particular commonly experienced treatment failures, and more effective management strategies are needed.
PMCID: PMC3867996  PMID: 24026554
4.  Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-up Cohort 
Diabetes Care  2013;36(12):3903-3908.
To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study.
DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN.
The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 ± 4.3 years, duration 6.2 ± 0.9 years) and 70 with type 2 diabetes (mean age 21.6 ± 4.1 years, duration 7.6 ± 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 ± 1.8% for type 1 vs. 8.5 ± 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05–5.02], P = 0.03).
DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN.
PMCID: PMC3836139  PMID: 24144652
5.  Absence of Evidence for an Association Between Resistin Gene Variants and Insulin Resistance in an Asian Population with Low and High Blood Pressure 
Although the function of resistin in human biology is unclear, some evidence suggests resistin gene variants influence insulin resistance, and insulin resistance-related hypertension. We searched for associations between common resistin gene variants and factors related to insulin resistance in Asian individuals with high or low blood pressure.
Non-diabetic Chinese or Japanese sibling pairs were included if one had extreme hypertension and the other was either hypertensive or hypotensive. Four common, non-coding single nucleotide polymorphisms (SNPs) were identified by sequencing the resistin gene in 24 hypertensive probands. Generalized estimating equations-based regressions were then performed to test for SNP associations using the entire study population (n=1556).
Of 72 tests, only one was significant at the 0.05 level; 3.5 significant tests were expected by chance alone. High variability in insulin and triglyceride levels created wide confidence intervals, thus the negative results are not conclusive for these phenotypes. However, the large sample size resulted in narrow confidence intervals for BMI, fasting and 120 minute post-load glucose, and high and low density lipoprotein cholesterol.
Factors associated with insulin resistance are not likely influenced by the resistin gene in non-diabetic Asian individuals with high and low blood pressure.
PMCID: PMC4156032  PMID: 18501464
resistin; hypertension; Asian population; insulin resistance; single nucleotide polymorphisms
6.  Relationship of dietary monounsaturated fatty acids to blood pressure: the international study of macro/micronutrients and blood pressure 
Journal of hypertension  2013;31(6):1144-1150.
In short-term feeding trials, replacement of other macronutrients with monounsaturated fatty acid reduces blood pressure. However, observational studies have not clearly demonstrated a relationship between monounsaturated fatty acid intake and blood pressure. We report associations of monounsaturated fatty acid intake of individuals with blood pressure in a cross-sectional study.
The International Study of Macro/Micronutrients and Blood Pressure is a cross-sectional epidemiologic study of 4680 men and women ages 40–59 years from 17 population samples in China, Japan, UK and USA. Nutrient intake data were based on four in-depth multipass 24-h dietary recalls/person and two-timed 24-h urine collections/person. Blood pressure was measured eight times at four visits.
Mean monounsaturated fatty acid intake ranged from 8.1%kcal (China) to 12.2%kcal (USA). With sequential models to control for possible confounders (dietary, other), linear regression analyses showed significant inverse relationship of total monounsaturated fatty acid intake with DBP for all participants; for 2238 ‘nonintervened’ individuals, the relationship was stronger. Estimated DBP differences with 2-SD higher monounsaturated fatty acids (5.35%kcal) were −0.82mmHg (P<0.05) for all participants and −1.70mmHg (P<0.01) for nonintervened individuals. Inverse associations of dietary total oleic acid (main monounsaturated) with blood pressure in nonintervened individuals were not significant, but those of oleic acid from vegetable sources were stronger and significant (P<0.05).
Dietary monounsaturated fatty acid intake, especially oleic acid from vegetable sources, may contribute to prevention and control of adverse blood pressure levels in general populations.
PMCID: PMC4109685  PMID: 23572200
blood pressure; monounsaturated fatty acids; nutrition; oleic acid; population study
7.  Projections of Type 1 and Type 2 Diabetes Burden in the U.S. Population Aged <20 Years Through 2050 
Diabetes Care  2012;35(12):2515-2520.
To forecast the number of U.S. individuals aged <20 years with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) through 2050, accounting for changing demography and diabetes incidence.
We used Markov modeling framework to generate yearly forecasts of the number of individuals in each of three states (diabetes, no diabetes, and death). We used 2001 prevalence and 2002 incidence of T1DM and T2DM from the SEARCH for Diabetes in Youth study and U.S. Census Bureau population demographic projections. Two scenarios were considered for T1DM and T2DM incidence: 1) constant incidence over time; 2) for T1DM yearly percentage increases of 3.5, 2.2, 1.8, and 2.1% by age-groups 0–4 years, 5–9 years, 10–14 years, and 15–19 years, respectively, and for T2DM a yearly 2.3% increase across all ages.
Under scenario 1, the projected number of youth with T1DM rises from 166,018 to 203,382 and with T2DM from 20,203 to 30,111, respectively, in 2010 and 2050. Under scenario 2, the number of youth with T1DM nearly triples from 179,388 in 2010 to 587,488 in 2050 (prevalence 2.13/1,000 and 5.20/1,000 [+144% increase]), with the greatest increase in youth of minority racial/ethnic groups. The number of youth with T2DM almost quadruples from 22,820 in 2010 to 84,131 in 2050; prevalence increases from 0.27/1,000 to 0.75/1,000 (+178% increase).
A linear increase in diabetes incidence could result in a substantial increase in the number of youth with T1DM and T2DM over the next 40 years, especially those of minority race/ethnicity.
PMCID: PMC3507562  PMID: 23173134
8.  Coronary Artery Calcification in Japanese Men in Japan and Hawaii 
American journal of epidemiology  2007;166(11):1280-1287.
Explanations for the low prevalence of atherosclerosis in Japan versus United States are often confounded with genetic variation. To help remove such confounding, coronary artery calcification (CAC), a marker of subclinical atherosclerosis, was compared between Japanese men in Japan and Japanese men in Hawaii. Findings are based on risk factor and CAC measurements that were made from 2001 to 2005 in 311 men in Japan and 300 men in Hawaii. Men were aged 40 to 50 years and without cardiovascular disease. After age-adjustment, there was a 3-fold excess in the odds of prevalent CAC scores ≥10 in Hawaii versus Japan (relative odds [RO] = 3.2; 95% confidence interval [CI] = 2.1,4.9). While men in Hawaii had a generally poorer risk factor profile, men in Japan were 4-times more likely to smoke cigarettes (49.5 vs. 12.7%, p<0.001). In spite of marked risk factor differences between the samples, none of the risk factors provided an explanation for the low amounts of CAC in Japan. After risk factor adjustment, the RO of CAC scores ≥10 in Hawaii versus Japan was 4.0 (95% CI = 2.2,7.4). Further studies are needed to identify factors that offer protection against atherosclerosis in Japanese men in Japan.
PMCID: PMC3660555  PMID: 17728270
Atherosclerosis; cohort studies; coronary disease; Japan; men; risk factors
9.  Late-life Hemoglobin and the Incidence of Parkinson’s Disease 
Neurobiology of Aging  2010;33(5):914-920.
Brain iron promotes neurodegeneration in Parkinson’s disease (PD). While hemoglobin (Hb) is the most abundant source of peripheral iron in humans, its relationship with PD is uncertain. This report examines the association between Hb in late-life and PD incidence.
From 1991-1993, Hb was measured in 3,507 men in the Honolulu-Asia Aging Study. Men were aged 71-93 years and without PD. Participants were followed until 2001 for incident PD.
Hb levels declined markedly with age. For men aged 71-75 years, 14.8% had levels <14 g/dL versus 53.6% in those aged 86 and older (p<0.001). During follow-up, 47 men developed PD (19.8/10,000 person-years). After age-adjustment, PD incidence rose significantly from 10.3 to 34.9/10,000 person-years as Hb increased from <14 to ≥16 g/dL (p=0.024, relative hazard 3.2, 95% CI 1.2-8.9). Associations persisted after accounting for early mortality and adjustments for concomitant risk factors.
While Hb declines with advancing age, evidence suggests that Hb that remains high in elderly men is associated with an increased risk of PD.
PMCID: PMC3006667  PMID: 20709430
Hemoglobin; iron; Parkinson’s disease; epidemiology
10.  Risk factors for fractures among Japanese-American men: the Honolulu Heart Program and Honolulu-Asia Aging Study 
Archives of osteoporosis  2011;6(1-2):197-207.
The objective of this study was to identify risk factors ascertained at baseline that were associated with prevalence and incidence of fractures at advanced age among Japanese-American men.
The present study used data from Honolulu Heart Program (HHP) and Honolulu-Asia Aging Study (HAAS). The HHP was a prospective study with primary focus on risk factors for cardiovascular diseases and stroke. A cohort of 8,006 men of Japanese ancestry aged 45–68 residing on Oahu was recruited in 1965, and followed through 1999. The HAAS started in 1991 in conjunction with the HHP with a focus on age-related health conditions. Self-reported cumulative prevalence of hip, spine and forearm fractures was ascertained in 1991–1993 among 3,845 men aged 71–93. Incidence was obtained during the follow-up period (1994–1999) among 2,737 men aged 74–98. Poisson regression models were used to determine multi-variable adjusted prevalence and incidence ratios for fracture.
Baseline age was directly and inversely associated with cumulative incident spine and prevalent forearm fracture, respectively. Education was inversely and directly associated with prevalent spine and forearm fracture, respectively. Body mass index (BMI) was independently and directly, and upper arm girth was inversely associated with incident hip fracture. Height and diabetic medication were directly associated with prevalent spine fracture. Physical activity and pack-years of smoking were independently and directly associated with incident and prevalent hip fracture, respectively.
These results indicated that multiple baseline demographic lifestyle and anthropometric characteristics predict fracture risk at advanced age. In addition, associations varied by fracture location.
PMCID: PMC3565433  PMID: 22886106
fracture; incidence ratio; men; prevalence ratio; risk factors
11.  Adherence to Guidelines for Youths With Diabetes Mellitus 
Pediatrics  2011;128(3):531-538.
To describe demographic and clinical characteristics associated with self-reported receipt of tests and measurements recommended by the American Diabetes Association (ADA) for children and youths with diabetes.
The study included 1514 SEARCH for Diabetes in Youth study participants who completed a survey about diabetes care received. Quality-of-care measures were based on ADA guidelines for eye examinations and glycohemoglobin (hemoglobin A1c [HbA1c]), lipid level, microalbuminuria, and blood pressure measurements, and a composite variable of these 5 indicators was created. Multivariate logistic regression models were used to assess the association of selected demographic and clinical characteristics with the reported receipt of all recommended tests and measurements according to age and diabetes type subgroups.
Overall, 95% of the participants reported having their blood pressure checked at all or most visits, 88% had lipid levels measured, 83% had kidney function tested, 68% underwent HbA1c testing, and 66% underwent an eye examination, in accordance with ADA recommendations. Participants aged 18 years or older, particularly those with type 2 diabetes, tended to have fewer tests of all kinds performed. Age and family income emerged as important correlates of overall quality of care in multivariate models; older age and lower income were associated with not meeting guidelines.
Although there was relatively good adherence to ADA-recommended guidelines for most indicators, efforts are needed to improve rates of HbA1c testing and eye examinations, particularly among older youths.
PMCID: PMC3164090  PMID: 21859914
quality of care; children and youths; diabetes mellitus
12.  Vasomotor symptoms and cardiovascular events in postmenopausal women 
Menopause (New York, N.Y.)  2011;18(6):603-610.
Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS).
We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N=60,027): (1) No VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]); (2) VMS at menopause onset, but not at WHI-OS enrollment (early VMS); (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]); and (4) VMS at WHI-OS enrollment, but not at menopause onset (late VMS).
For women with early VMS (N=24,753), compared to no VMS (N=18,799), hazard ratios (HRs) and 95% confidence intervals (CIs) in fully-adjusted models were: major CHD, 0.94 (0.84, 1.06); stroke, 0.83 (0.72, 0.96); total CVD, 0.89 (0.81, 0.97); and all-cause mortality, 0.92 (0.85, 0.99). For women with persistent VMS (N=15,084), there was no significant association with clinical events. For women with late VMS (N=1,391) compared to no VMS, HRs and 95% CIs were: major CHD, 1.32 (1.01, 1.71); stroke, 1.14 (0.82, 1.59); total CVD, 1.23 (1.00, 1.52); and all-cause mortality, 1.29 (1.08, 1.54).
Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from classical perimenopausal VMS.
PMCID: PMC3123435  PMID: 21358352
Vasomotor symptoms; Hot flashes; Cardiovascular disease; Women's health
Hypertension  2011;57(4):695-701.
The obesity epidemic has focused attention on relationships of sugars and sugar-sweetened beverages (SSB) to cardiovascular risk factors. Here we report cross-sectional associations of SSB, diet beverages, sugars with blood pressure (BP) for UK and USA participants of the International Study of Macro/Micro-nutrients and Blood Pressure (INTERMAP). Data collected includes four 24-h dietary recalls, two 24-h urine collections, eight BP readings, questionnaire data for 2,696 people ages 40-59 from 10 USA/UK population samples. Associations of SSB, diet beverages, and sugars (fructose, glucose, sucrose) with BP were assessed by multiple linear regression. Sugar-sweetened beverage intake related directly to BP, P-values 0.005 to <0.001 (systolic BP), 0.14 to <0.001 (diastolic BP). Sugar-sweetened beverage intake higher by 1 serving/day (355 ml/24-h) was associated with systolic/diastolic BP differences of +1.6/+0.8 mm Hg (both P <0.001); +1.1/+0.4 mm Hg (P <0.001/<0.05) with adjustment for weight, height. Diet beverage intake was inversely associated with BP, P 0.41 to 0.003. Fructose- and glucose-BP associations were direct, with significant sugar-sodium interactions: for individuals with above-median 24-h urinary sodium excretion, fructose intake higher by 2 SD (5.6 %kcal) was associated with systolic/diastolic BP differences of +3.4/+2.2 mm Hg (both P <0.001); 2.5/1.7 mm Hg (both P 0.002) with adjustment for weight, height. Observed independent, direct associations of SSB intake and BP are consistent with recent trial data. These findings, plus adverse nutrient intakes among SSB consumers, and greater sugar-BP differences for persons with higher sodium excretion, lend support to recommendations that intake of SSB, sugars, and salt be substantially reduced.
PMCID: PMC3086758  PMID: 21357284
Sugar-sweetened beverages; sodium; nutrition; blood pressure; epidemiology; population study
14.  Dietary Starch Intake of Individuals and Their Blood Pressure: The INTERMAP Study 
Journal of hypertension  2009;27(2):231-236.
Data from the Multiple Risk Factor Intervention Trial (MRFIT) show an independent direct association between starch intake and blood pressure (BP) in American men at higher risk of coronary heart disease (CHD). Cross-sectional INTERMAP data were used to assess relations of dietary starch intake to BP in men and women from four countries.
Data include 83 nutrients from four multi-pass 24-h dietary recalls and two timed 24-h urine collections; eight BP readings; and questionnaire data, for 4,680 participants ages 40–59 yr from 17 population samples in Japan, People's Republic of China, United Kingdom, and United States of America.
In multiple linear regression analyses – adjusted for urinary sodium, urinary potassium, consumption of alcohol, cholesterol, saturated fatty acids, polyunsaturated fatty acids, calcium, and other variables – starch intake higher by two standard deviations (14.1% kJ) was associated with systolic/diastolic BP differences of −1.0/−0.9 mm Hg (p =0.09, p <0.05). Results were similar with additional control for fibre, magnesium, or phosphorus; reduced to −0.5/−0.7 mm Hg (p =0.47, p =0.13) with separate adjustment for vegetable protein. Findings were similar for all INTERMAP men, for American men, and for American men at higher CHD risk.
INTERMAP data indicate that – if any – relations of starch intake to BP are modestly inverse. Current dietary guidelines for hypertension prevention and control remain relevant.
PMCID: PMC3111912  PMID: 19155780
Blood pressure; cross-sectional studies; diet; dietary carbohydrates; dietary starch; epidemiology
15.  Measures of Arterial Stiffness in Youth With Type 1 and Type 2 Diabetes 
Diabetes Care  2010;33(4):881-886.
Arterial stiffness occurs early in the atherosclerotic process; however, few data are available concerning risk factors for arterial stiffness in youth with diabetes. We identified factors associated with arterial stiffness in youth with diabetes and assessed the effects of these factors on the relationship between arterial stiffness and diabetes type (type 1 vs. type 2).
A subset of patients from the SEARCH for Diabetes in Youth study with type 1 (n = 535) and type 2 diabetes (n = 60), aged 10–23 years (52% male; 82% non-Hispanic white; diabetes duration 65 ± 49 months) had arterial stiffness, anthropometrics, blood pressure, fasting lipids, and A1C measured. Arterial stiffness was measured by brachial distensibility (brachD), pulse wave velocity (PWV), and augmentation index adjusted to heart rate of 75 beats/min (AI75).
Youth with type 2 diabetes had worse brachD (5.2 ± 0.9 vs. 6.1 ± 1.2%/mmHg), PWV (6.4 ± 1.3 vs. 5.3 ± 0.8 m/s), and AI75 (6.4 ± 9.9 vs. 2.2 ± 10.2%) than those with type 1 diabetes (P < 0.01 for each). These differences were largely mediated through increased central adiposity and higher blood pressure in youth with type 2 diabetes. We also found a pattern of association of arterial stiffness measures with waist circumference and blood pressure, independent of diabetes type.
Youth with type 2 diabetes have worse arterial stiffness than similar youth with type 1 diabetes. Increased central adiposity and blood pressure are associated with measures of arterial stiffness, independent of diabetes type. Whether these findings indicate that youth with type 2 diabetes will be at higher risk for future complications requires longitudinal studies.
PMCID: PMC2845046  PMID: 20067960
16.  Physical Aspects of Healthy Aging: Assessments of Three Measures of Balance for Studies in Middle-Aged and Older Adults 
Objectives. To investigate the reliability and correlations with age of the balance components of the EPESE, NHANES, and the Good Balance Platform System (GBPS) in a normal population of adults. Design. Cross-sectional. Setting. Urban Medical Center in the Pacific. Participants. A random sample of 203 healthy offspring of Honolulu Heart Program participants, ages 38–71. Measurements. Subjects were examined twice at visits one week apart using the balance components of the EPESE, NHANES, and the good balance system tests. Results. The EPESE and NHANES batteries of tests were not sufficiently challenging to allow successful discrimination among subjects in good health, even older subjects. The GBPS allowed objective quantitative measurements, but the test-retest correlations generally were not high. The GBPS variables correlated with age only when subjects stood on a foam pad; they also were correlated with anthropometric variables. Conclusion. Both EPESE and NHANES balance tests were too easy for healthy subjects. The GBPS had generally low reliability coefficients except for the most difficult testing condition (foam pad, eyes closed). Both height and body fat were associated with GBPS scores, necessitating adjusting for these variables if using balance as a predictor of future health.
PMCID: PMC3062992  PMID: 21437003
17.  Cardiovascular Disease Risk Factors in Youth With Type 1 and Type 2 Diabetes: Implications of a Factor Analysis of Clustering 
The extent to which cardiovascular disease (CVD) risk factors cluster in youth with a diagnosis of type 1 (T1DM) or type 2 diabetes mellitus (T2DM) is unclear. Therefore, we aimed to evaluate potential clustering of traditional CVD risk factors that may reflect an unmeasured but unifying single pathology that may explain the phenomenon of the metabolic syndrome in these youths.
Youths who participated in the SEARCH for Diabetes in Youth study with diabetes diagnosed <20 years, with current age >10 years (maximum current age, 22 years) were included. Confirmatory factor analysis (CFA) was performed to determine statistical associations among CVD risk factors, including obesity, blood pressure, triglycerides, and high-density lipoprotein cholesterol (HDL-C). Diabetes type was defined by diabetes autoantibodies (DAA) and fasting C-peptide (FCP); type 1 (T1DM, DAA positive, and FCP <0.8 ng/mL, n = 1198) and type 2 (T2DM, DAA negative, and FCP >2.9 ng/mL, n = 95). For T1DM, the sample was split randomly and analyses were conducted separately in each split sample.
Among five prespecified data structures ranging from a single underlying factor to a hierarchical structure of factors, the worst-fitting model for both of the T1DM split samples was the single-factor structure and the best-fitting model was a three-correlated-factor structure. The three correlated factors identified were obesity, lipids, and blood pressure. Results were very similar for youths with T2DM.
There is little evidence that a single factor underlies the CVD risk factor pattern in youths with diabetes. The concept of the metabolic syndrome provides a useful description of clinical characteristics but does not efficiently capture a single target for etiologic research among youths with diabetes.
PMCID: PMC3135884  PMID: 18847385
18.  Diabetes in Non-Hispanic White Youth 
Diabetes Care  2009;32(Suppl 2):S102-S111.
OBJECTIVE—To investigate the incidence, prevalence, and clinical characteristics of diabetes among U.S. non-Hispanic white (NHW) youth.
RESEARCH DESIGN AND METHODS—Data from the SEARCH for Diabetes in Youth Study (SEARCH study), a multicenter study of diabetes among youth aged 0–19 years, were examined. Incidence rates were calculated per 100,000 person-years across 4 incident years (2002–2005), and prevalence in 2001 was calculated per 1,000 youths. Information obtained by questionnaire, physical examination, and blood and urine collection was analyzed to describe the characteristics of youth who completed an in-person visit.
RESULTS—The prevalence of type 1 diabetes (at ages 0–19 years) was 2.00/1,000, which was similar for male (2.02/1,000) and female (1.97/1,000) subjects. The incidence of type 1 diabetes was 23.6/100,000, slightly higher for male compared with female subjects (24.5 vs. 22.7 per 100,000, respectively, P = 0.04). Incidence rates of type 1 diabetes among youth aged 0–14 years in the SEARCH study are higher than all previously reported U.S. studies and many European studies. Few cases of type 2 diabetes in youth aged <10 years were found. The prevalence of type 2 diabetes (at ages 10–19 years) was 0.18/1,000, which is significantly higher for female compared with male subjects (0.22 vs. 0.15 per 1,000, P = 0.01). Incidence of type 2 diabetes was 3.7/100,000, with similar rates for female and male subjects (3.9 vs. 3.4 per 1,000, respectively, P = 0.3). High levels of abnormal cardiometabolic and behavioral risk factor profiles were common among youth with both type 1 and type 2 diabetes. For example, within each of four age-groups for youth with type 1 diabetes and two age-groups for youth with type 2 diabetes, >40% had elevated LDL cholesterol, and <3% of youth aged >10 years met current recommendations for intake of saturated fat. Among youth aged ≥15 years, 18% with type 1 and 26% with type 2 diabetes were current smokers.
CONCLUSIONS—The SEARCH study is one of the most comprehensive studies of diabetes in NHW youth. The incidence of type 1 diabetes in NHW youth in the U.S. is one of the highest in the world. While type 2 diabetes is still relatively rare, rates are several-fold higher than those reported by European countries. We believe efforts directed at improving the cardiometabolic and behavioral risk factor profiles in this population are warranted.
PMCID: PMC2647694  PMID: 19246575
19.  Type 1 and Type 2 Diabetes in Asian and Pacific Islander U.S. Youth 
Diabetes Care  2009;32(Suppl 2):S133-S140.
OBJECTIVE—Given limited reports on diabetes among U.S. Asian and Pacific Islander youth, we describe the clinical characteristics, incidence, and prevalence of diabetes among Asian, Pacific Islander, and mixed Asian–Pacific Islander youth.
RESEARCH DESIGN AND METHODS—Data were collected from 245 Asian, Pacific Islander, and Asian–Pacific Islander participants in the SEARCH for Diabetes in Youth Study, a population-based study of diabetes in youth (aged <20 years). Additionally, we estimated the incidence and prevalence of type 1 and type 2 diabetes for Asian, Pacific Islander, and Asian–Pacific Islander youth combined.
RESULTS—Most participants with type 2 diabetes were obese (range Asian 71% to Pacific Islander 100%) with mean BMI >33 kg/m2. In those with type 1 diabetes, Pacific Islanders were more likely to be obese, with a mean BMI of 26 vs. 20 kg/m2 for Asian and Asian–Pacific Islander youth (P < 0.0001). The incidence of type 1 diabetes for youth aged 0–9 years was 6.4 per 100,000 person-years and 7.4 per 100,000 person-years for youth aged 10–19 years. The incidence of type 2 diabetes was 12.1 per 100,000 person-years for youth aged 10–19 years.
CONCLUSIONS—While Asian and Asian–Pacific Islanders with type 1 and type 2 diabetes had lower mean BMIs than Pacific Islanders, all Asian, Pacific Islander, and Asian–Pacific Islanders with type 2 diabetes had mean BMIs above adult ethnicity-specific definitions of obesity. While the majority of Asian, Pacific Islander, and Asian–Pacific Islander youth had type 1 diabetes, older Asian, Pacific Islander, and Asian–Pacific Islander youth (aged 10–19 years) have an incidence of type 2 diabetes almost double that of type 1 diabetes. Public health efforts to prevent type 2 diabetes and obesity in Asian, Pacific Islander, and Asian–Pacific Islander adolescents are needed.
PMCID: PMC2647693  PMID: 19246578
20.  Correlates of Sexual Satisfaction Among Sexually Active Postmenopausal Women in the Women’s Health Initiative-Observational Study 
Journal of General Internal Medicine  2008;23(12):2000-2009.
Satisfaction with sexual activity is important for health-related quality of life, but little is known about the sexual health of postmenopausal women.
Describe factors associated with sexual satisfaction among sexually active postmenopausal women.
Cross-sectional analysis.
All members of the Women’s Health Initiative-Observational Study (WHI-OS), ages 50–79, excluding women who did not respond to the sexual satisfaction question or reported no partnered sexual activity in the past year (N = 46,525).
Primary outcome: dichotomous response to the question, “How satisfied are you with your sexual activity (satisfied versus unsatisfied)?” Covariates included sociodemographic factors, measures of physical and mental health, and gynecological variables, medications, and health behaviors related to female sexual health.
Of the cohort, 52% reported sexual activity with a partner in the past year, and 96% of these answered the sexual satisfaction question. Nonmodifiable factors associated with sexual dissatisfaction included age, identification with certain racial or ethnic groups, marital status, parity, and smoking history. Potentially modifiable factors included lower mental health status and use of SSRIs. The final model yielded a c-statistic of 0.613, reflecting only a modest ability to discriminate between the sexually satisfied and dissatisfied.
Among postmenopausal women, the variables selected for examination yielded modest ability to discriminate between sexually satisfied and dissatisfied participants. Further study is necessary to better describe the cofactors associated with sexual satisfaction in postmenopausal women.
PMCID: PMC2596524  PMID: 18839256
sexual dysfunction; physiological; sexual dysfunctions; psychological; women; menopause; postmenopause; cohort studies
21.  Diagnosis of Insulin Resistance in Hypertensive Patients by the Metabolic Syndrome: AHA vs. IDF Definitions 
Subjects with the metabolic syndrome are accompanied by insulin resistance (IR). However, it is not clear how well the newly-defined metabolic syndrome identifying IR specifically in hypertensive subjects.
The purpose of the study is to evaluate the performance of the metabolic syndrome, defined by the American Heart Association (AHA) and the International Diabetes Federation (IDF) definitions, in identifying IR in hypertension.
The analysis is a cross-sectional study. Totally, 228 hypertensive patients and 92 non-diabetic normotensive controls who received insulin suppressive tests to directly evaluate their insulin sensitivity were included from the Stanford Asia and Pacific Program for Hypertension and IR. McNemar’s tests were used to compare sensitivity and specificity of the AHA-defined with the IDF-defined metabolic syndrome in diagnosis of IR.
The sensitivity of the metabolic syndrome for IR in hypertension was 89.7 % and the specificity 45.9 % by the AHA definition. Using the IDF definition, the sensitivity was 77.6 %, and the specificity increased to 63.5 %. The diagnostic power of individual components of the syndrome was also modest. The predictive discrimination of wider waist circumference was similar to that of the AHA-defined metabolic syndrome.
Use of the metabolic syndrome by the AHA definition provided good sensitivity but low specificity to diagnose IR in hypertension. The IDF definition improved in false positive rate, but it was still not specific enough to identify IR in hypertension.
PMCID: PMC2569973  PMID: 18564200
hypertension; insulin resistance; metabolic syndrome; steady-state plasma glucose
22.  Genome-wide Linkage Screen for Stature and Body-mass Index in 3.032 Families - Evidence for Sex- and Population-specific Genetic Effects 
Stature (adult body height), and body mass index (BMI) have a strong genetic component explaining observed variation in human populations, however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population-and sex-specific analyses as well. For stature we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23 as well as 15q26 and 19q13 which have not been linked to stature previously. For BMI we found evidence for two loci: one on 7q35 and another on 11q22 both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of 1) combining data to maximize the sample size and 2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping.
PMCID: PMC2628452  PMID: 18781184
Body Height; Body Mass Index; Linkage mapping; Quantitative Trait Loci
23.  Genome-wide linkage screen for stature and body mass index in 3.032 families: evidence for sex- and population-specific genetic effects 
Stature (adult body height) and body mass index (BMI) have a strong genetic component explaining observed variation in human populations; however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population- and sex-specific analyses as well. For stature, we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23, as well as 15q26 and 19q13, which have not been linked to stature previously. For BMI, we found evidence for two loci: one on 7q35 and another on 11q22, both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of (1) combining data to maximize the sample size and (2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping.
PMCID: PMC2628452  PMID: 18781184
body height; body mass index; linkage mapping; quantitative trait loci
24.  Circulating Levels of Endothelial Adhesion Molecules and Risk of Diabetes in an Ethnically Diverse Cohort of Women 
Diabetes  2007;56(7):1898-1904.
Elevated circulating levels of soluble adhesion molecules as markers of endothelial dysfunction have been related to insulin resistance and its associated metabolic abnormalities. However, their associations with type 2 diabetes remain inconclusive. We conducted a prospective nested case-control study to examine the associations between plasma levels of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) and diabetes risk among 82,069 initially healthy women aged 50 to 79 years from the Women’s Health Initiative Observational Study. During a median follow-up of 5.9 years, 1,584 incident diabetes case subjects were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. Baseline median levels of the biomarkers were each significantly higher among case subjects than among control subjects (E-selectin, 49 vs. 37 ng/ml; ICAM-1, 324 vs. 280 ng/ml; and VCAM-1, 765 vs. 696 ng/ml [all P values <0.001]). After adjustment for risk factors, the relative risks of diabetes among women in the highest quartile versus those in the lowest quartile were 3.46 for E-selectin (95% confidence interval 2.56–4.68; P for trend <0.0001), 2.34 for ICAM-1 (1.75–3.13; P for trend <0.0001), and 1.48 for VCAM-1 (1.07–2.04; P for trend = 0.009). E-selectin and ICAM-1 remain significant in each ethnic group. Higher levels of E-selectin and ICAM-1 were consistently associated with increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women, implicating an etiological role of endothelial dysfunction in the pathogenesis of type 2 diabetes.
PMCID: PMC1952236  PMID: 17389327

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