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Kernel-based logistic regression model for protein sequence without vectorialization.

ABSTRACT: Protein sequence data arise more and more often in vaccine and infectious disease research. These types of data are discrete, high-dimensional, and complex. We propose to study the impact of protein sequences on binary outcomes using a kernel-based logistic regression model, which models the effect of protein through a random effect whose variance-covariance matrix is mostly determined by a kernel function. We propose a novel, biologically motivated, profile hidden Markov model (HMM)-based mutual information (MI) kernel. Hypothesis testing can be carried out using the maximum of the score statistics and a parametric bootstrap procedure. To improve the power of testing, we propose intuitive modifications to the test statistic. We show through simulation studies that the profile HMM-based MI kernel can be substantially more powerful than competing kernels, and that the modified test statistics bring incremental gains in power. We use these proposed methods to investigate two problems from HIV-1 vaccine research: (1) identifying segments of HIV-1 envelope (Env) protein that confer resistance to neutralizing antibody and (2) identifying segments of Env that are associated with attenuation of protective vaccine effect by antibodies of isotype A in the RV144 vaccine trial.

SUBMITTER: Fong Y

PROVIDER: S-EPMC4794618 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Kernel-based logistic regression model for protein sequence without vectorialization.

Fong Youyi Y Datta Saheli S Georgiev Ivelin S IS Kwong Peter D PD Tomaras Georgia D GD

Biostatistics (Oxford, England) 20141222 3

Protein sequence data arise more and more often in vaccine and infectious disease research. These types of data are discrete, high-dimensional, and complex. We propose to study the impact of protein sequences on binary outcomes using a kernel-based logistic regression model, which models the effect of protein through a random effect whose variance-covariance matrix is mostly determined by a kernel function. We propose a novel, biologically motivated, profile hidden Markov model (HMM)-based mutua ...[more]

PMID: 25532524

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Project description:BACKGROUND:Hinge-bending movements in proteins comprising two or more domains form a large class of functional movements. Hinge-bending regions demarcate protein domains and collectively control the domain movement. Consequently, the ability to recognise sequence features of hinge-bending regions and to be able to predict them from sequence alone would benefit various areas of protein research. For example, an understanding of how the sequence features of these regions relate to dynamic properties in multi-domain proteins would aid in the rational design of linkers in therapeutic fusion proteins. RESULTS:The DynDom database of protein domain movements comprises sequences annotated to indicate whether the amino acid residue is located within a hinge-bending region or within an intradomain region. Using statistical methods and Kernel Logistic Regression (KLR) models, this data was used to determine sequence features that favour or disfavour hinge-bending regions. This is a difficult classification problem as the number of negative cases (intradomain residues) is much larger than the number of positive cases (hinge residues). The statistical methods and the KLR models both show that cysteine has the lowest propensity for hinge-bending regions and proline has the highest, even though it is the most rigid amino acid. As hinge-bending regions have been previously shown to occur frequently at the terminal regions of the secondary structures, the propensity for proline at these regions is likely due to its tendency to break secondary structures. The KLR models also indicate that isoleucine may act as a domain-capping residue. We have found that a quadratic KLR model outperforms a linear KLR model and that improvement in performance occurs up to very long window lengths (eighty residues) indicating long-range correlations. CONCLUSION:In contrast to the only other approach that focused solely on interdomain hinge-bending regions, the method provides a modest and statistically significant improvement over a random classifier. An explanation of the KLR results is that in the prediction of hinge-bending regions a long-range correlation is at play between a small number amino acids that either favour or disfavour hinge-bending regions. The resulting sequence-based prediction tool, HingeSeek, is available to run through a webserver at hingeseek.cmp.uea.ac.uk.

Project description:Background Spread through air space (STAS) is a novel invasive pattern of lung adenocarcinoma and is also a risk factor for recurrence and worse prognosis of lung adenocarcinoma. This study aimed to develop and validate a computed tomography (CT)-based logistic regression model to predict STAS in lung adenocarcinoma. Methods This retrospective study was approved by the institutional review board of two centers and included 578 patients (462 from center I and 116 from center II) with pathologically confirmed lung adenocarcinoma. STAS was identified from 90 center I patients (19.5%) and 28 center II patients (24.1%) from. The maximum diameter, nodule area, and area of solid components in part-solid nodules were measured. Twenty-one semantic characteristics were assessed. Univariate analysis was used to select CT characteristics, which were associated with STAS in the patient cohort of center I. Multivariable logistic regression was used to develop a CT characteristics-based model on those variables with statistical significance. The model was validated in the validation cohort and then tested in the external test cohort (patients from center II). The diagnostic performance of the model was measured by area under the curve (AUC) of receiver operating characteristic (ROC). Results At univariate analysis, age and 11 CT characteristics, including the maximum diameter of the tumor, the maximum area of the tumor, the area and ratio of the solid component, nodule type, pleural thickening, pleural retraction, mediastinal lymph node enlargement, vascular cluster sign, and lobulation, specula were found to be significantly associated with STAS. The optimal logistic regression model included age, maximum diameter and ratio of solid component with odds ratio (OR) value of 0.967 (95% CI: 0.944–0.988), 1.027 (95% CI: 1.008–1.046) and 5.14 (95% CI: 2.180–13.321), respectively. This model achieved an AUC of 0.801 (95% CI: 0.709–0.892) and 0.692 (95% CI: 0.518–0.866) in the validation cohort and the external test cohort, respectively. The difference was not statistically significant (P=0.280). Conclusions CT-based logistic regression machine learning model could preoperatively predict STAS in lung adenocarcinoma with excellent diagnosis performance, which could be supplementary to routine CT interpretation.

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Kernel-based logistic regression model for protein sequence without vectorialization.

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Kernel-based logistic regression model for protein sequence without vectorialization.

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