Estimating influence of cofragmentation on peptide quantification and identification in iTRAQ experiments by simulating multiplexed spectra.

Li, Honglan,Hwang, Kyu-Baek,Mun, Dong-Gi,Kim, Hokeun,Lee, Hangyeore,Lee, Sang-Won,Paek, Eunok American Chemical Society 2014 JOURNAL OF PROTEOME RESEARCH Vol.13 No.7

<P>Isobaric tag-based quantification such as iTRAQ and TMT is a promising approach to mass spectrometry-based quantification in proteomics as it provides wide proteome coverage with greatly increased experimental throughput. However, it is known to suffer from inaccurate quantification and identification of a target peptide due to cofragmentation of multiple peptides, which likely leads to under-estimation of differentially expressed peptides (DEPs). A simple method of filtering out cofragmented spectra with less than 100% precursor isolation purity (PIP) would decrease the coverage of iTRAQ/TMT experiments. In order to estimate the impact of cofragmentation on quantification and identification of iTRAQ-labeled peptide samples, we generated multiplexed spectra with varying degrees of PIP by mixing the two MS/MS spectra of 100% PIP obtained in global proteome profiling experiments on gastric tumor-normal tissue pair proteomes labeled by 4-plex iTRAQ. Despite cofragmentation, the simulation experiments showed that more than 99% of multiplexed spectra with PIP greater than 80% were correctly identified by three different database search engines-MODa, MS-GF+, and Proteome Discoverer. Using the multiplexed spectra that have been correctly identified, we estimated the effect of cofragmentation on peptide quantification. In 74% of the multiplexed spectra, however, the cancer-to-normal expression ratio was compressed, and a fair number of spectra showed the 'ratio inflation' phenomenon. On the basis of the estimated distribution of distortions on quantification, we were able to calculate cutoff values for DEP detection from cofragmented spectra, which were corrected according to a specific PIP and probability of type I (or type II) error. When we applied these corrected cutoff values to real cofragmented spectra with PIP larger than or equal to 70%, we were able to identify reliable DEPs by removing about 25% of DEPs, which are highly likely to be false positives. Our experimental results provide useful insight into the effect of cofragmentation on isobaric tag-based quantification methods. The simulation procedure as well as the corrected cutoff calculation method could be adopted for quantifying the effect of cofragmentation and reducing false positives (or false negatives) in the DEP identification with general quantification experiments based on isobaric labeling techniques.</P>

Evaluation of the Redundancy in Decoy Database Generation for Tandem Mass Analysis

Honglan Li(이홍란),Duanhui Liu(류단휘),Kiwook Lee(이기욱),Kyu-Baek Hwang(황규백) 한국정보과학회 2016 정보과학회 컴퓨팅의 실제 논문지 Vol.22 No.1

탠덤 질량 분석에서는 신뢰도 높은 펩타이드 동정을 위해 목표 데이터베이스의 참조 단백질 순서를 재배치한 디코이 데이터베이스가 주로 이용된다. 한편 목표 데이터베이스와 디코이 데이터베이스 사이 혹은 디코이 데이터베이스 내부에 서열이 동일한 중복 펩타이드가 존재할 수 있으며, 이는 단백질 동정을 어렵게 하는 요인이 된다. 따라서 디코이 데이터베이스의 중복성을 최소화하는 것은 중요한 문제이다. 본 논문에서는 디코이 데이터베이스 생성에 널리 사용되는 의사셔플(pseudo-shuffling)과 의사역순(pseudo-reversing) 방법이 디코이 데이터베이스의 중복성에 미치는 영향을 조사하였다. 실험 결과, 목표 데이터베이스 크기와 데이터베이스 생성 시 허용되는 ‘missed cleavage site’의 최대 개수는 중복성을 증가시킴을 확인하였다. 또한 동일한 조건에서는 의사역순 방법이 의사셔플보다 항상 낮은 수준의 중복성을 가지는 디코이 데이터베이스를 생성하였다. Peptide identification in tandem mass spectrometry is usually done by searching the spectra against target databases consisting of reference protein sequences. To control false discovery rates for high-confidence peptide identification, spectra are also searched against decoy databases constructed by permuting reference protein sequences. In this case, a peptide of the same sequence could be included in both the target and the decoy databases or multiple entries of a same peptide could exist in the decoy database. These phenomena make the protein identification problem complicated. Thus, it is important to minimize the number of such redundant peptides for accurate protein identification. In this regard, we examined two popular methods for decoy database generation: ‘pseudo-shuffling’ and ‘pseudo-reversing’. We experimented with target databases of varying sizes and investigated the effect of the maximum number of missed cleavage sites allowed in a peptide (MC), which is one of the parameters for target and decoy database generation. In our experiments, the level of redundancy in decoy databases was proportional to the target database size and the value of MC, due to the increase in the number of short peptides (7 to 10 AA). Moreover, ‘pseudo-reversing’ always generated decoy databases with lower levels of redundancy compared to ‘pseudo-shuffling’.

A study on redundancy in decoy database for tandem spectrometry search

Honglan Li(이홍란),Duanhui Liu(류단휘),Kyu-Baek Hwang(황규백) 한국정보과학회 2015 한국정보과학회 학술발표논문집 Vol.2015 No.6

Systematic Comparison of False-Discovery-Rate-Controlling Strategies for Proteogenomic Search Using Spike-in Experiments

Li, Honglan,Park, Jonghun,Kim, Hyunwoo,Hwang, Kyu-Baek,Paek, Eunok American Chemical Society 2017 Journal of Proteome Research Vol.16 No.6

<P>Proteogenoinit searches are useful for novel peptide identification from tandem mass spectra. Usually, separate and multistage approaches are adopted to accurately control the false discovery rate (FDR) for: proteogenomic search. Their performance on novel peptide identification has not been thoroughly evaluated; however, mainly due to the. difficulty in Confirming existence of identified novel peptides.' We, simulated a proteogenomic search controlled, spike-in proteomic data set. After confirming that the results of the simulated proteogenomic search were similar to those of a real proteogenomic search using,a human cell line data set, we evaluated the performance of six FDR Control methods-global, separate, and multistage FDR estimation) respectively, coupled to a target-decoy search and a mixture model-based: method on novel peptide identification. The multistage approach showed the highest accuracy for FDR. estimation. However, global and separate FDR estimation with the mixture model-based method showed higher sensitivities than others at the same true FDR. Furthermore, the mixture model based method performed equally well when applied without or with a reduced set of decoy sequences: Considering different prior probabilities for novel and known protein identification, we recommend using mixture model-based methods with separate FDR estimation for sensitive and reliable identification of novel peptides from proteogenomic searches.</P>

하플로타입 페이징 알고리즘에 관한 조사연구

이홍란(Honglan Li),이제근(Je-Keun Rhee),장병탁(Byoung-Tak Zhang),황규백(Kyu-Baek Hwang),신수용(Soo-Yong Shin) 한국정보과학회 2013 정보과학회논문지 : 소프트웨어 및 응용 Vol.40 No.11

인간 유전체 서열 결정이 가능해 짐에 따라 개인 맞춤형 의학을 위한 개인의 유전적 다형성을 밝히는 연구가 광범위하게 진행되고 있다. 특히 최근 들어 동일 염색체 복수좌위에서의 대립형질을 고려하여 단일염기다형성에 기반한 유전체 서열 하플로타입(haplotype)을 생성하는 하플로타입 페이징(phasing) 분석이 주목을 받고 있다. 기존에는 주로 작은 범위 내에서의 하플로타입 페이징 연구가 수행되었으나, 최근 차세대 시퀀싱 기술의 급격한 비용 하락으로 인해 유전체 전체를 대상으로 한 페이징 연구도 시도되고 있다. 본 논문에서는 최근까지 제시된 하플로타입 페이징 알고리즘을 조사하고 분석하며, 향후 연구 방향에 대해 모색해 보고자 한다. Based on the recent achievement of sequencing technologies, the research on the genetic variation have been highlighted for realizing personalized medicine. Since human genome consists of diploid, the approach to find haploid which is a combination of alleles at adjacent locations on the chromosome, called haplotype phasing studies have drawn attention. Haplotype phasing is the method to detect haplotype block based on heterogeneous single nucleotide polymorphisms (SNPs). Usually, the research has been widely applied in a small part of chromosome, but the recent research starts to focus on the phasing of whole genome, using next generation sequencing data. In this paper, we will review the computational methods for haplotype phasing, and then suggest the promising direction of the computational haplotype phasing approaches.

The Mobile Visual Search Guiding System Based on SIFT

Gongwen Xu,Xiaomei Li,Honglan Zhou,Jian Lei,Zhijun Zhang 보안공학연구지원센터 2016 International Journal of Future Generation Communi Vol.9 No.6

In order to provide personal guiding service to visitors in the Picture Gallery, a mobile visual search guiding system based on SIFT(Scale Invariant Feature Transform) is proposed in this paper. The visitors can achieve the paintings’ information using the camera function of the mobile phones when they enjoy the famous paintings in the Picture Gallery. The mobile search visual system proposed in this paper can identify the paintings in the server side so there are no extra performance requirements for the mobile phones. Firstly, the mobile visual search system was introduced. Then the system was designed and realized. The classification training was based on SVM (Support Vector Machine). The SIFT feature extraction algorithm was used to enhance the recognition rate. After the image retrieval, the geometric consistency check was employed to choose the best matching image. Finally, the experimental results verified the feasibility and practicability of this system. Compared with the present guiding systems, this system can communicate with the visitors conveniently and offer abundant and all-around information to the visitors. In addition, using this guiding system, any auxiliary devices are not needed to be installed in the Picture Gallery.

Survey of computational haplotype determination methods for single individual

Rhee, Je-Keun,Li, Honglan,Joung, Je-Gun,Hwang, Kyu-Baek,Zhang, Byoung-Tak,Shin, Soo-Yong 한국유전학회 2016 Genes & Genomics Vol.38 No.1

<P>Genome-wide association studies have expanded our understanding of the relationship between the human genome and disease. However, because of current technical limitations, it is still challenging to clearly resolve diploid sequences, that is, two copies for each chromosome. One copy of each chromosome is inherited from each parent and the genomic function is determined by the interplay between the alleles represented as genotypes in the diploid sequences. Thus, to understand the nature of genetic variation in biological processes, including disease, it is necessary to determine the complete genomic sequence of each haplotype. Although there are experimental approaches for haplotype sequencing that physically separate the chromosomes, these methods are expensive and laborious and require special equipment. Here, we review the computational approaches that can be used to determine the haplotype phase. Since 1990, many researchers have tried to reconstruct the haplotype phase using a variety of computational methods, and some researches have been successfully help to determine the haplotype phase. In this review, we investigate how the computational haplotype determination methods have been developed, and we present the remaining problems affecting the determination of the haplotype of single individual using next-generation sequencing methods.</P>

A Theoretical Study on the Mechanism of Decarboxylations for Hydroxymandelate Synthase

Qing-An Qiao,Qiuxian Li,Changchun Liu,Xiao Sun,Honglan Cai,Lixiang Sun,Huayang Wang 대한화학회 2017 Bulletin of the Korean Chemical Society Vol.38 No.6

Hydroxymandelate synthase is one type of alpha-keto acid-dependent oxygenases and plays an important role in the biosynthesis of hydroxyphenyl-pyruvate. The ferrous and ferryl intermediates in the reaction were considered to be very important in the DNA repair process. The mechanism of hydroxymandelate synthase was investigated by a theoretical method based on B3LYP/LACVP*. The data indicated that each decarboxylation went through a process of direct dioxygen insertion. The first oxidative decarboxylation experienced only one transition state, while there were two potential pathways for the second decarboxylation process. The calculation data showed that the stepwise one was favored to the concerted one due to the lower energy barrier. The process to form the iron-superoxide was the rate-limiting step. After two consecutive decarboxylations, a proton transfer reaction was needed to obtain the target products. Two possible transition states were found out to achieve this step. The one with a six-membered ring structure was preferred because of the lower activation energy. In addition, several ferryl species with high spins were captured in the whole process, which could be supplied as requisite substrates for DNA repair reaction.

Comparative Analysis of Assembly-based Insertion and Deletion Calling Tools

Duanhui Liu(류단휘),Honglan Li(이홍란),Kyu-Baek Hwang(황규백) 한국정보과학회 2016 한국정보과학회 학술발표논문집 Vol.2016 No.6

Diabetes Medication Use in Association with Survival among Patients of Breast, Colorectal, Lung, or Gastric Cancer

Michelle L. Baglia,Yong Cui,Tao Zheng,Gong Yang,Honglan Li,Mingrong You,Liling Xu,Harvey Murff,Yu-Tang Gao,Wei Zheng,Yong-Bing Xiang,Xiao-Ou Shu 대한암학회 2019 Cancer Research and Treatment Vol.51 No.2

Purpose Studies suggest that regular use of metformin may decrease cancer mortality. We investigated the association between diabetes medication use and cancer survival. Materials and Methods The current study includes 633 breast, 890 colorectal, 824 lung, and 543 gastric cancer cases identified from participants of two population-based cohort studies in Shanghai. Information on diabetes medication use was obtained by linking to electronic medical records. The associations between diabetes medication use (metformin, sulfonylureas, and insulin) and overall and cancer-specific survival were evaluated using time-dependent Cox proportional hazards models. Results After adjustment for clinical characteristics and treatment factors, use of metformin was associated with better overall survival among colorectal cancer patients (hazards ratio [HR], 0.55; 95% confidence interval [CI], 0.34 to 0.88) and for all four types of cancer combined (HR, 0.75; 95% CI, 0.57 to 0.98). Ever use of insulin was associated with worse survival for all cancer types combined (HR, 1.89; 95% CI, 1.57 to 2.29) and for the four cancer types individually. Similar associations were seen for diabetic patients. Sulfonylureas use was associated with worse overall survival for breast or gastric cancer (HR, 2.87; 95% CI, 1.22 to 6.80 and HR, 2.05; 95% CI, 1.09 to 3.84, respectively) among diabetic patients. Similar association patterns were observed between diabetes medication use and cancer-specific survival. Conclusion Metformin was associated with improved survival among colorectal cancer cases, while insulin use was associated with worse survival among patients of four major cancers. Further investigation on the topic is needed given the potential translational impact of these findings.