A novel approach to quantifying individual's biological aging using Korea's national health screening program toward precision public health.

Accurate prediction of biological age can inform public health measures to extend healthy lifespans and reduce chronic conditions. Multiple theoretical models and methods have been developed; however, their applicability and accuracy are still not extensive. Here, we report Differential Aging and Health Index (DAnHI), a novel measure of age deviation, developed using physical and serum biomarkers from four million individuals in Korea's National Health Screening Program. Participants were grouped into aging statuses (< 26 vs. ≥ 26, < 27 vs. ≥ 27, …, < 75 vs. ≥ 75 years) as response variables in a binary logistic regression model with thirteen biomarkers as independent variables. DAnHI for each individual was calculated as the weighted mean of their relative probabilities of being classified into each older age status, based on model ages ranging from 26 to 75. DAnHI in our large study population showed a steady increase with the increase in age and was positively associated with death after adjusting for chronological age. However, the effect size of DAnHI on the risk of death varied according to the age group and sex. The hazard ratio was highest in the 50-59-year age group and then decreased as the individuals aged. This study demonstrates that routine health check-up biomarkers can be integrated into a quantitative measure for predicting aging-related health status and death via appropriate statistical models and methodology. Our DAnHI-based results suggest that the same level of aging-related health status does not indicate the same degree of risk for death.

Predictability of Macrosomic Birth based on Maternal Factors and Fetal Aneuploidy Screening Biochemical Markers in Hyperglycemic Mothers.

Background: Macrosomic birth weight has been implicated as a significant risk factor for developing various adult metabolic diseases such as diabetes mellitus and coronary heart diseases; it has also been associated with higher incidences of complicated births. This study aimed to examine the predictability of macrosomic births in hyperglycemic pregnant women using maternal clinical characteristics and serum biomarkers of aneuploidy screening performed in the first half of pregnancy. Methods: A retrospective observational study was performed on a cohort of 1,668 pregnant women who 1) had positive outcomes after undergoing 50-g oral glucose challenge test (OGCT) at two university-based hospitals and 2) underwent any one of the following maternal biomarker screening tests for fetal aneuploidy: triple test, quadruple test, and integrated test. Logistic regression-based models for predicting macrosomic births using maternal characteristics and serum biomarkers were developed and evaluated for prediction power. A nomogram, which is a graphical display of the best predictable model, was then generated. Results: The study cohort included 157 macrosomic birth cases defined as birth weight ≥3,820 g, which was equivalent to the top 10 percentile of the modeling cohort. Three primary models solely based on serum biomarkers achieved area under curves (AUCs) of 0.55-0.62. Expanded models, including maternal demographic and clinical factors, demonstrated an improved performance by 25% (AUCs, 0.69-0.73). Conclusion: Our prediction models will help to identify pregnancies with an elevated risk of macrosomic births in hyperglycemic mothers using maternal clinical factors and serum markers from routine antenatal screening tests. Prediction of macrosomic birth at mid-pregnancy may allow customized antenatal care to reduce the risk of macrosomic births.

Prognostic effects of cytokine levels on patients treated with taxane and zoledronic acid for metastatic breast cancer in bone (BEAT-ZO) (KCSG BR 10-13).

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-ß1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-ß1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-ß1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-ß1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy.

The Clinical Usefulness of Predictive Models for Preterm Birth with Potential Benefits: A KOrean Preterm collaboratE Network (KOPEN) Registry-Linked Data-Based Cohort Study.

Background: Preterm birth is strongly associated with increasing mortality, incidence of disability, intensity of neonatal care required, and consequent costs. We examined the clinical utility of the potential preterm birth risk factors from admitted pregnant women with symptomatic preterm labor and developed prediction models to obtain information for prolonging pregnancies. Methods: This retrospective study included pregnant women registered with the KOrean Preterm collaboratE Network (KOPEN) who had symptomatic preterm labor, between 16 and 34 gestational weeks, in a tertiary care center from March to November 2016. Demographics, obstetric and medical histories, and basic laboratory test results obtained at admission were evaluated. The preterm birth probability was assessed using a nomogram and decision tree according to birth gestational age: early preterm, before 32 weeks; late preterm, between 32 and 37 weeks; and term, after 37 weeks. Results: Of 879 registered pregnant women, 727 who gave birth at a designated institute were analyzed. The rates of early preterm, late preterm, and term births were 18.16%, 44.02%, and 37.83%, respectively. With the developed nomogram, the concordance index for early and late preterm births was 0.824 (95% CI: 0.785-0.864) and 0.717 (95% CI: 0.675-0.759) respectively. Preterm birth was significantly more likely among women with multiple pregnancy and had water leakage due to premature rupture of membrane. The prediction rate for preterm birth based on decision tree analysis was 86.9% for early preterm and 73.9% for late preterm; the most important nodes are watery leakage for early preterm birth and multiple pregnancy for late preterm birth. Conclusion: This study aims to develop an individual overall probability of preterm birth based on specific risk factors at critical gestational times of preterm birth using a range of clinical variables recorded at the initial hospital admission. Therefore, these models may be useful for clinicians and patients in clinical decision-making and for hospitalization or lifestyle coaching in an outpatient setting.

Introduction of Fall Risk Assessment (FRA) System and Cross-Sectional Validation Among Community-Dwelling Older Adults.

OBJECTIVE: To predict the risk of falls, Fall Risk Assessment (FRA) system has been newly developed to measure multi-systemic balance control among community-dwelling older adults. The aim of this study was to examine the association between FRA and fall-related physical performance tests. METHODS: A total of 289 community-dwelling adults aged 65 years and older participated in this cross-sectional study. All participants underwent FRA test and physical performance tests such as Short Physical Performance Battery (SPPB), Berg Balance Scale (BBS), and Timed Up and Go Test (TUG). RESULTS: Participants who were younger, male, highly educated, living with family members, having high body mass index, having high appendicular lean mass index, and having no irritative lower urinary tract syndrome were more likely to have higher FRA scores. SPPB (ß=1.012), BBS (ß=0.481), and TUG (ß=-0.831) were significantly associated with FRA score after adjusting for the variables (all p<0.001). CONCLUSION: FRA composite score was closely correlated with SPPB, BBS, and TUG, suggesting that FRA is a promising candidate as a screening tool to predict falls among community-dwelling elderly people.

Predicting risk of type 2 diabetes mellitus in Korean adults aged 40-69 by integrating clinical and genetic factors.

AIMS: The purpose of our investigation was to identify the genetic and clinical risk factors of type 2 diabetes mellitus (T2DM) and to predict the incidence of T2DM in Korean adults aged 40-69 at follow-up intervals of 5, 7, and 10years. METHODS: Korean Genome and Epidemiology Study (KoGES) cohort data (n=10,030) were used to develop T2DM prediction models. Both clinical-only and integrated (clinical factors+genetic factors) models were derived using the Cox proportional hazards model. Internal validation was performed to evaluate the prediction capabilities of the clinical and integrated models. RESULTS: The clinical model included 10 selected clinical risk factors. The selected SNPs for the integrated model were rs9311835 in PTPRG, rs10975266 in RIC1, rs11057302 in TMED2, rs17154562 in ADAM12, and rs8038172 in CGNL1. For the clinical model, validated c-indices with time points of 5, 7, and 10 years were 0.744, 0.732, and 0.732, respectively. Slightly higher validated c-indices were observed for the integrated model at 0.747, 0.736, and 0.738, respectively. The p-values of the survival net reclassification improvement (NRI) for the SNP point-based score were statistically significant. CONCLUSIONS: Clinical and integrated models can be effectively used to predict the incidence of T2DM in Koreans.

Calf Circumference as a Screening Tool for Cognitive Frailty in Community-Dwelling Older Adults: The Korean Frailty and Aging Cohort Study (KFACS).

The aim of this study was to examine calf circumference in relation to cognitive frailty in community-dwelling older adults. Cross-sectional analysis was performed on the first-year baseline data of 1559 adults aged 70⁻84 years enrolled in the Korean Frailty and Aging Cohort Study. The final analysis included 1221 adults who were non-dependent in terms of instrumental activities of daily living, who underwent frailty and cognitive function assessments. Physical frailty was defined using the Fried Frailty Index. Cognitive impairment was defined as a score 1.5 standard deviations below the age-, sex- and education-matched norms on any of four cognitive-function tests. The prevalence of cognitive frailty was 2.8% for men and 3.8% for women. After adjusting for potential confounders, in comparison to the "physically robust without cognitive impairment" group, the estimates of increased odds ratios (ORs) for low calf circumference (<32 cm) were much greater in the prefrail with cognitive impairment (OR 4.62, 95% confidence interval (CI): 2.02⁻10.61) and frail with cognitive impairment (OR 10.94, 95% CI: 2.87⁻41.68) groups in men but not in women. Low calf circumference was strongly related to cognitive frailty in men only, suggesting calf circumference can be used as an indicator of these outcomes.

Modified Criteria for Diagnosing "Cognitive Frailty".

The concept of cognitive frailty has recently been proposed by an International Consensus Group as the presence of physical frailty and cognitive impairment [defined using the Clinical Dementia Ratings (CDR)=0.5], without concurrent dementia. However, CDR is difficult to implement and not often available in epidemiologic studies or busy clinical settings, and an alternative to CDR is required. We suggest an alternative definition of cognitive frailty as: 1) physical frailty, 2) more than 1.5 standard deviation below the mean for age-, gender-, and education-adjusted norms on any cognitive function test (e.g., the Montreal Cognitive assessment test, the Alzheimer's disease assessment scale-cognitive subscale, verbal learning test, Digit Span, Boston Naming Test, Trail Making Test, and Frontal Assessment Battery), and 3) no dependency in instrumental activities of daily living. The redefined criteria for cognitive frailty would be more feasible to implement and thus more applicable in epidemiologic studies and busy clinical settings.

The Association Between the Number of Natural Remaining Teeth and Appendicular Skeletal Muscle Mass in Korean Older Adults.

BACKGROUND: The aim of this study was to examine the correlation between the number of remaining natural teeth (NRT) and the appendicular skeletal muscle mass index (SMI) in older adults. METHODS: This study was based on data from the 2008-2010 Korea National Health and Nutritional Examination Surveys. The participants were 2,378 older participants (984 men and 1,394 women) aged over 65 years. Survey dentists conducted oral health examinations, and ASM was measured using dual-energy X-ray absorptiometry. RESULTS: The participants with NRT≥20 had more ASM and SMI than those with NRT<20 in both sexes. SMI was correlated with NRT in men (r=0.018, p<0.001) and in women (r=-0.007, p<0.001). The positive correlation between the NRT and SMI remained significant in men even after adjusting for age, marital status, income, smoking, drinking, physical activity, protein intake, energy intake, calcium intake, body mass index, fasting blood glucose level, medications, and prostheses (ß=0.011, p=0.001). In women, the correlation disappeared after adjustment for smoking, alcohol, physical activity, protein intake, energy intake, calcium intake, marital status, income, fasting basal glucose, medication administration, and prostheses. CONCLUSION: This study showed a correlation between NRT and SMI in those ≥65 years of age in Korea. The relationship persisted in men, but not in women, even after adjusting for confounders.

Is Helicobacter pylori Associated Functional Dyspepsia Correlated With Dysbiosis?

BACKGROUND/AIMS: To assess the long-term effect of Helicobacter pylori eradication on symptomatic improvement according to the type of antibiotic and the duration of treatment in H. pylori-associated functional dyspepsia. METHODS: We searched Pubmed, Embase, CINAHL, and the Cochrane library databases for randomized controlled trials written in English and undertaken up to August 2016 that met our eligibility criteria. The search methodology used combinations of the following keywords: Helicobacter pylori OR H. pylori OR HP; dyspepsia OR functional dyspepsia OR non-ulcer dyspepsia; eradication OR cure OR treatment. The study outcome was the summary odds ratio (OR) for symptomatic improvement in H. pylori-associated functional dyspepsia with successful eradication therapy. Subgroup analyses were performed based on the type of antibiotic, and the duration of treatment, whether or not patients had symptoms of irritable bowel syndrome, and on race. RESULTS: Sixteen randomized controlled trials met the inclusion criteria. The summary OR for symptomatic improvement in patients in our eradication group was 1.33 (95% confidence interval [CI], 1.16-1.54; P < 0.01). In a subgroup analysis on type of antibiotic, symptomatic improvement with metronidazole-containing regimen (OR, 1.87; 95% CI, 1.26-2.77) was better than treatment with clarithromycin (OR, 1.29; 95% CI, 1.11-1.50). H. pylori eradication therapy given for 10-14 days was the more effective for symptom improvement than 7-day therapy. When the studies excluding irritable bowel syndrome cases were analyzed, there were no therapeutic effects of H. pylori eradication on symptomatic improvement. CONCLUSIONS: In the clinical setting, the most effective H. pylori eradication regimen for functional dyspepsia to provide relief of symptoms is a metronidazole-based treatment regimen for at least 10 days. The explanation for this is that H. pylori-associated functional dyspepsia could be associated with dysbiosis.

Corticosteroids for tuberculous pleurisy.

BACKGROUND: Corticosteroids used in addition to antituberculous therapy have been reported to benefit people with tuberculous pleurisy. However, research findings are inconsistent and raise doubt as to whether such treatment is worthwhile. There is also concern regarding the potential adverse effects of corticosteroids, especially in HIV-positive people. OBJECTIVES: To evaluate the effects of adding corticosteroids to drug regimens for tuberculous pleural effusion. SEARCH METHODS: In April 2016, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library), MEDLINE, Embase, LILACS, Current Controlled Trials, and the reference lists of articles identified by the literature search. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs that compared any corticosteroid with no treatment, placebo, or other active treatment (both groups should have received the same antituberculous drug regimen) in people diagnosed with tuberculous pleurisy. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, extracted data from the included trials, and assessed trial methodological quality using the Cochrane 'Risk of bias' tool. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs). We applied the fixed-effect model in the absence of statistically significant heterogeneity. MAIN RESULTS: Six trials with 590 participants met the inclusion criteria, which were conducted in Asia (three trials), Africa (two trials), and Europe (one trial). Two trials were in HIV-negative people, one trial was in HIV-positive people, and three trials did not report HIV status.Corticosteroids may reduce the time to resolution of pleural effusion. Risk of residual pleural effusion on chest X-ray was reduced by 45% at eight weeks (RR 0.54, 95% CI 0.37 to 0.78; 237 participants, 2 trials, low certainty evidence), and 65% at 24 weeks (RR 0.35, 95% CI 0.18 to 0.66; 237 participants, 2 trials, low certainty evidence).Compared with control, corticosteroids may reduce the risk of having pleural changes (such as pleural thickening or pleural adhesions), on chest X-ray at the end of follow-up by almost one third (RR 0.72, 95% CI 0.57 to 0.92; 393 participants, 5 trials,low certainty evidence), which translates to an absolute risk reduction of 16%.One trial reported deaths in people that were HIV-positive, with no obvious difference between the groups; the trial authors' analysis suggests that the deaths observed in this trial were related to HIV disease rather than pleural TB (RR 0.91, 95% CI 0.64 to 1.31; 197 participants, 1 trial).We found limited data on long-term functional respiratory impairment on 187 people in two trials, which reported that average percentage predicted forced vital capacity was similar in the group receiving prednisolone and in the control group (very low certainty evidence).The risk of adverse events that led to discontinuation of the trial drug was higher in people with pleural TB receiving corticosteroids (RR 2.78, 95% CI 1.11 to 6.94; 587 participants, 6 trials, low certainty evidence). The trial in HIV-positive people reported on six different HIV-related infections, with no obvious differences. However, cases of Kaposi's sarcoma were only seen in the corticosteroid group (with 6/99 cases in the steroid group compared to 0/98 in the control group) (very low certainty evidence). AUTHORS' CONCLUSIONS: Long-term respiratory function is potentially the most important outcome for assessing the effects of adjunctive treatments for people with pleural TB. However, the information on the impact of pleural TB on long-term respiratory function is unknown and could be eclipsed by other risk factors, such as concurrent pulmonary TB, smoking, and HIV. This probably needs to be quantified to help decide whether further trials of corticosteroids for pleural TB would be worthwhile.

Biological age as a useful index to predict seventeen-year survival and mortality in Koreans.

BACKGROUND: Many studies have been conducted to quantitatively estimate biological age using measurable biomarkers. Biological age should function as a valid proxy for aging, which is closely related with future work ability, frailty, physical fitness, and/or mortality. A validation study using cohort data found biological age to be a superior index for disease-related mortality than chronological age. The purpose of this study is to demonstrate the validity of biological age as a useful index to predict a person's risk of death in the future. METHODS: The data consists of 13,106 cases of death from 557,940 Koreans at 20-93 years old, surveyed from 1994 to 2011. Biological ages were computed using 15 biomarkers measured in general health check-ups using an algorithm based on principal component analysis. The influence of biological age on future mortality was analyzed using Cox proportional hazards regression considering gender, chronological age, and event type. RESULTS: In the living subjects, the average biological age was almost the same as the average chronological age. In the deceased, the biological age was larger than the chronological age: largest increment of biological age over chronological age was observed when their baseline chronological age was within 50-59 years. The death rate significantly increased as biological age became larger than chronological age (linear trend test, p value < 0.0001). The largest hazard ratio was observed in subjects whose baseline chronological age was within 50-59 years when the cause was death from non-cancerous diseases (HR = 1.30, 95% confidence intervals = 1.26 - 1.34). The survival probability, over the 17 year term of the study, was significantly decreased in the people whose biological age was larger than chronological age (log rank test, p value < 0.001). CONCLUSIONS: Biological age could be used to predict future risk of death, and its effect size varied according to gender, chronological age, and cause of death.

Genetic polymorphisms to predict gains in maximal O2 uptake and knee peak torque after a high intensity training program in humans.

PURPOSE: The study aimed to identify single nucleotide polymorphisms (SNPs) that significantly influenced the level of improvement of two kinds of training responses, including maximal O2 uptake (V'O2max) and knee peak torque of healthy adults participating in the high intensity training (HIT) program. The study also aimed to use these SNPs to develop prediction models for individual training responses. METHODS: 79 Healthy volunteers participated in the HIT program. A genome-wide association study, based on 2,391,739 SNPs, was performed to identify SNPs that were significantly associated with gains in V'O2max and knee peak torque, following 9 weeks of the HIT program. To predict two training responses, two independent SNPs sets were determined using linear regression and iterative binary logistic regression analysis. False discovery rate analysis and permutation tests were performed to avoid false-positive findings. RESULTS: To predict gains in V'O2max, 7 SNPs were identified. These SNPs accounted for 26.0 % of the variance in the increment of V'O2max, and discriminated the subjects into three subgroups, non-responders, medium responders, and high responders, with prediction accuracy of 86.1 %. For the knee peak torque, 6 SNPs were identified, and accounted for 27.5 % of the variance in the increment of knee peak torque. The prediction accuracy discriminating the subjects into the three subgroups was estimated as 77.2 %. CONCLUSIONS: Novel SNPs found in this study could explain, and predict inter-individual variability in gains of V'O2max, and knee peak torque. Furthermore, with these genetic markers, a methodology suggested in this study provides a sound approach for the personalized training program.

Effects of mechanical deformation on energy conversion efficiency of piezoelectric nanogenerators.

Piezoelectric nanogenerators (PNGs) are capable of converting energy from various mechanical sources into electric energy and have many attractive features such as continuous operation, replenishment and low cost. However, many researchers still have studied novel material synthesis and interfacial controls to improve the power production from PNGs. In this study, we report the energy conversion efficiency (ECE) of PNGs dependent on mechanical deformations such as bending and twisting. Since the output power of PNGs is caused by the mechanical strain of the piezoelectric material, the power production and their ECE is critically dependent on the types of external mechanical deformations. Thus, we examine the output power from PNGs according to bending and twisting. In order to clearly understand the ECE of PNGs in the presence of those external mechanical deformations, we determine the ECE of PNGs by the ratio of output electrical energy and input mechanical energy, where we suggest that the input energy is based only on the strain energy of the piezoelectric layer. We calculate the strain energy of the piezoelectric layer using numerical simulation of bending and twisting of the PNG. Finally, we demonstrate that the ECE of the PNG caused by twisting is much higher than that caused by bending due to the multiple effects of normal and lateral piezoelectric coefficients. Our results thus provide a design direction for PNG systems as high-performance power generators.

Susceptibility for ischemic stroke in Korean population is associated with polymorphisms of the Fc gamma receptor IIA.

Fc gamma receptor IIA could influence atherogenic processes through the production of superoxide anions, cytokines, and proteolytic enzymes as well as by oxidation of lipoproteins and enhancement of foam cell formation. In this study, we performed an interaction analysis between FCGR2A polymorphisms and ischemic stroke using direct DNA sequencing after the selection of Fc gamma receptor IIA gene based on genome-wide association study. Four of the FCGR2A polymorphisms, rs7511868 [odds ratio (OR) = 3.21; P = 0.027], rs6427595 (OR = 3.12; P = 0.008), rs7512140 (OR = 5.71; P = 0.002), and rs6696854 (OR = 3.65; P = 0.004) were significantly associated with ischemic stroke. These four polymorphisms still showed significant association after stratification analysis using the Mantel-Haenszel method. In the multivariate logistic regression, the adjusted OR estimates for rs6427595, rs7512140, and rs6696854 were 3.04 (P = 0.016), 4.84 (P = 0.015), and 3.80 (P = 0.006), respectively. The diplotype consisting of two homozygous haplotypes (H2 = AAAC) was significantly associated with ischemic stroke (OR = 17.39; P < 0.001). These results suggest that FCGR2A polymorphisms may be associated with a genetic susceptibility to ischemic stroke in a Korean population.

Recent progress in toxicogenomics research in South Korea.

BACKGROUND: The importance of toxicogenomics was recognized early in Korea and a group of researchers was trying to build up a research infrastructure and educational system. However, since the scale of the Korean pharmaceutical industry, which was expected to play the key role in toxicogenomics was small compared to that of advanced countries, industry-sponsored large-scale research projects and supporting infrastructures have been lacking in Korea. RESULTS: To improve this situation, the Korean government has exerted special efforts to promote toxicogenomics research and development the last few years as an initiative to stimulate a premature drug development industry on par with global competition and launched several large scale research projects recently. Researchers are also trying to keep pace with government efforts by organizing local scientist groups, training young toxicogenomics scientists, and widening the toxicogenomic research efforts to environmental toxicity as well. Research and development from bioinformatics and genomics venture companies are also contributing to uplifting the competitiveness of the toxicogenomics industry. CONCLUSION: Toxicogenomics in Korea is making steady progress in many directions. It is gaining ground by government and related industries as well, the research is diversified to embrace environmental genomics, and local research groups are making strategic links to international research groups such as the MicroArray Quality Control (MAQC) consortium. We expect the advancement of the Korean toxicogenomics research program will be beneficial not only to the local society alone, but also to international scientists as a whole.

SNPAnalyzer 2.0: a web-based integrated workbench for linkage disequilibrium analysis and association analysis.

BACKGROUND: Since the completion of the HapMap project, huge numbers of individual genotypes have been generated from many kinds of laboratories. The efforts of finding or interpreting genetic association between disease and SNPs/haplotypes have been on-going widely. So, the necessity of the capability to analyze huge data and diverse interpretation of the results are growing rapidly. RESULTS: We have developed an advanced tool to perform linkage disequilibrium analysis, and genetic association analysis between disease and SNPs/haplotypes in an integrated web interface. It comprises of four main analysis modules: (i) data import and preprocessing, (ii) haplotype estimation, (iii) LD blocking and (iv) association analysis. Hardy-Weinberg Equilibrium test is implemented for each SNPs in the data preprocessing. Haplotypes are reconstructed from unphased diploid genotype data, and linkage disequilibrium between pairwise SNPs is computed and represented by D', r2 and LOD score. Tagging SNPs are determined by using the square of Pearson's correlation coefficient (r2). If genotypes from two different sample groups are available, diverse genetic association analyses are implemented using additive, codominant, dominant and recessive models. Multiple verified algorithms and statistics are implemented in parallel for the reliability of the analysis. CONCLUSION: SNPAnalyzer 2.0 performs linkage disequilibrium analysis and genetic association analysis in an integrated web interface using multiple verified algorithms and statistics. Diverse analysis methods, capability of handling huge data and visual comparison of analysis results are very comprehensive and easy-to-use.

SNPAnalyzer: a web-based integrated workbench for single-nucleotide polymorphism analysis.

SNPAnalyzer is a software that performs four essential statistical analyses of SNPs in a common computational environment. It is composed of three main modules: (i) data manipulation, (ii) analysis and (iii) visualization. The data manipulation module is responsible for data input and output, and handles genotype, phenotype and genetic distance data. To ensure user convenience, the data format is simple. The analysis module performs statistical calculations and consists of four subcomponents: (i) Hardy-Weinberg equilibrium, (ii) Haplotype Estimation, (iii) linkage disequilibrium (LD) and (iv) quantitative trait locus analysis. The main feature of the analysis module is multiple implementations of different algorithms and indices for haplotype estimation and for LD analysis. This enables users to compare separate results generated by different algorithms, which help to avoid biased results acquired by applying a single statistical algorithm. The performance of all implemented algorithms has been validated using experimentally proven datasets. The visualization module presents most of the analyzed results as figures, rather than as simple text, which aids in the intuitive understanding of complex data. The SNPAnalyzer has been developed using C and C++ and is available at http://www.istech.info/istech/board/login_form.jsp.