Power and Robustness of Linkage Tests for Quantitative Traits in General Pedigrees

There are numerous statistical methods for quantitative trait linkage analysis in human studies. An ideal such method would have high power to detect genetic loci contributing to the trait, would be robust to non-normality in the phenotype distribution, would be appropriate for general pedigrees, would allow the incorporation of environmental covariates, and would be appropriate in the presence of selective sampling. We recently described a general framework for quantitative trait linkage analysis, based on generalized estimating equations, for which many current methods are special cases. This procedure is appropriate for general pedigrees and easily accommodates environmental covariates. In this paper, we use computer simulations to investigate the power robustness of a variety of linkage test statistics built upon our general framework. We also propose two novel test statistics that take account of higher moments of the phenotype distribution, in order to accommodate non-normality. These new linkage tests are shown to have high power and to be robust to non-normality. While we have not yet examined the performance of our procedures in the context of selective sampling via computer simulations, the proposed tests satisfy all of the other qualities of an ideal quantitative trait linkage analysis method

Unification of Variance Components and Haseman-Elston Regression for Quantitative Trait Linkage Analysis

Two of the major approaches for linkage analysis with quantitative traits in humans include variance components and Haseman-Elston regression. Previously, these have been viewed as quite separate methods. We describe a general model, fit by use of generalized estimating equations (GEE), for which the variance components and Haseman-Elston methods (including many of the extensions to the original Haseman-Elston method) are special cases, corresponding to different choices for a working covariance matrix. We also show that the regression-based test of Sham et al.(2002) is equivalent to a robust score statistic derived from our GEE approach. These results have several important implications. First, this work provides new insight regarding the connection between these methods. Second, asymptotic approximations for power and sample size allow clear comparisons regarding the relative efficiency of the different methods. Third, our general framework suggests important extensions to the Haseman-Elston approach which make more complete use of the data in extended pedigrees and allow a natural incorporation of environmental and other covariates

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome: A case report

AbstractRemitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare form of paraneoplastic tenosynovitis, which is more prone to occur in elderly males. A 78-year-old male had a past history of gastric cancer 23 years ago and underwent subtotal gastrectomy then. He led a fair life after the surgery. However, fever, edema in four extremities, gait disturbance, and liver function impairment bothered him for 5 months, which caused significant physical functional decline. Despite of extensive laboratory and imaging examinations, no definite diagnosis and treatment were provided. He was referred to Kyoto University hospital and RS3PE was diagnosed. After the diagnosis of RS3PE syndrome was made, systemic steroid was given and fever, edema and liver function impairment improved dramatically within 7 days. The patient was well managed by oral prednisolone 30mg per day after discharge. RS3PE should be considered when an elderly man with aforementioned presentations in order to prevent significant functional decline in daily living

Undiagnosed diabetes mellitus among residents in Taiwanese long-term care facilities: A comparison of fasting glucose, postprandial plasma glucose, and hemoglobin A1c

AbstractBackgroundThe prevalence of diabetes mellitus (DM) is escalating with an aging population, and the chances of diabetic older patients admitted to long-term care facilities (LTCFs) are increased because of DM-related complications. However, undiagnosed DM among LTCF residents is a recognized hidden problem in this setting and may result in adverse outcomes.MethodsIn May 2011, 10 private LTCFs in northern Taipei participated in this study. Trained research nurses reviewed the medical records and performed physical examinations and blood sampling for all participants. Diabetes mellitus was diagnosed, based on the levels of fasting glucose, 2-hour postprandial plasma glucose, and hemoglobin A1c (HbA1c). Patients were categorized as having DM if they met the diagnostic cut-offs of the aforementioned criteria.ResultsOne hundred and ninety-nine residents (mean age, 79.6 ± 10.5 years; 52.3% males) participated in this study. They were all moderately/severely disabled (Karnofsky Performance Scale mean score was 50 ± 13). Forty-six (23.1%) residents were diabetic, based on their medical records, or were current users of antidiabetic agents. The prevalence was 29.6% after testing with a mean HbA1c level of 6.9% ± 0.9%. The overall undiagnosed DM rate was 4%, 3.5%, and 4.5%, based on fasting glucose, 2-hour postprandial plasma glucose, and HbA1c criteria, respectively. Diabetic patients had significantly higher serum levels of prealbumin, compared to nondiabetic patients (220.8 ± 45.9 vs. 201.1 ± 62.2 mg/L; p = 0.03), but there were no differences in the levels of hemoglobin, serum albumin, or total cholesterol. Diabetic patients had a significantly higher serum triglyceride level, compared to the nondiabetic patients (1.6 ± 0.7 vs. 1.1 ± 0.5 mmol/L; p < 0.01) and a lower high-density lipoprotein level (1.0 ± 0.3 vs. 1.2 ± 0.3 mmol/L; p < 0.01). Among 43 pharmacologically treated diabetic patients, 65.1% (28/43) of patients were using oral antidiabetic agents and 41.9% (18/43) of patients had been prescribed insulin, whereas 32.6% of the patients were managed by combination therapy.ConclusionThe prevalence of DM among LTCF residents in Taipei was 29.6%, and the undiagnosed rate was no more than 5%, based on fasting glucose, 2-hour postprandial plasma glucose, or HbA1c. Further study is needed for the optimal treatment strategy of DM in LTCFs

Nondiabetic older adults with untreated hypertension in Taiwan: Treatment implication in elderly hypertension

AbstractBackgroundHypertension is common and often left undiagnosed in the elderly. The main purpose of this study was to evaluate the clinical characteristics of nondiabetic hypertensive older adults.MethodsCommunity-living older adults in Taipei City participating in annual health examinations were invited for study. Subjects with diabetes mellitus, whether treated or newly diagnosed, were excluded for further analysis. All participants were classified into three groups: normotension, untreated hypertension (UH), and treated hypertension (TH).ResultsIn total, 3244 subjects (mean age: 73.4±5.4 years, 56.2% males) were enrolled. The prevalence of hypertension, chronic kidney disease (CKD), and left ventricular hypertrophy (LVH) was 52.9% (36.1% TH and 16.8% UH), 20.9%, and 6.2%, respectively. Compared with the normotension group, UH subjects were older (73.8±5.5 years vs. 72.9±5.6 years, p=0.003); having higher body mass index (24.2±3.4kg/m2 vs. 23.6±3.4kg/m2, p=0.001), fasting glucose (101.7±9.1mg/dL vs. 100.5±9.0mg/dL, p=0.007), total cholesterol (TC) (205.0±37.8mg/dL vs. 196.5±36.4mg/dL, p<0.001), triglyceride (TG) (134.5±84.9mg/dL vs. 119.4±77.0mg/dL, p<0.001); and higher prevalence of overt proteinuria (19.3% vs. 13.5%, p=0.001), CKD (21.1% vs. 16.6%, p=0.025), and LVH (8.1% vs. 3.8%, p<0.001). However, the prevalence of overt proteinuria (19.3% vs. 21.1%, p=0.378) and LVH (8.1% vs. 8.5%, p=0.79) between UH and TH groups was similar. Adjusted for age, TC, TG, fasting plasma glucose, and the incidence of LVH, both UH [odds ratio (OR)=1.30, 95% confidence interval (CI)=1.01–1.66, p=0.040] and TH (OR=1.69, 95% CI=1.39–2.05, p<0.001) were significant risk factor for CKD. In addition, independent risk factors for CKD included age (OR=1.07, 95% CI=1.05–1.09, p<0.001), body mass index (OR=1.07, 95% CI=1.04–1.10, p<0.001), TC (OR=1.003, 95% CI=1.001–1.005, p=0.021), TG (OR=1.002, 95% CI=1.001–1.003, p<0.001), and hypertension (TH or UH) (OR=1.44, 95% CI=1.20–1.72, p<0.001).ConclusionIn conclusion, risk of CKD existing along with blood pressure rises among nondiabetic older hypertensive adults, and hypertension (TH or UH) carries a significant risk of CKD after adjustment of other cardiovascular risk factors. Renal protection should be highlighted in the antihypertensive treatment strategy in older hypertensive patients

Associated clinical characteristics of patients with candidemia among different Candida species

BackgroundThe rising incidence of non-albicans Candida (NAC) infection has been associated with a potentially adverse outcome for patients with candidemia. However, categorizing various species causing candidemia into a single NAC group might lead to inappropriate conclusions due to heterogeneity in species. Thus we examined the associated factors among patients with candidemia caused by different species.MethodsThis retrospective study was conducted at a tertiary medical center in Taiwan from 2006 to 2009. Mortality rate, demographic and clinical characteristics, albumin levels, and severity scores of acute illness of patients at the onset of candidemia were analyzed.ResultsA total of 447 episodes among 418 patients were included for analysis. The overall 30-day crude mortality was 48.2%, with no significant difference between C. albicans and NAC candidemia, but apparently C. parapsilosis candidemia was associated with a lower mortality rate. Time to positivity for yeast was significantly different between species. Compared with infection involving C. albicans, more frequent use of total parenteral nutrition, lower Sequential Organ Failure Assessment score and higher albumin levels were observed for C. parapsilosis candidemia.ConclusionIdentifying associated factors for each species may be a more effective approach than single NAC grouping. Time to positivity may be a hint for treatment guidance in candidemia. More frequent use of total parenteral nutrition and less virulent nature were noted for C. parapsilosis candidemia

Induced pluripotent stem cells and regenerative medicine

AbstractStem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from the adult hippocampal and subventricular regions possess the utilizing potential to develop the transplantation strategies and to screen the candidate agents for neurogenesis, neuroprotection, and neuroplasticity in neurodegenerative diseases. In this article, we review the roles of NSCs and other stem cells in neuroprotective and neurorestorative therapies for neurological and psychiatric diseases. We show the evidences that NSCs play the key roles involved in the pathogenesis of several neurodegenerative disorders, including depression, stroke, and Parkinson’s disease. Moreover, the potential and possible utilities of induced pluripotent stem cells, reprogramming from adult fibroblasts with ectopic expression of four embryonic genes, are also reviewed and further discussed. An understanding of the biophysiology of stem cells could help us elucidate the pathogenicity and develop new treatments for neurodegenerative disorders. In contrast to cell transplantation therapies, the application of stem cells can further provide a platform for drug discovery and small molecular testing, including Chinese herbal medicines. In addition, the high-throughput stem cell-based systems can be used to elucidate the mechanisms of neuroprotective candidates in translation medical research for neurodegenerative diseases

Clinical significance of time to positivity for yeast in candidemia

PurposeCandidemia is an important issue of nosocomial bloodstream infections, and is associated with a high mortality rate. However, little information is available before final species identification, which takes days after the episode of candidemia. This study tried to determine whether time to positivity (TTP) for yeast helps in predicting the species of candidemia.MethodsA retrospective cohort study was conducted in Taiwan, which included 434 episodes of nonduplicated candidemia during the period between 2006 and 2009. The demographic features, clinical characteristics, TTP for yeast, and acute illness scores were included for analysis.ResultsThe mean age of patients with candidemia was 70.4 ± 15.2 years, and the 30-day crude mortality rate was 48.2%. Forty-five percent of patients suffered from shock status with a mean Acute Physiological and Chronic Health Evaluation II score of 27.0 ± 8.7 and a mean Sequential Organ Failure Assessment score of 9.7 ± 4.5, whereas 50% were admitted to the intensive care units. Candida albicans was still the most commonly identified pathogen (58.1%), followed by C. tropicalis (14.7%), C. parapsilosis (13.1%), and C. glabrata (8.3%). Results of multivariate logistic regression showed that TTP for yeast within 48 hours would more favor C. tropicalis (p = 0.044), and less favor C. glabrata (p = 0.025) and C. parapsilosis (p < 0.001). Patients with parenteral nutrition usage were more frequently associated with a TTP for yeast within 48 hours, whereas those with previous exposure to an antifungal agent had a longer TTP for yeast.ConclusionThe TTP for yeast might provide a hint of the responsible Candida species before final identification among critical patients with candidemia. The association between antifungal agents and TTP would need more evidence for elucidation

Functional decline and mortality in long-term care settings: Static and dynamic approach

AbstractBackground/PurposeFunctional impairment is known to be associated with higher mortality risk and adverse health outcomes. However, little is known about whether functional decline could predict mortality among the elderly in the long-term care setting.MethodsThis is a prospective cohort study in two veteran homes in northern Taiwan with active use of the minimum data set (MDS). Evaluation tools retrieved from the MDS, including MDS Resource Utilization Group-III for Activities of Daily Living (RUG-III ADL), MDS Cognitive Scale, MDS Social engagement, triggers for resident assessment protocol (RAP) and Pain scale, were utilized for the analysis.ResultsA total of 1125 male participants were included in this study. The mean age of the participants was 83.1 ± 5.1 years, and 65 (5.8%) developed physical functional decline within a 6-month period. Participants with functional decline [odds ratio (OR) 2.305, 95% confidence interval (CI) 1.002–5.303], poor baseline functional status (OR 1.116, 95% CI 1.002–1.242), positive RAP triggers for dehydration (OR 13.857, 95% CI 3.07–62.543), and underlying chronic lung diseases (OR 2.279, 95% CI 1.149–4.522), depression (OR 2.994, 95% CI 1.161–7.721), and cancer (OR 3.23, 95% CI 1.078–9.682) were more likely to have an additional 12-month mortality. By contrast, Parkinsonism (OR 3.875, 95% CI 1.169–12.841), increase in sum of RAP triggers (OR 6.096, 95% CI 2.741–13.562), and positive RAP triggers for cognitive loss (OR 3.164, 95% CI 1.612–6.212) and mood (OR 2.894, 95% CI 1.466–5.71) are strong predictors for functional decline within 6 months.ConclusionPhysical function decline within 6 months predicted the subsequent 1-year mortality, whereas increased sum of RAP triggers and positive trigger for cognitive loss and mood were associated with functional decline