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Disease relapse occurs in patients with leukemia even hematopoietic stem cell transplantation (HSCT) was performed with human leukocyte antigen (HLA)-matched donors. As revealed previously by Petersdorf et al., there are nine single nucleotide polymorphisms (SNPs) located in the HLA region that potentially modulate the efficacy of HSCT. In this study, we investigated whether or not the genomic variants 500 base pairs flanking the nine transplantation-related SNPs were related to the risk of post-HSCT relapse for patients with leukemia (n = 141). The genomic DNAs collected from 85 patients with acute myeloid leukemia (AML), 56 patients with acute lymphocytic leukemia (ALL), and their respective HLA-matched donors were subject to SNPs analysis, conferred by the mode of mismatch between donor-recipient pair or by recipient or donor genotype analysis. Seven SNPs were revealed to associate with the risk of relapse post-HSCT. For patients with AML, the increased risk of post-HSCT relapse was associated with the donor SNP of rs111394117 in the intron of NOTCH4 gene, and the recipient SNPs of rs213210 in the ring finger protein 1 (RING1) gene promoter, and rs17220087 and rs17213693 in the intron of HLA-DOB gene. For patients with ALL, the increased risk of post-HSCT relapse was associated with the donor SNP of rs213210 in the RING1 gene promoter, and the recipient SNPs of rs79327197 in the HLA-DOA gene promoter, rs2009658 in the telomeric end of lymphotoxin-alpha (LTA) gene, rs17220087 and rs17213693 in the intron of HLA-DOB gene, and rs2070120 in the 3′-UTR of HLA-DOB gene. This study sheds new insight into selecting better candidate donors for performing HSCT in patients with AML and ALL.

Background: Varicose veins are a common problem worldwide. Although it was reported that varicose veins have cosmetic and symptomatic effects and can also lead to an increased risk of incident deep venous thrombosis, pulmonary embolism, and peripheral artery disease, whether varicose vein treatment prevents those serious complications is unknown. Methods: This retrospective cohort study used claims data extracted from the Chang Gung Research Database and National Health Insurance Research Database in Taiwan. The study subjects were patients aged ≥20 years who underwent endovenous thermal ablation (ETA) from 2005 to 2016 and a group of untreated subjects who were matched by sex and year of birth. All patients were followed from the index date to the earliest occurrence of peripheral artery disease, deep venous thrombosis, or pulmonary embolism or death or the end of the study. To avoid possible selection bias, 1:4 propensity score matching was implemented and a Cox proportional-hazards model was applied while controlling for potential confounders. We also collected data on complications within 28 days of ETA. Results: In total, data on 1323 ETA-treated patients with varicose veins were extracted from the Chang Gung Research Database, while data on 149 586 untreated patients with varicose veins were extracted from the National Health Insurance Research Database. Compared with the untreated group, ETA-treated patients had decreased risks of deep venous thrombosis and peripheral artery disease (adjusted hazard ratio, 0.49 [95% CI, 0.32–0.75] and 0.64 [95% CI, 0.49–0.85]). The incidence rates of deep venous thrombosis and pulmonary embolism after ETA (≤28 days) were 0.296% and 0.074%, respectively. Conclusions: ETA treatment of varicose veins was associated with a substantial decrease in the subsequent incidence of thromboembolism and peripheral artery disease compared with that in the absence of treatment. In addition, the incidence rate of postprocedural thromboembolic complications after ETA was low in the Asian population. We suggest that improved disease awareness and appropriate early treatment may help reduce the risk of serious complications.

Background The optimal timing of renal replacement therapy (RRT) initiation is debatable. Many articles in this field enrolled trials not based on acute kidney injury. The safety of the watchful waiting strategy has not been fully discussed, and late RRT initiation criteria vary across studies. The effect of early RRT initiation in the AKI population with high plasma neutrophil gelatinase-associated lipocalin (NGAL) has not been examined yet. Methods In accordance with PRISMA guidelines, the PubMed, Embase, and Cochrane databases were systemically searched for randomized controlled trials (RCTs). Trials not conducted in the AKI population were excluded. Data of study characteristics, primary outcome (all-cause mortality), and related secondary outcomes [mechanical ventilation (MV) days, length of hospital stay, RRT days, and length of ICU stay] were extracted. The outcomes were compared between early and late RRT groups by estimating the pooled odds ratio (OR) for binary outcomes and the weighted mean difference for continuous outcomes. Prospective trials were also examined and analyzed using the same method. Results Nine RCTs with 1938 patients were included. Early RRT did not provide a survival benefit (pooled OR, 0.88; 95% confidence interval [CI] 0.62–1.27). However, the early RRT group had significantly fewer MV days (pooled mean difference, − 3.98 days; 95% CI − 7.81 to − 0.15 days). Subgroup analysis showed that RCTs enrolling the surgical population (P = .001) and the AKI population with high plasma NGAL (P = .031) had favorable outcomes regarding RRT days in the early initiation group. Moreover, 6 of 9 RCTs were selected for examining the safety of the watchful waiting strategy, and no significant differences were found in primary and secondary outcomes between the early and late RRT groups. Conclusions Overall, early RRT initiation did not provide a survival benefit, but a possible benefit of fewer MV days was detected. Early RRT might also provide the benefit of shorter MV or RRT support in the surgical population and in AKI patients with high plasma NGAL. Depending on the conventional indication for RRT initiation, the watchful waiting strategy is safe on the basis of all primary and secondary outcomes.

Background Febrile non-hemolytic transfusion reaction (FNHTR) is the most common type of transfusion reactions, and it could be reduced by transfusing patients with leukocyte-poor blood products. However, FNHTR still occur in certain patients transfused with leukocyte-poor red blood cell (LPR) products. It is examined whether human platelet antigen (HPA) could be a potential membrane antigen that plays a role in FNHTR. Methods A total of 120 inpatient subjects who transfused with LPR (60 in FNHTR group, 60 in control group) were typed for HPA-2, HPA-3, and HPA-15 using sequence specific primer-polymerase chain reaction (SSP-PCR) and electrophoresis. Results HPA-2 unmatched rate between donors and patients in FNHTR group was 18%, and only 3% unmatched rate was observed in control group (p = 0.0082). FNHTR group was further classified according to the imputability. There was a significant difference (p = 0.0041) between FNHTR (probable imputability, infection) group and control group, and more significant difference (p = 0.0008) was seen between FNHTR (probable imputability, febrile neutropenia) group and control group. Conclusions Those results indicated that HPA-2 might play roles on inducing FNHTR in patients suffering from infectious diseases and febrile neutropenia. HPA-2 genotyping between donors and recipients might be worth integrating in pre-transfusion testing to increase transfusion safety.

The FloTrac system is a system for cardiac output (CO) measurement that is less invasive than the pulmonary artery catheter (PAC). The purposes of this study were to (1) compare the level of agreement and trending abilities of CO values measured using the fourth version of the FloTrac system (CCO-FloTrac) and PAC-originated continuous thermodilution (CCO-PAC) and (2) analyze the inadequate CO-discriminating ability of the FloTrac system before and after cardiopulmonary bypass (CPB). Fifty patients were included. After exclusion, 32 patients undergoing cardiac surgery with CPB were analyzed. All patients were monitored with a PAC and radial artery catheter connected to the FloTrac system. CO was assessed at 10 timing points during the surgery. In the Bland–Altman analysis, the percentage errors (bias, the limits of agreement) of the CCO-FloTrac were 61.82% (0.16, − 2.15 to 2.47 L min) and 51.80% (0.48, − 1.97 to 2.94 L min) before and after CPB, respectively, compared with CCO-PAC. The concordance rates in the four-quadrant plot were 64.10 and 62.16% and the angular concordance rates (angular mean bias, the radial limits of agreement) in the polar-plot analysis were 30.00% (17.62°, − 70.69° to 105.93°) and 38.63% (− 10.04°, − 96.73° to 76.30°) before and after CPB, respectively. The area under the receiver operating characteristic curve for CCO-FloTrac was 0.56, 0.52, 0.52, and 0.72 for all, ≥ ± 5, ≥ ± 10, and ≥ ± 15% CO changes (ΔCO) of CCO-PAC before CPB, respectively, and 0.59, 0.55, 0.49, and 0.46 for all, ≥ ± 5, ≥ ± 10, and ≥ ± 15% ΔCO of CCO-PAC after CPB, respectively. When CO

It remains unclear whether infection events before entering end stage renal disease (ESRD) have a long-term negative impact on patients with advanced chronic kidney disease (CKD) who survive to permanent dialysis. We enrolled 62,872 patients with advanced CKD who transitioned to maintenance dialysis between January 1, 2004 and December 31, 2013. We used multivariable Cox as well as Fine and Gray models to determine the association of pre-dialysis infection exposure with all-cause mortality after starting dialysis. Compared with no infection during advanced CKD, the presence of infection exposure during that period was independently associated with a higher risk of all-cause mortality in the first year of dialysis (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.27–1.42) and also during the entire follow-up period (HR 1.19, 95% CI 1.16–1.22). The increased risks of all-cause mortality increased incrementally with higher annual number of infections during advanced CKD. Similar results were found for all other adverse outcomes, e.g. post-ESRD infection-related hospitalization and major cardiac and cerebrovascular events. In conclusion, infection events during advanced CKD was associated with increased risks of adverse outcomes after dialysis has been started. Timely interventions in such a vulnerable group may help attenuate these risks.

Purpose Patients receiving extracorporeal membrane oxygenation (ECMO) commonly develop acute kidney injury (AKI) and frequently require continuous renal replacement therapy (CRRT). The impact of different CRRT modalities on survival in patients receiving ECMO remains unclear. Materials and methods Using claims data from Taiwan's National Health Insurance Research Database, a total of 1077 patients who received ECMO and either continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD) for AKI were identified. Inverse probability of treatment weighting was applied using propensity scores to balance the baseline covariates of the two groups. The primary outcome was in-hospital morality. Results We identified 1077 patients (mean age 57.9; 71.8% men). Postcardiotomy shock (49.2%) was the most frequently reported indication for ECMO. The CVVH group had a lower risk of in-hospital mortality (68.4% vs. 76.9%; odds ratio 0.65; 95% confidence interval [CI] 0.50–0.85) compared with the CVVHD group. The CVVH group also had a shorter mean ICU stay compared with the CVVHD group (mean difference −4.59 days, 95% CI −9.15 to −0.03 days). Conclusion Our results suggest that compared with CVVHD, CVVH may be associated with a lower risk of in-hospital mortality in patients with AKI who receive ECMO.

To determine the relationships between exposure to environmental contaminants in water and chronic kidney disease (CKD), we investigated the associations of 61 water attributes with the prevalence of CKD and End-Stage Renal Disease (ESRD) using data from 2005 to 2011 from all 22 counties and cities in the main island of Taiwan. We acquired patient information from the Taiwan Longitudinal Health Insurance Database to calculate the age-standardized CKD and ESRD prevalence rates and linked the patients&rsquo, residences to the water quality monitoring data, which were sampled periodically for a total of over 45,000 observations obtained from the Taiwan Environmental Water Quality Information Database. The association analysis adjusting for gender, age, and annual effects showed that the zinc (Zn), ammonia, chemical oxygen demand (COD), and dissolved oxygen in rivers were weakly correlated with CKD (&tau, = 0.268/0.250/0.238/&minus, 0.267, p = 6.01&times, 10&minus, 6/2.52&times, 5/6.05&times, 5/3.30&times, 5, respectively), but none for ESRD. The importances of Zn and COD in rivers were also demonstrated in a CKD regression model. Moreover, an unusually high CKD prevalence was related to arsenic contamination in groundwater. A further prospective cohort study would improve our understanding of what level of environmental water with risky properties could affect the development of CKD.

Genetic profiles of hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) in Asians remain elusive. A 10-year prospective cohort study was conducted with 1043 consecutive HCV Ab-positive Taiwanese surveyed with 13 single nucleotide polymorphisms (SNPs). Of 1043, 589 (56.5%) had baseline MC, 934 (89.5%) had positive HCV RNA, 796 completed anti-HCV therapy, and 715 had sustained virological responses (SVRs). SNP associations were surveyed withgenotypic, allelic, trend, permutation and multivariate analyses. At baseline, higher male sex and MC rates were noted in HCV RNA-positive than RNA-negative patients, higher female sex and positive HCV RNA rates but lower HCV RNA levels were noted in patients with than those without MC. Baseline associations were: HLA II-rs9461776 A allele, IFNL3-rs12979860 T allele, SERPINE1-rs6976053 C allele and MC with HCV RNA positivity, IFNL3-rs12979860 C allele, ARNTL-rs6486122 T allele and HCV RNA positivity with baseline MC. In SVR patients, RETN-rs1423096 C allele and SERPINE1-rs6976053 T allele were associated with 24-week and 10-year post-therapy MC, respectively. Conclusions: HCV RNA, IFNL3-rs12979860 and ARNTL-rs6486122 were associated with baseline MC, RETN-rs1423096 and SERPINE1-rs6976053 were associated with short- and long-term post-therapy MC in SVR patients, respectively. Links with HCV RNA and immune-associated SNPs suggest MC an immune reaction to expel HCV.

Background and Purpose— We investigated whether use of acupuncture within a 3-month poststroke period after hospital discharge is associated with reduced risk of depression. Methods— This cohort study included 16 046 patients aged ≥18 years with an initial hospitalization for stroke during 2000 and 2012 in the claims database of a universal health insurance program. Patients who had received acupuncture therapies within 3 months of discharge were defined as acupuncture users (n=1714). All patients were followed up for incidence of depression until the end of 2013. We assessed the association between use of acupuncture and incidence of depression using Cox proportional hazards models in all subjects and in propensity score–matched samples consisting of 1714 pairs of users and nonusers. Results— During the follow-up period, the incidence of depression per 1000 person-years was 11.1 and 9.7 in users and nonusers, respectively. Neither multivariable-adjusted Cox models (hazard ratio, 1.04; 95% confidence interval, 0.84–1.29) nor the propensity score-matching model (hazard ratio, 1.06; 95% confidence interval, 0.79–1.42) revealed an association between use of acupuncture and incidence of depression. Conclusions— In patients admitted to hospital for stroke, acupuncture therapy within 3 months after discharge was not associated with subsequent incidence of depression.

Over the past decades, the incidence of prostate cancer in Taiwan kept rising. Many possible factors including the utility of prostate specific antigen tests, lifestyle remodeling, and patient's comorbidities may contribute to the increasing of incidence or prostate cancer. We aim to use the nationwide Health and Welfare Database (HWD) to investigate possible associated factors.We used HWD, a nationwide database of medical information, to assess the incidence of prostate cancer, utilization of prostate-specific antigen (PSA) test, and underlying diseases of patients and to evaluate whether there was a common trend among these factors.In total, 32,508 patients with newly diagnosed prostate cancer from 2006 to 2013 were identified. The incidence rate of prostate cancer per 100,000 men increased from 35.47 in 2006 to 52.87 in 2012. The number of patients with prostate cancer and underlying diseases related to metabolic syndrome increased every year. The number of total PSA tests and patients undergoing PSA testing, as well as average times of PSA testing per person in the whole population, increased every year. The average PSA test times of patients with newly diagnosed prostate cancer within 3 years before the diagnosis of prostate cancer also increased every year. There was a high correlation between the average PSA test times and the number of patients with newly diagnosed prostate cancer (r = 0.9734).The trends of incidence of prostate cancer, utilization of PSA testing, and underlying diseases related to metabolic syndrome at the diagnoses of cancer were similar, increasing every year in the study period. The results suggested that increasing use of PSA tests may increase the diagnosis of prostate cancers. Underlying diseases related to metabolic syndrome might also affect the incidence of prostate cancer.

The prevalence of depression in patients with cancer is high, especially for patients with advanced cancer. In this study, we evaluated the prevalence of depression in prostate cancer patients in Taiwan and the association between depression and mortality in prostate cancer. This study included 1101 newly diagnosed patients with prostate cancer. We tracked the medical information of these patients from diagnosis until the end of 2012. Patients were divided into two groups according to presence or absence of depression diagnosis, and were further divided into three stages by initial treatments: localized or locally advanced, metastatic, and castration-resistant prostate cancer. Of 1101 participants, 267 (24.3%) had depression. By the end of the follow-up period (M = 8.30 ± 3.12 years), 77 (28.8%) patients in the depression group and 194 (23.3%) in the non-depressed group died. Depression was associated with higher mortality risk, (aHR 1.37, 95% CI [ 1.04–1.80], p value 0.01). Patients in the metastatic prostate cancer group with depression had a significantly higher mortality risk compared to the non-depressed group, (aHR, 1.49, 95% CI [1.05–2.11], p value 0.02). The impact of depression on mortality risk was not significant in either the localized or locally advanced or the castration-resistant prostate cancer groups. Our study showed that depression is related to an increased mortality risk for patients with prostate cancer, especially for metastatic prostate cancer. These results indicate that urologists should pay attention to the mood and psychiatric disorders of patients with prostate cancer.

Background: A beneficial effect of a ketoanalogue-supplemented low-protein diet (sLPD) in postponing dialysis has been demonstrated in numerous previous studies. However, evidence regarding its effect on long-term survival is limited. Our study assessed the long-term outcomes of patients on an sLPD after commencing dialysis. Methods: This retrospective study examined patients with new-onset end-stage renal disease with permanent dialysis between 2001 and 2013, extracted from Taiwan&rsquo, s National Health Insurance Research Database. Patients who received more than 3 months of sLPD treatment in the year preceding the start of dialysis were extracted. The outcomes studied were all-cause mortality, infection rate, and major cardiac and cerebrovascular events (MACCEs). Results: After propensity score matching, the sLPD group (n = 2607) showed a lower risk of all-cause mortality (23.1% vs. 27.6%, hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.70&ndash, 0.84), MACCEs (19.2% vs. 21.5%, HR 0.86, 95% CI 0.78&ndash, 0.94), and infection-related death (9.9% vs. 12.5%, HR 0.76, 95% CI 0.67&ndash, 0.87) than the non-sLPD group did. Conclusion: We found that sLPD treatment might be safe without long-term negative consequences after dialysis treatment.

Ying-Hsu Chang,1,2,* Su-Wei Chang,3,4,* Chung-Yi Liu,1,2 Po-Hung Lin,1,2 Kai-Jie Yu,1,2 See-Tong Pang,1,2 Cheng-Keng Chuang,1,2 Hung-Cheng Kan,1,2 I-Hung Shao1,2 1Division of Urology, Department of Surgery, LinKou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 4Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan *These authors contributed equally to this work Introduction: Renal cell carcinoma (RCC) is one of the most lethal urological malignancies, and surgeries remain the mainstay for localized RCC. This study aimed to compare the selection of open surgery and minimally invasive kidney surgery for RCCs for the aspects of complication, medical costs, and patient preference. Materials and methods: We conducted a population-based case–control study by using the National Health Insurance Research Database of Taiwan, which included data from 23 million Taiwanese residents. Patients newly diagnosed with RCC during 2006–2012 were included. We compared the general characteristics, underlying disease, complications, hospital stay, postoperative analgesic dosage, and medical costs between open group and minimally invasive group. Results: A total of 3,172 patients who received radical nephrectomy (RN) or partial nephrectomy (PN) for RCC were included. The mean age was 61.1 years, with a male to female ratio of 1.88. In the minimally invasive groups, the mean hospital stay was significantly shorter than in open groups (12.4 days in open RN versus 10.3 days in minimally invasive RN, and 9.7 days in open PN versus 8.2 days in minimally invasive PN). There was no significant difference between the medical costs and the incidence of major bleeding complication between the open group and the minimally invasive group. Female patients and patients with higher monthly income were more likely to receive minimally invasive surgery. Conclusion: During past decades, open RN has gradually been replaced by minimally invasive surgeries and PN. Compared to open surgeries, minimally invasive surgeries could lead to less postoperative pain and faster recovery. Economic status of the patients potentially hinders them from receiving minimally invasive surgeries, which may cost more. Keywords: renal cell carcinoma, minimally invasive, open surgery, complication, NHIRD

Background Although urinary neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a promising biomarker for the early detection of kidney injury, previous studies of adult patients who underwent cardiac surgery have reported only moderate discrimination. The age, creatinine, and ejection fraction (ACEF) score is a preoperative validated risk model with satisfactory accuracy for predicting AKI following cardiac surgery. It remains unknown whether combining preoperative risk assessment through ACEF scores followed by urinary NGAL test in a population of high-risk individuals is an optimal approach with improved predictive performance. Material and methods A total of 177 consecutive patients who underwent cardiac surgery were enrolled. Clinical characteristics, prognostic model scores, and outcomes were assessed. Urinary NGAL were examined within 6 hours after cardiac surgery. Patients were stratified according to preoperative ACEF scores, and comparisons were made using the area under the receiver operator characteristic curve (AUROC) for the prediction of AKI. Results A total of 45.8% (81/177) of the patients had AKI. As expected, patients with ACEF scores ≥ 1.1 were older and more likely to have class III or IV heart failure. They were also more likely to have diabetes mellitus, myocardial infarction, and peripheral arterial disease. Urinary NGAL alone moderately predicted AKI, with an AUROC of 0.732. Risk stratification by ACEF scores ≥ 1.1 substantially improved the AUROC of urinary NGAL to 0.873 (95% confidence interval, 0.784–0.961; P < .001). Conclusions Risk stratification by preoperative ACEF scores ≥ 1.1, followed by postoperative urinary NGAL, provides more satisfactory risk discrimination than does urinary NGAL alone for the early detection of AKI after cardiac surgery. Future studies should investigate whether this strategy could improve the outcomes and cost-effectiveness of care in patients undergoing cardiac surgery.

INTRODUCTION Phosphate level is often deranged during acute illness, regardless of the presence of kidney injury or not. A few studies described that hypophosphatemia may associated with outcome in patients admitted to the burn unit, but the literatures for hyperphosphatemia is limited. Our study aims to evaluate if hyperphosphatemia, one of the sign of severe tissue damage or kidney injury, will associate with mortality of patients with severe burns. MATERIALS AND METHODS The study was a post hoc analysis of prospectively collected data from patients admitted to the burn unit between September 2006 and December 2011. Patients were stratified into normophosphatemic or hyperphosphatemic group by baseline plasma phosphate level. The primary endpoint is 90-day mortality. RESULTS Total 301 patients were included (hyperphosphatemia: n = 52; normophosphatemia: n = 249). The hyperphosphatemic group had lower Glasgow Coma Scale, mean arterial blood pressure, hemoglobin level, albumin, and higher TBSA of burns, APACHE II score, ABSI score, Acute kidney injury (AKI), and creatinine. The 90-day mortality was higher in the hyperphosphatemic group than in the normal group (53.8% vs 18.1%, P < .001) and this difference was still significant when adjusting for several confounding factors (hazard ratio, 2.05; 95% CI, 1.17-3.59). Multivariable Cox analysis showed risk factors of mortality included TBSA of burns, hyperphosphatemia, reduced urine output, and APACHE II score. CONCLUSIONS Our study found in addition to TBSA of burns and inhalation injury, baseline hyperphosphatemia in patients with severe burns is also associated with higher mortality.

Background Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are severe drug-induced cutaneous adverse reactions with high mortality. Acute kidney injury (AKI) was a common complication in an SJS/TEN group and noted as an independent risk factor for mortality in patients with SJS/TEN. To determine whether AKI staging can predict the outcome of patients with SJS/TEN, we compared the discriminative power of an AKI KDIGO staging system with that of SCROTEN, APACHE II, APACHE III, and SOFA. Materials and methods We retrospectively analyzed the data of 75 patients who were diagnosed with SJS, TEN, or SJS/TEN overlap syndrome at a tertiary care university hospital between January 1, 2011 and December 31, 2014. The baseline characteristics, biochemical analysis data, medication use, and outcomes of the patients were assessed, and the discriminative ability for predicting mortality was determined for each prognostic model. Results Of the 75 patients, 23 (30.7%) had AKI, of whom 13 (56.5%) died during the index admission. Of the prognostic risk models analyzed, the KDIGO staging system showed similar discriminative ability in predicting in-hospital mortality as did the other models. In addition, combining KDIGO with other scoring systems yielded significantly more accurate risk prediction for in-hospital mortality compared with the other individual scores alone, as measured by net reclassification index. The patients with KDIGO stages 2 and 3 exhibited a significantly lower 1-year survival rate than did those with KDIGO stages 0 and 1. Conclusion AKI KDIGO staging has good discriminative ability and is easy to utilize for predicting mortality.

Background How hepatitis C virus (HCV)–associated lipid metabolic alterations recover after sustained virological response (SVR) remains elusive. Objective The aforementioned recovery pattern was investigated. Methods In a prospective cohort study of 438 chronic hepatitis C (CHC) patients with SVR after anti-HCV therapy, 164 sex- and age-matched genotype I (G1) and G2 patients underwent paired-serum liquid chromatography-tandem mass spectrometry analyses before and 24 weeks after therapy. Subjects without CHC served as controls (n = 100). Results CHC patients had lower baseline lipid levels than controls. Among CHC patients, pre-therapy total cholesterol levels were positively associated with HCV RNA levels; G1 patients had higher pre-therapy HCV RNA levels than G2 patients. Repeated measures analysis of variance of CHC patients showed that lathosterol, lanosterol, total hydroxysphingomyelin, and total phosphatidylcholines levels, and total dicarboxyacylcarnitine/total acylcarnitine (indicators of ω-oxidation) and pre-β-lipoprotein ratios elevated 24 weeks after therapy compared with the levels before therapy. Levels of total lysophosphatidylcholines and α- and β-lipoprotein ratios decreased. Subgroup analyses showed elevated 7-dehydrocholesterol and lanosterol levels, particularly in G2 and male patients, who had broader spectra of altered phosphatidylcholines and acylcarnitines than G1 and female patients, respectively. Compared with controls, CHC patients had higher post-therapy levels of total lysophosphatidylcholines and hydroxysphingomyelins and ratios of total dicarboxyacylcarnitines/total acylcarnitines but lower cholesterol levels. Conclusions At 24 weeks after therapy, accelerated cholesterol biosynthesis, hepatic lipid export, ω-oxidation, and decreased systemic inflammation were noted in CHC patients with SVR, with greater efficiency in G2 and male patients. Regardless, HCV-associated lipid metabolic alterations required >24 weeks for restoration or were incompletely reversible after SVR.

Background Mortality after coronary artery bypass grafting (CABG) is generally associated with underlying disease and surgical factors overlooked in preoperative prognostic models. Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE II) scores are widely used in intensive care units for outcome prediction. This study investigated the accuracy of these models in predicting mortality. Methods Between January 2010 and April 2013, 483 patients who underwent isolated CABG were enrolled. The clinical characteristics, outcomes, and prognostic model scores of the patients were collected. Discrimination was assessed using the area under the curve approach. Results Both SOFA and APACHE II scores were effective for predicting in-hospital mortality. Among the organ systems examined in the SOFA, the cardiac and renal systems were the strongest predictors of CABG mortality. Multivariate analysis identified only the SOFA score as being an independent risk factor for mortality. Conclusion In summary, the SOFA score can be used to accurately identify mortality after isolated CABG.

Exposure to tobacco smoke has been associated with harmful effects on child health. The association between tobacco smoke exposure and childhood rhinitis has not been established in developed or developing countries. We investigated the association between serum cotinine levels and rhinitis in a population sample of 1,315 Asian children. Serum cotinine levels were positively associated with rhinitis ever (adjusted odds ratio [AOR] = 2.95; 95% confidence interval [CI]: 1.15–7.60) and current rhinitis (AOR = 2.71; 95% CI: 1.07–6.89), while the association for physician-diagnosed rhinitis approaching borderline significance (AOR = 2.26; 95% CI: 0.88–5.83). Stratified analyses demonstrated significant association of serum cotinine levels with current rhinitis among children without allergic sensitization (AOR = 6.76; 95% CI: 1.21–37.74), but not among those with allergic sensitization. Serum cotinine levels were positively associated with rhinitis ever (AOR = 3.34; 95% CI: 1.05–10.61) and current rhinitis (AOR = 4.23; 95% CI: 1.28–13.97) among adolescents but not in children aged less than 10 years. This population-based study demonstrates supportive evidence for positive association of tobacco smoke exposure with rhinitis, while the effect is mainly confined to non-allergic rhinitis and more pronounced in adolescents than in young children, highlighting the need for raising public health awareness about the detrimental effects of tobacco smoke exposure on children’s respiratory health.

Background: Urinary calprotectin is a novel biomarker that distinguishes between intrinsic or prerenal acute kidney injury (AKI) in different studies. However, these studies were based on different populations and different AKI criteria. We evaluated the diagnostic accuracy of urinary calprotectin and compared its diagnostic performance in different AKI criteria and study populations. Method: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched PubMed, Embase, and the Cochrane database up to September 2018. The diagnostic performance of urinary calprotectin (sensitivity, specificity, predictive ratio, and cutoff point) was extracted and evaluated. Result: This study included six studies with a total of 502 patients. The pooled sensitivity and specificity were 0.90 and 0.93, respectively. The pooled positive likelihood ratio (LR) was 15.15, and the negative LR was 0.11. The symmetric summary receiver operating characteristic (symmetric SROC) with pooled diagnostic accuracy was 0.9667. The relative diagnostic odds ratio (RDOC) of the adult to pediatric population and RDOCs of different acute kidney injury criteria showed no significant difference in their diagnostic accuracy. Conclusion: Urinary calprotectin is a good diagnostic tool for the discrimination of intrinsic and prerenal AKI under careful inspection after exclusion of urinary tract infection and urogenital malignancies. Its performance is not affected by different AKI criteria and adult or pediatric populations.

Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan's Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.

Recovery of amino acid (AA) metabolism and the associated clinical implications in chronic hepatitis C (CHC) patients with sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remains elusive. A prospective cohort study was conducted on 222 CHC patients with SVR. Eighty-two age-matched male genotype 1 (G1) and G2 patients underwent paired serum metabolomics analyses with liquid chromatography–tandem mass spectrometry to examine AAs before and 24 weeks after anti-HCV therapy. Before anti-HCV therapy, G1 patients had a higher HCV RNA level than G2 patients. Twenty-four weeks post-therapy versus pre-therapy, repeated-measures ANOVA showed that the levels of alanine aminotransferase and most AAs decreased while those of lipids, glutamine and putrescine increased in CHC patients. The methionine sulfoxide/methionine ratio decreased, while the asymmetric dimethylarginine/arginine, glutamine/glutamate, citrulline/arginine, ornithine/arginine, kynurenine/tryptophan, tyrosine/phenylalanine and Fisher’s ratios increased. Genotype-specific subgroup analyses showed that valine and serotonin/tyrosine increased in G1 and that kynurenine and tyrosine/phenylalanine increased and sarcosine decreased in G2 patients. Viral clearance in CHC patients pan-genotypically restored fuel utilization by decelerating the tricarboxylic acid cycle. Following improvement in liver function, the urea, nitric oxide, methionine, and polyamine cycles were accelerated. The cardiometabolic risk attenuated, but the augmented kynurenine pathway activity could increase the oncogenesis risk. The trends in neurotransmitter formation differed between G1 and G2 patients after SVR. Moreover, the HCV-suppressing effect of valine was evident in G1 patients; with the exception of prostate cancer, the oncogenesis risk increased, particularly in G2 patients, at least within 24 weeks post-anti-HCV therapy.

Unrelated cord blood transplantation has become a reliable alternative therapy for children and adults owing to that one or two antigen/allele mismatches between a patient and the cord blood donor are acceptable without occurrence of graft-versus-host disease. To investigate the relationship between the number and types of mismatches and relapse, we compared the number of mismatched and non-mismatched donor-recipient pairs, number of mismatched alleles, and number of mismatched antigens at each of the Human Leukocyte Antigen (HLA) -A, -B, and -DR loci, respectively. The result indicates that the number of mismatched antigens at the HLA-A locus was significantly associated with occurrence of relapse (X2P-value=0.0243; RR=1.49, 95% CI: 1.04-2.13). Additionally, the number of mismatched donor-recipient pairs and the number of mismatched alleles at the HLA-DR locus was negatively associated with risks of relapse (X2P-value=0.0028; RR=0.52, 95% CI: 0.31-0.89). In this study, we found that the mismatch at the HLA-A locus is associated with increased risk of relapse; while the mismatch at the HLA-DR locus is innocuous. Hence, we suggest that the well-matched HLA-A alleles were most critical for matching HLA alleles between umbilical-cord blood transplantation donors and recipients. In other words, cord blood transplantation requires less stringent HLA matching, if there are two 5/6 or 4/6 HLA matched donors, it's better to choose HLA-A matched donor at least.

Disease relapse occurs in unrelated cord blood transplantation (CBT) even when the alleles of human leukocyte antigen (HLA) are fully matched between donor and recipient. This is similar to that observed in other types of hematopoietic stem cell transplantation. Fourteen single nucleotide polymorphisms (SNPs) within the HLA region have been reported previously by Petersdorf et al. and Piras et al. as transplantation determinants in unrelated hematopoietic cell transplantation. In this study, the genomic sequences within 500 base pairs upstream and downstream of the fourteen transplantation-related SNPs from 53 patients and their HLA-matched unrelated donors were analyzed for determining whether or not genetic variants, conferred by either recipient or donor SNP genotype or by recipient-donor SNP mismatching, were associated with the risk of relapse. Seven SNPs were associated with the risk of relapse in unrelated CBT. These included the donor genotype with the SNPs of rs2523675 and rs2518028 at the telomeric end of HCP5 gene, rs2071479 in the intron of the HLA-DOB gene, and rs2523958 in the MICD gene; and the recipient genotype with SNPs of rs9276982 in the HLA-DOA gene, and rs435766 and rs380924 in the MICD gene. As measured by pair-wise linkage disequilibrium (LD) withD′ as the parameter for normalized standard measurement of LD which compares the observed and expected frequencies of one haplotype comprised by alleles at different loci, rs2523675 had high LD with rs4713466 (D′ = 0.86) and rs2523676 (D′ = 0.91) in the HCP5 gene. The rs2518028 had no LD with all other SNPs except rs2523675 (D′ = 0.76). This study provides the basis for developing a method or algorithm for selecting better unrelated CBT candidate donors.

Importance Varicose veins are common but rarely associated with serious health risks. Deep venous thrombosis (DVT), pulmonary embolism (PE), and peripheral artery disease (PAD) are also vascular diseases but associated with serious systemic effects. Little is known about the association between varicose veins and the incidence of other vascular diseases including DVT, PE, and PAD. Objective To investigate whether varicose veins are associated with an increased risk of DVT, PE, or PAD. Design, Setting, and Participants A retrospective cohort study using claims data from Taiwan’s National Health Insurance program. Patients aged 20 years and older with varicose veins were enrolled from January 1, 2001-December 31, 2013, and a control group of patients without varicose veins were matched by propensity score. Patients previously diagnosed with DVT, PE, or PAD were excluded. Follow-up ended December 31, 2014. Exposures Presence of varicose veins. Main Outcomes and Measures Incidence rates of DVT, PE, and PAD were assessed in people with and without varicose veins. Cox proportional hazards models were used to estimate relative hazards, with the control group as reference. Results There were 212 984 patients in the varicose veins group (mean [SD] age, 54.5 [16.0] years; 69.3% women) and 212 984 in the control group (mean [SD] age, 54.3 [15.6] years; 70.3% women). The median follow-up duration was 7.5 years for DVT, 7.8 years for PE, and 7.3 years for PAD for patients with varicose veins, and for the control group, follow-up duration was 7.6 years for DVT, 7.7 years for PE, and 7.4 years for PAD. The varicose veins group had higher incidence rates than the control group for DVT (6.55 vs 1.23 per 1000 person-years [10 360 vs 1980 cases]; absolute risk difference [ARD], 5.32 [95% CI, 5.18-5.46]), for PE (0.48 for the varicose veins group vs 0.28 for the control group per 1000 person-years [793 vs 451 cases]; ARD, 0.20 [95% CI, 0.16-0.24]), and for PAD (10.73 for the varicose veins group vs 6.22 for the control group per 1000 person-years [16 615 vs 9709 cases]; ARD, 4.51 [95% CI, 4.31-4.71]). The hazard ratios for the varicose veins group compared with the control group were 5.30 (95% CI, 5.05-5.56) for DVT, 1.73 (95% CI, 1.54-1.94) for PE, and 1.72 (95% CI, 1.68-1.77) for PAD. Conclusions and Relevance Among adults diagnosed with varicose veins, there was a significantly increased risk of incident DVT; the findings for PE and PAD are less clear due to the potential for confounding. Whether the association between varicose veins and DVT is causal or represents a common set of risk factors requires further research.

Background Although there is evidence that exposure to tobacco smoke is harmful to children's respiratory health, the effects of tobacco smoke exposure on the regulation of immunoglobulin E (IgE)-mediated immune responses to specific allergens remain unclear. This study aimed to investigate the relationship between objectively assessed tobacco smoke exposure and specific IgE profiles for a broad spectrum of allergens in a population setting. Methods Children aged 5–18 years (N = 1315) were assessed using serum cotinine measurement and microarray-based multiplexed detection of specific IgE against 40 allergens. Results Serum cotinine levels were positively associated with sensitization to foods (adjusted odds ratio [AOR] = 4.95; 95% CI: 1.59–15.34), cockroaches (AOR = 3.77; 95% CI: 1.49–9.51), and pollen (AOR = 2.84; 95% CI: 1.20–6.73) while the association was borderline significant for animals (AOR = 2.53; 95% CI: 0.92–6.93). No associations were found for sensitization against mites, mold, and latex. When considering the degree of allergic sensitization, serum cotinine levels were positively correlated to the number of sensitization to cockroaches (P = 0.004), pollen (P = 0.006), and foods (P < 0.001), with statistically significant positive dose–response relationships (all P < 0.01). Similar results were observed when summing up specific IgE concentrations for the aforementioned allergen categories. Conclusions The association between tobacco smoke exposure and IgE sensitization to environmental allergens varies for different allergens among children. This study demonstrates that elevated serum cotinine levels are significantly associated with IgE sensitization to cockroaches, grass pollen, and certain foods, with potential dose-dependent relationships.

Background: Acute kidney injury (AKI) after cardiac surgery is associated with short-term and long-term adverse outcomes. Novel biomarkers have been identified for the early detection of AKI; however, examining these in every patient who undergoes cardiac surgery is prohibitively expensive. Society of Thoracic Surgeons (STS) and Age, Creatinine, and Ejection Fraction (ACEF) scores have been proven to predict mortality in bypass surgery. The aim of this study was to determine whether these scores can be used to predict AKI after mitral valve repair. Materials and Methods: Between January 2010 and December 2013, 196 patients who underwent mitral valve repair were enrolled. The clinical characteristics, outcomes, and scores of prognostic models were collected. The primary outcome was postoperative AKI, defined using the Kidney Disease Improving Global Outcome 2012 clinical practice guidelines for AKI. Results: A total of 76 patients (38.7%) developed postoperative AKI. The STS renal failure (AUROC: 0.797, P < .001) and ACEF scores (AUROC: 0.758, P < .001) are both satisfactory tools for predicting all AKI. The STS renal failure score exhibited superior accuracy compared with the ACEF score in predicting AKI stage 2 and 3. The overall accuracy of both scores was similar for all AKI and AKI stage 2 and 3 when the cut-off points of the STS renal failure and ACEF scores were 2.2 and 1.1, respectively. Conclusion: In conclusion, the STS renal failure score can be used to accurately predict stage 2 and 3 AKI after mitral valve repair. The ACEF score is a simple tool with satisfactory power in screening patients at risk of all AKI stages. Additional studies can aim to determine the clinical implications of combining preoperative risk stratification and novel biomarkers.

Background The current literature focusing on the effect of obesity and overweight on lung function and fraction of exhaled nitric oxide (FeNO) in children, particularly among healthy children of non-European descent, remains controversial. Furthermore, whether the relationship of obesity and overweight with lung function and FeNO in children is modified by atopy is unclear. The objective of this study was to examine the effect of excess weight on lung function parameters and FeNO among Asian children, with a particular focus on exploring the potential effect modification by atopy. Methods We investigated the effect of excess weight on lung function and FeNO in a population sample of 1,717 children aged 5 to 18 years and explored the potential modifying effect of atopy. Results There were positive associations of body mass index (BMI) z-score with forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF), and forced expiratory flow at 25–75% (FEF25-75) (all P

Acute kidney injury (AKI) is overlooked in patients with pulmonary embolism (PE). Risk factors for and long-term outcomes of this complication remain unknown. This study evaluated the predictors and prognosis of AKI in patients with PE.This retrospective cohort study used Taiwan's National Health Insurance Research Database. We enrolled a total of 7588 patients who were admitted to a hospital for PE from January1997 to December 2011 and administered anticoagulation or thrombolytic agents. All demographic data, risk factors, and outcomes were analyzed.AKI was diagnosed in 372 (4.9%) patients. Multivariate logistic regression analysis revealed pre-existing chronic kidney disease, hypertension, diabetes mellitus, massive PE, anemia, and sepsis as independent risk factors for AKI. In the long-term follow-up, the survival rate was similar in the AKI and non-AKI groups.Careful risk factor screening and intensive intervention in patients with AKI might yield outcomes similar to those in patients without AKI.

Objectives Acute kidney injury (AKI) after coronary artery bypass grafting (CABG) is associated with short-term and long-term adverse outcomes. The European System for Cardiac Operative Risk Evaluation (EuroSCORE), EuroSCORE II, the Society of Thoracic Surgeons (STS) score and Age, Creatinine and Ejection Fraction (ACEF) score, have been widely used for predicting the operative risk of cardiac surgery. The aim of this study is to investigate the discriminant ability among current available models in predicting postoperative AKI. Methods From January 2010 to December 2012, 353 patients who underwent isolated CABG were enrolled. The clinical characteristics, outcomes and scores of prognostic models were collected. The primary outcome was postoperative AKI, defined based on the Kidney Disease Improving Global Outcome (KDIGO) Clinical Practice Guideline for AKI, in 2012. Results 102 patients (28.9%) developed postoperative AKI. For AKI prediction, EuroSCORE II, STS score and ACEF score were all good tools for stage-3 AKI. The ACEF score was shown to have satisfied discriminant ability to predict postoperative AKI with area under a receiver operating characteristic curve: 0.781±0.027, (95% CI 0.729 to 0.834, p value

Introduction Ankylosing spondylitis (AS) is a familial, heritable disease specified by syndesmophyte formation leading to an ankylosed spine. Endoplasmic reticulum aminopeptidase 1 (ERAP1) genetic variations have been widely proved to be associated with AS in several ethnic populations. The aim of this study was to investigate whether ERAP1 single nucleotide polymorphisms (SNPs) are associated with AS susceptibility and disease severity in Taiwanese. Methods Four ERAP1 SNPs (rs27037, rs27980, rs27044 and rs30187) were genotyped in 797 Taiwanese AS patients and 1,150 healthy controls. Distributions of genotype and alleles were compared between AS patients and healthy controls, and among AS patients stratified by clinical parameters. Results The SNP rs27037T allele appeared to be a risk factor for AS susceptibility (P = 5.5 × 10-5, OR 1.30, 95% CI: 1.15 to 1.48; GT+TT vs. GG P = 9.3 × 10-5, OR 1.49, 95% CI: 1.22 to 1.82). In addition, the coding SNP (cSNP) rs27044G allele (P = 1.5 × 10-4, OR 1.28, 95% CI: 1.13 to 1.46; CG+GG vs. CC, P = 1.7 × 10-3, OR 1.44, 95% CI: 1.15 to 1.81) and the cSNP rs30187T allele (P = 1.7 × 10-3, OR 1.23, 95% CI: 1.08 to 1.40; CT+TT vs. CC P = 6.1 × 10-3, OR 1.38, 95% CI: 1.10 to 1.74) were predisposing factors for AS. Notably, the rs27044G allele carriers (CG+GG vs. CC, P = 0.015, OR 1.59, 95% CI: 1.33 to 2.30) and rs30187T allele carriers (CT+TT vs. CC, P = 0.011, OR 1.63, 95% CI: 1.12 to 2.38) were susceptible to syndesmophyte formation in AS patients. Furthermore, two cSNPs (rs27044 and rs30187) strongly associated with HLA-B27 positivity in AS patients. Finally, the ERAP1 SNP haplotype TCG (rs27037T/rs27980C/rs27044G) is a major risk factor for AS (adjusted P

BACKGROUND: Graves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR] = 1.33, Bonferroni corrected combined P [P(Bc)] = 1.17 x 10⁻²), DPB1*05:01 (OR = 2.34, P(Bc) = 2.58 x 10⁻¹⁰), DQB1*03:02 (OR = 0.62, P(Bc) = 1.97 x 10⁻²), DRB1*15:01 (OR = 1.68, P(Bc) = 1.22 x 10⁻²) and DRB1*16:02 (OR = 2.63, P(Bc) = 1.46 x 10⁻⁵) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk. CONCLUSIONS/SIGNIFICANCE: These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation.

We examined the properties of growth mixture modeling in finding longitudinal quantitative trait loci in a genome-wide association study. Two software packages are commonly used in these analyses: Mplus and the SAS TRAJ procedure. We analyzed the 200 replicates of the simulated data with these programs using three tests: the likelihood-ratio test statistic, a direct test of genetic model coefficients, and the chi-square test classifying subjects based on the trajectory model's posterior Bayesian probability. The Mplus program was not effective in this application due to its computational demands. The distributions of these tests applied to genes not related to the trait were sensitive to departures from Hardy-Weinberg equilibrium. The likelihood-ratio test statistic was not usable in this application because its distribution was far from the expected asymptotic distributions when applied to markers with no genetic relation to the quantitative trait. The other two tests were satisfactory. Power was still substantial when we used markers near the gene rather than the gene itself. That is, growth mixture modeling may be useful in genome-wide association studies. For markers near the actual gene, there was somewhat greater power for the direct test of the coefficients and lesser power for the posterior Bayesian probability chi-square test.

The power of linkage analysis of a quantitative disease endophenotype was compared for the following family selection designs: 1) Random samples: randomly chosen nuclear families, 2) "coronary artery calcification (CAC)" samples: selection of each nuclear family through a proband with abnormally high levels of the simulated quantitative endophenotype, CAC, and (3) "MI" samples: selection of each nuclear family through a disease affected proband, in this case a proband who had been simulated to have a myocardial infarction (MI) event. We assessed the power to detect linkage to five loci (two pairs of epistatic loci and one locus with an over-dominant allele) that were modeled as determinants of the simulated CAC levels. We did this using a Haseman-Elston regression-based linkage analysis of the adjusted CAC levels that considered each locus separately and then used a multiple regression extension of the Haseman-Elston method in which we considered the allele sharing at two true epistatic loci simultaneously and their interaction as possible factors related to the squared sibpair differences in adjusted CAC. Based on comparison of the mean square root of the LOD scores, there was no one sampling design that resulted in consistently greater power for these five loci. That is, we observed significant locus-by-sampling-design interaction (p < 0.0001). We noted however, that the largest average score was observed for the epistasis between τ3 and τ4 (mean > 1.8, SE = 0.06) in the MI-selected samples and the CAC-selected samples.