Clarabelle Lin - Academia.edu (original) (raw)

Papers by Clarabelle Lin

Asian populations are currently underrepresented in human genetics research. Here we present whol... more Asian populations are currently underrepresented in human genetics research. Here we present whole-genome sequencing data of 4,810 Singaporeans from three diverse ethnic groups: 2,780 Chinese, 903 Malays, and 1,127 Indians. Despite a medium depth of 13.7×, we achieved essentially perfect (>99.8%) sensitivity and accuracy for detecting common variants and good sensitivity (>89%) for detecting extremely rare variants with <0.1% allele frequency. We found 89.2 million single-nucleotide polymorphisms (SNPs) and 9.1 million small insertions and deletions (INDELs), more than half of which have not been cataloged in dbSNP. In particular, we found 126 common deleterious mutations (MAF>0.01) that were absent in the existing public databases, highlighting the importance of local population reference for genetic diagnosis. We describe fine-scale genetic structure of Singapore populations and their relationship to worldwide populations from the 1000 Genomes Project. In addition to revealing noticeable amounts of admixture among three Singapore populations and a Malay-related novel ancestry component that has not been captured by the 1000 Genomes Project, our analysis also identified some fine-scale features of genetic structure consistent with two waves of prehistoric migration from south China to Southeast Asia. Finally, we demonstrate that our data can substantially improve genotype imputation not only for Singapore populations, but also for populations across Asia and Oceania. These results highlight the genetic diversity in Singapore and the potential impacts of our data as a resource to empower human genetics discovery in a broad geographic region. .

PLOS ONE

Background While the aetiology of age-related macular degeneration (AMD)-a major blinding disease... more Background While the aetiology of age-related macular degeneration (AMD)-a major blinding disease-remains unknown, the disease is strongly associated with variants in the complement factor H (CFH) gene. CFH variants also confer susceptibility to invasive infection with several bacterial colonizers of the nasopharyngeal mucosa. This shared susceptibility locus implicates complement deregulation as a common disease mechanism, and suggests the possibility that microbial interactions with host complement may trigger AMD. In this study, we address this possibility by testing the hypothesis that AMD is associated with specific microbial colonization of the human nasopharynx. Results High-throughput Illumina sequencing of the V3-V6 region of the microbial 16S ribosomal RNA gene was used to comprehensively and accurately describe the human pharyngeal microbiome, at genus level, in 245 AMD patients and 386 controls. Based on mean and differential microbial abundance analyses, we determined an overview of the pharyngeal microbiota, as well as candidate genera (Prevotella and Gemella) suggesting an association towards AMD health and disease conditions. Conclusions Utilizing an extensive study population from Singapore, our results provided an accurate description of the pharyngeal microbiota profiles in AMD health and disease conditions. Through identification of candidate genera that are different between conditions, we provide preliminary evidence for the existence of microbial triggers for AMD.

PLOS ONE, 2015

The National Comprehensive Cancer Network (NCCN) has proposed guidelines for the genetic testing ... more The National Comprehensive Cancer Network (NCCN) has proposed guidelines for the genetic testing of the BRCA1 and BRCA2 genes, based on studies in western populations. This current study assessed potential predictive factors for BRCA mutation probability, in an Asian population. Methods A total of 359 breast cancer patients, who presented with either a family history (FH) of breast and/or ovarian cancer or early onset breast cancer, were accrued at the National Cancer Center Singapore (NCCS). The relationships between clinico-pathological features and mutational status were calculated using the Chi-squared test and binary logistic regression analysis. Results Of 359 patients, 45 (12.5%) had deleterious or damaging missense mutations in BRCA1 and/or BRCA2. BRCA1 mutations were more likely to be found in ER-negative than ERpositive breast cancer patients (P=0.01). Moreover, ER-negative patients with BRCA mutations were diagnosed at an earlier age (40 vs. 48 years, P=0.008). Similarly, triple-negative breast cancer (TNBC) patients were more likely to have BRCA1 mutations (P=0.001

The aim of this study was to evaluate the epidemiology of diabetic foot problems (DFP) and predic... more The aim of this study was to evaluate the epidemiology of diabetic foot problems (DFP) and predictive factors for major amputations (below-and above-knee). Methods: This is a prospective study of 202 patients treated in National University Hospital (NUH) during the period of January 2005 to May 2006. A protocol was designed for documentation including patient profile, type of DFP, presence of risk factors, comorbidities and complications, clinical presentation, investigations, treatment given, and final outcome. The predictors for limb loss were determined using univariate and stepwise logistic regression analysis. Results: One hundred ninety-two patients had Type 2 diabetes. Mean age of cohort was 60 years, with male to female ratio of 1:1. Incidence of DFP was significantly higher in Malays (P=.0015) and Indians (P=.036) and significantly lower in Chinese (Pb.05). Of patients, 72.8% had poor endocrine control (GHb level N7%), and 42.1% of patients had sensory neuropathy based on 5.07 Semmes-Weinstein Monofilament test. Common DFP included gangrene (31.7%), infection (abscess, osteomyelitis) (28.7%), ulcer (27.7%), cellulitis (6.4%), necrotizing fasciitis (3.5%) and Charcot's osteoarthropathy (2.0%). Surgery was performed in 74.8% of patients and major amputation in 27.2% of patients (below-knee in 20.3% and above-knee in 6.9%). Conclusions: This is the first detailed prospective study evaluating predictive factors for major amputations in patients with DFP. Significant univariate predictive factors for limb loss were age above 60 years, stroke, ischaemic heart disease, nephropathy, peripheral vascular disease (PVD), sensory neuropathy, glycosylated haemoglobin level, Ankle Brachial Index (ABI) b0.8, gangrene, infection, and pathogens such as methicillin-resistant Streptococcus aureus (MRSA) and Staphylococcus aereus. Upon stepwise logistic regression analysis, only PVD and infection were significant.

Diabetic Foot Problems, 2008

Diabetic Foot & …, 2011

Assessment of sensory neuropathy in patients with diabetic foot problems.

Targeted resequencing technologies have allowed for efficient and cost-effective detection of gen... more Targeted resequencing technologies have allowed for efficient and cost-effective detection of genomic variants in specific regions of interest. Although capture sequencing has been primarily used for investigating single nucleotide variants and indels, it has the potential to elucidate a broader spectrum of genetic variation, including copy number variants (CNVs). Various methods exist for detecting CNV in whole-genome and exome sequencing datasets. However, no algorithms have been specifically designed for contiguous target sequencing, despite its increasing importance in clinical and research applications. We have developed cnvCapSeq, a novel method for accurate and sensitive CNV discovery and genotyping in long-range targeted resequencing. cnvCapSeq was benchmarked using a simulated contiguous capture sequencing dataset comprising 21 genomic loci of various lengths. cnvCapSeq was shown to outperform the best existing exome CNV method by a wide margin both in terms of sensitivity (92.0 versus 48.3%) and specificity (99.8 versus 70.5%). We also applied cnvCapSeq to a real capture sequencing cohort comprising a contiguous 358 kb region that contains the Complement Factor H gene cluster. In this dataset, cnvCapSeq identified 41 samples with CNV, including two with duplications, with a genotyping accuracy of 99%, as ascertained by quantitative real-time PCR.

Asian populations are currently underrepresented in human genetics research. Here we present whol... more Asian populations are currently underrepresented in human genetics research. Here we present whole-genome sequencing data of 4,810 Singaporeans from three diverse ethnic groups: 2,780 Chinese, 903 Malays, and 1,127 Indians. Despite a medium depth of 13.7×, we achieved essentially perfect (>99.8%) sensitivity and accuracy for detecting common variants and good sensitivity (>89%) for detecting extremely rare variants with <0.1% allele frequency. We found 89.2 million single-nucleotide polymorphisms (SNPs) and 9.1 million small insertions and deletions (INDELs), more than half of which have not been cataloged in dbSNP. In particular, we found 126 common deleterious mutations (MAF>0.01) that were absent in the existing public databases, highlighting the importance of local population reference for genetic diagnosis. We describe fine-scale genetic structure of Singapore populations and their relationship to worldwide populations from the 1000 Genomes Project. In addition to revealing noticeable amounts of admixture among three Singapore populations and a Malay-related novel ancestry component that has not been captured by the 1000 Genomes Project, our analysis also identified some fine-scale features of genetic structure consistent with two waves of prehistoric migration from south China to Southeast Asia. Finally, we demonstrate that our data can substantially improve genotype imputation not only for Singapore populations, but also for populations across Asia and Oceania. These results highlight the genetic diversity in Singapore and the potential impacts of our data as a resource to empower human genetics discovery in a broad geographic region. .

PLOS ONE

Background While the aetiology of age-related macular degeneration (AMD)-a major blinding disease... more Background While the aetiology of age-related macular degeneration (AMD)-a major blinding disease-remains unknown, the disease is strongly associated with variants in the complement factor H (CFH) gene. CFH variants also confer susceptibility to invasive infection with several bacterial colonizers of the nasopharyngeal mucosa. This shared susceptibility locus implicates complement deregulation as a common disease mechanism, and suggests the possibility that microbial interactions with host complement may trigger AMD. In this study, we address this possibility by testing the hypothesis that AMD is associated with specific microbial colonization of the human nasopharynx. Results High-throughput Illumina sequencing of the V3-V6 region of the microbial 16S ribosomal RNA gene was used to comprehensively and accurately describe the human pharyngeal microbiome, at genus level, in 245 AMD patients and 386 controls. Based on mean and differential microbial abundance analyses, we determined an overview of the pharyngeal microbiota, as well as candidate genera (Prevotella and Gemella) suggesting an association towards AMD health and disease conditions. Conclusions Utilizing an extensive study population from Singapore, our results provided an accurate description of the pharyngeal microbiota profiles in AMD health and disease conditions. Through identification of candidate genera that are different between conditions, we provide preliminary evidence for the existence of microbial triggers for AMD.

PLOS ONE, 2015

The National Comprehensive Cancer Network (NCCN) has proposed guidelines for the genetic testing ... more The National Comprehensive Cancer Network (NCCN) has proposed guidelines for the genetic testing of the BRCA1 and BRCA2 genes, based on studies in western populations. This current study assessed potential predictive factors for BRCA mutation probability, in an Asian population. Methods A total of 359 breast cancer patients, who presented with either a family history (FH) of breast and/or ovarian cancer or early onset breast cancer, were accrued at the National Cancer Center Singapore (NCCS). The relationships between clinico-pathological features and mutational status were calculated using the Chi-squared test and binary logistic regression analysis. Results Of 359 patients, 45 (12.5%) had deleterious or damaging missense mutations in BRCA1 and/or BRCA2. BRCA1 mutations were more likely to be found in ER-negative than ERpositive breast cancer patients (P=0.01). Moreover, ER-negative patients with BRCA mutations were diagnosed at an earlier age (40 vs. 48 years, P=0.008). Similarly, triple-negative breast cancer (TNBC) patients were more likely to have BRCA1 mutations (P=0.001

The aim of this study was to evaluate the epidemiology of diabetic foot problems (DFP) and predic... more The aim of this study was to evaluate the epidemiology of diabetic foot problems (DFP) and predictive factors for major amputations (below-and above-knee). Methods: This is a prospective study of 202 patients treated in National University Hospital (NUH) during the period of January 2005 to May 2006. A protocol was designed for documentation including patient profile, type of DFP, presence of risk factors, comorbidities and complications, clinical presentation, investigations, treatment given, and final outcome. The predictors for limb loss were determined using univariate and stepwise logistic regression analysis. Results: One hundred ninety-two patients had Type 2 diabetes. Mean age of cohort was 60 years, with male to female ratio of 1:1. Incidence of DFP was significantly higher in Malays (P=.0015) and Indians (P=.036) and significantly lower in Chinese (Pb.05). Of patients, 72.8% had poor endocrine control (GHb level N7%), and 42.1% of patients had sensory neuropathy based on 5.07 Semmes-Weinstein Monofilament test. Common DFP included gangrene (31.7%), infection (abscess, osteomyelitis) (28.7%), ulcer (27.7%), cellulitis (6.4%), necrotizing fasciitis (3.5%) and Charcot's osteoarthropathy (2.0%). Surgery was performed in 74.8% of patients and major amputation in 27.2% of patients (below-knee in 20.3% and above-knee in 6.9%). Conclusions: This is the first detailed prospective study evaluating predictive factors for major amputations in patients with DFP. Significant univariate predictive factors for limb loss were age above 60 years, stroke, ischaemic heart disease, nephropathy, peripheral vascular disease (PVD), sensory neuropathy, glycosylated haemoglobin level, Ankle Brachial Index (ABI) b0.8, gangrene, infection, and pathogens such as methicillin-resistant Streptococcus aureus (MRSA) and Staphylococcus aereus. Upon stepwise logistic regression analysis, only PVD and infection were significant.

Diabetic Foot Problems, 2008

Diabetic Foot & …, 2011

Assessment of sensory neuropathy in patients with diabetic foot problems.

Targeted resequencing technologies have allowed for efficient and cost-effective detection of gen... more Targeted resequencing technologies have allowed for efficient and cost-effective detection of genomic variants in specific regions of interest. Although capture sequencing has been primarily used for investigating single nucleotide variants and indels, it has the potential to elucidate a broader spectrum of genetic variation, including copy number variants (CNVs). Various methods exist for detecting CNV in whole-genome and exome sequencing datasets. However, no algorithms have been specifically designed for contiguous target sequencing, despite its increasing importance in clinical and research applications. We have developed cnvCapSeq, a novel method for accurate and sensitive CNV discovery and genotyping in long-range targeted resequencing. cnvCapSeq was benchmarked using a simulated contiguous capture sequencing dataset comprising 21 genomic loci of various lengths. cnvCapSeq was shown to outperform the best existing exome CNV method by a wide margin both in terms of sensitivity (92.0 versus 48.3%) and specificity (99.8 versus 70.5%). We also applied cnvCapSeq to a real capture sequencing cohort comprising a contiguous 358 kb region that contains the Complement Factor H gene cluster. In this dataset, cnvCapSeq identified 41 samples with CNV, including two with duplications, with a genotyping accuracy of 99%, as ascertained by quantitative real-time PCR.