Biomedical subjects

Marie Loh

Publications and source records attributed to Marie Loh.

11 recordsLinked to original sources

PubMed2024

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N = 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

Humans↗

PubMed2006

DNA polymorphisms and renal disease: a critical appraisal of studies presented at the annual ERA/EDTA and ASN conferences in 2004 and 2005.

Countless studies try to associate single DNA polymorphisms with disease, while there is growing evidence that many of these studies are of flawed design. Based on the Journal of the American Society of Nephrology (JASN) requirements for gene-disease association study quality, the abstracts presented at the two major international nephrology conferences in 2004 and 2005 organized by the European Renal Association/European Dialysis and Transplantation Association (ERA/EDTA) and American Society of Nephrology (ASN) are analysed to show how this problem affects nephrology. Over time, average sample numbers have increased, as have the numbers of abstracts compliant with the JASN requirements. This indicates a potential beneficial effect of the published stricter guidelines on study quality. Alternative options include pre-registration of studies in dedicated databases, secondary assessment of association studies through meta-analysis and participation in network approaches, such as the Human Genome Epidemiology Network (HuGE Net) and the Renal Genome Network.

Congresses as Topic↗

PubMed2006

RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer.

A tumor suppressor function has been attributed to RUNX3, a member of the RUNX family of transcription factors. Here, we examined alterations in the expression of three members, RUNX1, RUNX2, and RUNX3, and their interacting partner, CBF-beta, in breast cancer. Among them, RUNX3 was consistently underexpressed in breast cancer cell lines and primary tumors. Fifty percent of the breast cancer cell lines (n = 19) showed hypermethylation at the promoter region and displayed significantly lower levels of RUNX3 mRNA expression (P < 0.0001) and protein (P < 0.001). In primary Singaporean breast cancers, 9 of 44 specimens showed undetectable levels of RUNX3 by immunohistochemistry. In 35 of 44 tumors, however, low levels of RUNX3 protein were present. Remarkably, in each case, protein was mislocalized to the cytoplasm. In primary tumors, hypermethylation of RUNX3 was observed in 23 of 44 cases (52%) and was undetectable in matched adjacent normal breast epithelium. Mislocalization of the protein, with or without methylation, seems to account for RUNX3 inactivation in the vast majority of the tumors. In in vitro and in vivo assays, RUNX3 behaved as a growth suppressor in breast cancer cells. Stable expression of RUNX3 in MDA-MB-231 breast cancer cells led to a more cuboidal phenotype, significantly reduced invasiveness in Matrigel invasion assays, and suppressed tumor formation in immunodeficient mice. This study provides biological and mechanistic insights into RUNX3 as the key member of the family that plays a role in breast cancer. Frequent protein mislocalization and methylation could render RUNX3 a valuable marker for early detection and risk assessment.

Antimetabolites, Antineoplastic↗

PubMed2006

Mutational hotspot in exon 20 of PIK3CA in breast cancer among Singapore Chinese.

The recent identification of somatic mutations in the catalytic region of PIK3 (PIK3CA) in breast cancer and demonstration of their oncogenic function has implicated PIK3CA in mammary carcinogenesis. To investigate possible ethnic differences in patterns of PIK3CA mutations in Singaporean Chinese breast cancer and to characterize these in a panel of cell lines, we sequenced exons 9 and 20 in 80 primary tumors, 19 breast cancer cell lines and 7 normal human mammary epithelial cells (HMECs). Searching for novel hotspots of mutation, we sequenced additional exons (1, 2, 6, 7, 14 and 18) in 20 primary tumors and 6 breast cancer cell lines. We detected 33 point mutations in 31 of 80 (39%) breast cancers, and 11 mutations in 10 of 19 (53%) breast cancer cell lines. No mutations were detected in normal breast tissue adjacent to the tumor, or in the 6 normal HMECs. The exon 20 A3140G (H1047R) substitution was identified most frequently (22/31, 71%) and showed a significant association with patient age (p = 0.043) and stage of the disease (p = 0.025), but not with ER/PR status or histological grade of the tumor. The incidence of point mutations in PIK3CA, the A3140G substitution in particular, in Singapore breast cancers are among the most frequent reported to date for any gene in breast cancer. The results suggest that mutation of PIK3CA might contribute to development of early stage breast cancer and could provide a potent target for early diagnosis and therapy.

Asian People↗

PubMed2006

Singapore Human Mutation/Polymorphism Database: a country-specific database for mutations and polymorphisms in inherited disorders and candidate gene association studies.

There is a need for country/population-specific databases because the existence of population-specific mutations for single gene disorders is well documented, and there is also good evidence for ethnic differences in the frequencies of genetic variations involved in complex disorders. Thus the Singapore Human Mutation/Polymorphism Database (SHMPD) was created to provide clinicians and scientists access to a central genetic database for the Singapore population. The data catalogued in the database include mutations identified in Singapore for Mendelian diseases, and frequencies of polymorphisms that have been investigated in either healthy controls or samples associated with specific phenotypes. Data from journal articles identified by searches in PubMed and other online resources, and via personal communications with researchers were compiled and assembled into a single database. Genes are categorized alphabetically and are also searchable by name and disease. The information provided for each variant of the gene includes the protein encoded, phenotype association, gender, size, and ethnic origin of the sample, as well as the reported genotype and allele frequencies, and direct links to the corresponding abstracts on PubMed. Our database will facilitate molecular diagnosis of Mendelian disorders and improve study designs for complex traits. It will be useful not only for researchers in Singapore, but also for those in countries with similar ethnic backgrounds, such as China, Taiwan, Hong Kong, Indonesia, and Malaysia.

Alleles↗

PubMed2005

The "impact factor" revisited.

The number of scientific journals has become so large that individuals, institutions and institutional libraries cannot completely store their physical content. In order to prioritize the choice of quality information sources, librarians and scientists are in need of reliable decision aids. The "impact factor" (IF) is the most commonly used assessment aid for deciding which journals should receive a scholarly submission or attention from research readership. It is also an often misunderstood tool. This narrative review explains how the IF is calculated, how bias is introduced into the calculation, which questions the IF can or cannot answer, and how different professional groups can benefit from IF use.

Journal Article↗

PubMed2005

Relevance similarity: an alternative means to monitor information retrieval systems.

BACKGROUND: Relevance assessment is a major problem in the evaluation of information retrieval systems. The work presented here introduces a new parameter, "Relevance Similarity", for the measurement of the variation of relevance assessment. In a situation where individual assessment can be compared with a gold standard, this parameter is used to study the effect of such variation on the performance of a medical information retrieval system. In such a setting, Relevance Similarity is the ratio of assessors who rank a given document same as the gold standard over the total number of assessors in the group. METHODS: The study was carried out on a collection of Critically Appraised Topics (CATs). Twelve volunteers were divided into two groups of people according to their domain knowledge. They assessed the relevance of retrieved topics obtained by querying a meta-search engine with ten keywords related to medical science. Their assessments were compared to the gold standard assessment, and Relevance Similarities were calculated as the ratio of positive concordance with the gold standard for each topic. RESULTS: The similarity comparison among groups showed that a higher degree of agreements exists among evaluators with more subject knowledge. The performance of the retrieval system was not significantly different as a result of the variations in relevance assessment in this particular query set. CONCLUSION: In assessment situations where evaluators can be compared to a gold standard, Relevance Similarity provides an alternative evaluation technique to the commonly used kappa scores, which may give paradoxically low scores in highly biased situations such as document repositories containing large quantities of relevant data.

Journal Article↗

PubMed2005

Polymorphisms of the insertion / deletion ACE and M235T AGT genes and hypertension: surprising new findings and meta-analysis of data.

BACKGROUND: Essential hypertension is a common, polygenic, complex disorder resulting from interaction of several genes with each other and with environmental factors such as obesity, dietary salt intake, and alcohol consumption. Since the underlying genetic pathways remain elusive, currently most studies focus on the genes coding for proteins that regulate blood pressure as their physiological role makes them prime suspects. The present study examines how polymorphisms of the insertion/deletion (I/D) ACE and M235T AGT genes account for presence and severity of hypertension, and embeds the data in a meta-analysis of relevant studies. METHODS: The I/D polymorphisms of the ACE and M235T polymorphisms of the AGT genes were determined by RFLP (restriction fragment length polymorphism) and restriction analysis in 638 hypertensive patients and 720 normotensive local blood donors in Weisswasser, Germany. Severity of hypertension was estimated by the number of antihypertensive drugs used. RESULTS: No difference was observed in the allele frequencies and genotype distributions of ACE gene polymorphisms between the two groups, whereas AGT TT homozygotes were more frequent in controls (4.6% vs. 2.7%, P = .08). This became significant (p = 0.035) in women only. AGT TT genotype was associated with a 48% decrease in the risk of having hypertension (odds ratio: 0.52; 95% CI, 0.28 to 0.96), and this risk decreased more significantly in women (odds ratio: 0.28; 95% CI, 0.1 to 0.78). The meta-analysis showed a pooled odds ratio for hypertension of 1.21 (TT vs. MM, 95% CI: 1.11 to 1.32) in Caucasians. No correlation was found between severity of hypertension and a specific genotype. CONCLUSION: The ACE I/D polymorphism does not contribute to the presence and severity of essential hypertension, while the AGT M235T TT genotype confers a significantly decreased risk for the development of hypertension in the population studied here. This contrasts to the findings of meta-analyses, whereby the T allele is associated with increased risk for hypertension.

Adult↗

PubMed2004

Quantitative evaluation of recall and precision of CAT Crawler, a search engine specialized on retrieval of Critically Appraised Topics.

BACKGROUND: Critically Appraised Topics (CATs) are a useful tool that helps physicians to make clinical decisions as the healthcare moves towards the practice of Evidence-Based Medicine (EBM). The fast growing World Wide Web has provided a place for physicians to share their appraised topics online, but an increasing amount of time is needed to find a particular topic within such a rich repository. METHODS: A web-based application, namely the CAT Crawler, was developed by Singapore's Bioinformatics Institute to allow physicians to adequately access available appraised topics on the Internet. A meta-search engine, as the core component of the application, finds relevant topics following keyword input. The primary objective of the work presented here is to evaluate the quantity and quality of search results obtained from the meta-search engine of the CAT Crawler by comparing them with those obtained from two individual CAT search engines. From the CAT libraries at these two sites, all possible keywords were extracted using a keyword extractor. Of those common to both libraries, ten were randomly chosen for evaluation. All ten were submitted to the two search engines individually, and through the meta-search engine of the CAT Crawler. Search results were evaluated for relevance both by medical amateurs and professionals, and the respective recall and precision were calculated. RESULTS: While achieving an identical recall, the meta-search engine showed a precision of 77.26% (+/-14.45) compared to the individual search engines' 52.65% (+/-12.0) (p < 0.001). CONCLUSION: The results demonstrate the validity of the CAT Crawler meta-search engine approach. The improved precision due to inherent filters underlines the practical usefulness of this tool for clinicians.

Data Collection↗

PubMed2004

Active collaboration with primary care providers increases specialist referral in chronic renal disease.

BACKGROUND: Late referral to specialist nephrological care is associated with increased morbidity, mortality, and cost. Consequently, nephrologists' associations recommend early referral. The recommendations' effectiveness remains questionable: 22-51% of referrals need renal replacement therapy (RRT) within 3-4 months. This may be due to these recommendations addressing the specialist, rather than the primary care providers (PCP). The potential of specialist intervention aiming at slowing progression of chronic renal failure was introduced individually to some 250 local PCPs, and referral strategies were discussed. To overcome the PCPs' most often expressed fears, every referred patient was asked to report back to his PCP immediately after the initial specialist examination, and new medications were prescribed directly, and thus allotted to the nephrologist's budget. METHODS: In retrospective analysis, the stage of renal disease in patients referred within three months before the introductory round (group A, n = 18), was compared to referrals two years later (group B, n = 50). RESULTS: Relative number of patients remained stable (28%) for mild/ moderate chronic kidney disease (MMCKD), while there was a noticeable shift from patients referred severe chronic kidney disease (SCKD) (group A: 44%, group B: 20%) to patients referred in moderate chronic kidney disease (MCKD) (group A: 28%, group B: 52%). CONCLUSION: Individually addressing PCPs' ignorance and concerns noticeably decreased late referral. This stresses the importance of enhancing the PCPs' problem awareness and knowledge of available resources in order to ensure timely specialist referral.

Adult↗

PubMedDate not supplied

Analyses of promoter hypermethylation for RUNX3 and other tumor suppressor genes in nasopharyngeal carcinoma.

BACKGROUND: Aberrant methylation of cytosine in promoter CpG islands is a recognized contributory process to carcinogenesis. This study explores the methylation profile of RUNX3 in combination with p16, RASSF1A, CDH1 and hMLH1 in nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Genomic DNA was extracted from 19 fresh frozen NPC biopsies, which were then subjected to bisulfite conversion and methylation-specific PCR for analysis of promoter hypermethylation for the five respective genes. Three cell lines, SNU1, RKO and LS174T, were used as controls. RESULTS: The incidences of promoter methylation were as follows: RUNX3 0/19 (0%), p16 6/19 (32%), RASSF1A 13/19 (68%), CDH1 9/19 (47%) and hMLH1 4/19 (21%). Ninety-five percent of the tumor specimens displayed aberrant methylation in at least one of these genes. No significant correlation between methylation status of these genes and clinical parameters was found. CONCLUSION: Methylation of multiple genes is involved in critical pathways for cancer development in NPC. Promoter hypermethylation for RUNX3 was, however, not present.

Base Sequence↗