Dataset Information

Scoring methods for building genotypic scores: an application to didanosine resistance in a large derivation set.

ABSTRACT:

Background

Several attempts have been made to determine HIV-1 resistance from genotype resistance testing. We compare scoring methods for building weighted genotyping scores and commonly used systems to determine whether the virus of a HIV-infected patient is resistant.

Methods and principal findings

Three statistical methods (linear discriminant analysis, support vector machine and logistic regression) are used to determine the weight of mutations involved in HIV resistance. We compared these weighted scores with known interpretation systems (ANRS, REGA and Stanford HIV-db) to classify patients as resistant or not. Our methodology is illustrated on the Forum for Collaborative HIV Research didanosine database (N = 1453). The database was divided into four samples according to the country of enrolment (France, USA/Canada, Italy and Spain/UK/Switzerland). The total sample and the four country-based samples allow external validation (one sample is used to estimate a score and the other samples are used to validate it). We used the observed precision to compare the performance of newly derived scores with other interpretation systems. Our results show that newly derived scores performed better than or similar to existing interpretation systems, even with external validation sets. No difference was found between the three methods investigated. Our analysis identified four new mutations associated with didanosine resistance: D123S, Q207K, H208Y and K223Q.

Conclusions

We explored the potential of three statistical methods to construct weighted scores for didanosine resistance. Our proposed scores performed at least as well as already existing interpretation systems and previously unrecognized didanosine-resistance associated mutations were identified. This approach could be used for building scores of genotypic resistance to other antiretroviral drugs.

SUBMITTER: Houssaini A

PROVIDER: S-EPMC3605419 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Scoring methods for building genotypic scores: an application to didanosine resistance in a large derivation set.

Houssaini Allal A Assoumou Lambert L Miller Veronica V Calvez Vincent V Marcelin Anne-Geneviève AG Flandre Philippe P

PloS one 20130321 3

<h4>Background</h4>Several attempts have been made to determine HIV-1 resistance from genotype resistance testing. We compare scoring methods for building weighted genotyping scores and commonly used systems to determine whether the virus of a HIV-infected patient is resistant.<h4>Methods and principal findings</h4>Three statistical methods (linear discriminant analysis, support vector machine and logistic regression) are used to determine the weight of mutations involved in HIV resistance. We c ...[more]

PMID: 23555613

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Project description:The statistical validation of peptide and protein identifications in mass spectrometry proteomics is a critical step in the analytical workflow. This is particularly important in discovery experiments to ensure only confident identifications are accumulated for downstream analysis and biomarker consideration. However, the inherent nature of discovery proteomics experiments leads to scenarios where the search space will inflate substantially due to the increased number of potential proteins that are being queried in each sample. In these cases, issues will begin to arise when the machine learning algorithms that are trained on an experiment specific basis cannot accurately distinguish between correct and incorrect identifications and will struggle to accurately control the false discovery rate. Here, we propose an alternative validation algorithm trained on a curated external data set of 2.8 million extracted peakgroups that leverages advanced machine learning techniques to create a generalizable peakgroup scoring (GPS) method for data independent acquisition (DIA) mass spectrometry. By breaking the reliance on the experimental data at hand and instead training on a curated external dataset, GPS can confidently control the false discovery rate while increasing the number of identifications and providing more accurate quantification in different search space scenarios. To first test the performance of GPS in a standard experimental environment and to provide a benchmark against other methods, a novel spike-in data set with known varying concentrations was analyzed. When compared to existing methods GPS increased the nunmber of identifications by 5-18% and was able to provide more accurate quantification by increasing the number of ratio validated identifications by 24-74%. To evaluate GPS in a larger search space, a novel data set of 141 blood plasma samples from patients developing acute kidney injury after sepsis was searched with a human tissue spectral library (10000+ proteins). Using GPS, we were able to provide a 207-377% increase in the number of candidate differentially abundant proteins compared to the existing methods while maintaining competitive numbers of global identifications. Finally, using an optimized human tissue library and workflow we were able to identify 1205 proteins from the 141 plasma samples and increase the number of candidate differentially abundant proteins by 70.87%. With the addition of machine learning aided differential expression, we were able to identify potential new biomarkers for stratifying subphenotypes of acute kidney injury in sepsis. These findings suggest that by using a generalized model such as GPS in tandem with a massive scale spectral library it is possible to expand the boundaries of discovery experiments in DIA proteomics. GPS is open source and freely available on github at https://github.com/InfectionMedicineProteomics/gps

Dataset Information

Scoring methods for building genotypic scores: an application to didanosine resistance in a large derivation set.

Background

Methods and principal findings

Conclusions

Publications

Scoring methods for building genotypic scores: an application to didanosine resistance in a large derivation set.

Similar Datasets

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