Joint and individual analysis of breast cancer histologic images and genomic covariates

A key challenge in modern data analysis is understanding connections between complex and differing modalities of data. For example, two of the main approaches to the study of breast cancer are histopathology (analyzing visual characteristics of tumors) and genetics. While histopathology is the gold standard for diagnostics and there have been many recent breakthroughs in genetics, there is little overlap between these two fields. We aim to bridge this gap by developing methods based on Angle-based Joint and Individual Variation Explained (AJIVE) to directly explore similarities and differences between these two modalities. Our approach exploits Convolutional Neural Networks (CNNs) as a powerful, automatic method for image feature extraction to address some of the challenges presented by statistical analysis of histopathology image data. CNNs raise issues of interpretability that we address by developing novel methods to explore visual modes of variation captured by statistical algorithms (e.g. PCA or AJIVE) applied to CNN features. Our results provide many interpretable connections and contrasts between histopathology and genetics

STATISTICAL LEARNING OF INTEGRATIVE ANALYSIS

Integrative analysis is of great interest in modern scientific research. This dissertation mainly focuses on developing new statistical methods for integrative analysis. We first discuss a clustering analysis of a microbiome dataset in combination with phylogenetic information. Discovering disease related pneumotypes of the infected lower lung is difficult because the lower lung typically has few species of microbes and there is a low level of overlap from patient- to-patient, which makes it hard to calculate reliable distances between patients. We address this challenge by incorporating information from phylogenetic relationships, which results in improved clustering. When applied to an existing dataset, the method produces statistically distinct, easily described pneumotypes, which are better than those from standard approaches. In the second part, we discuss an integrative analysis of disparate data blocks measured on a common set of experimental subjects. We introduce Angle-Based Joint and Individual Variation Explained (AJIVE) capturing both joint and individual variation within each data block. This is a major improvement over earlier approaches to this challenge in terms of a new conceptual understanding, much better adaption to data heterogeneity and a fast linear algebra computation. Detailed comparison between AJIVE and competitors is discussed using a particular optimization view point. In the third part, we introduce a new perturbation framework, which estimates the angle between an arbitrary given direction and the underlying signal spaces. We also propose an efficient data-driven bootstrap procedure to compute this angle. While the Wedin bound in the AJIVE is “subspace oriented” and uniform for both row space and column space, this angle is “direction oriented” and specially adaptive to give improved inference in the row space.Doctor of Philosoph

Methodological and anatomical modifiers of Achilles tendon moment arm estimates implications for biomechanical modelling: Implications for biomechanical modelling

This thesis was submitted for the degree of Doctor of Philosophy and was awarded by Brunel University.Moment arms are important in many contexts. Various methods have been used to estimate moment arms. It has been shown that a moment arm changes as a function of joint angle and contraction state. However, besides the influence of these anatomical factors, results from recent studies suggest that the estimation of moment arm is also dependent on the methods employed. The overall goal of this thesis was to explore the interaction between the methodological and anatomical influences on moment arm and their effect on estimates of muscle-tendon forces during biomechanical modelling. The first experiment was a direct comparison between two different moment arm methods that have been previously used for the estimation of Achilles tendon moment arm. The results of this experiment revealed a significant difference in Achilles tendon moment arm length dependent on the moment arm method employed. However, besides the differences found, results from both methods were well correlated. Based on these results, methodological differences between these two methods were compared across different joint angles and contraction states in study two. Results of experiment two revealed that Achilles tendon moment arms obtained using both methods change in a similar way as a function of joint angle and contraction state. In the third experiment, results from the first two experiments were used to determine how methodological and anatomical influences on Achilles tendon moment arm would change muscle-tendon forces during the task of submaximal cycling. Results of the third experiment showed the importance of taking the method, ankle angle and contraction state dependence of Achilles tendon moment arm into account when using biomechanical modelling techniques. Together, these findings emphasis the importance of carefully considering methodological and anatomical modifiers when estimating Achilles tendon moment arm

Vertical stiffness asymmetries during drop jumping are related to ankle stiffness asymmetries

Asymmetry in vertical stiffness has been associated with increased injury incidence and impaired performance. The determinants of vertical stiffness asymmetry have not been previously investigated. Eighteen healthy males performed three unilateral drop jumps during which vertical stiffness and joint stiffness of the ankle and knee were calculated. Reactive strength index was also determined during the jumps using the ratio of flight time to ground contact time. ‘Moderate’ differences in vertical stiffness (t17 = 5.49; P < 0.001), ‘small’ differences in centre of mass displacement (t17 = -2.19; P = 0.043) and ‘trivial’ differences in ankle stiffness (t17 = 2.68; P = 0.016) were observed between stiff and compliant limbs. A model including ankle stiffness and reactive strength index symmetry angles explained 79% of the variance in vertical stiffness asymmetry (R2 = 0.79; P < 0.001). None of the symmetry angles were correlated to jump height or reactive strength index. Results suggest that asymmetries in ankle stiffness may play an important role in modulating vertical stiffness asymmetry in recreationally trained males

Determination of mass of IGR J17091-3624 from "Spectro-Temporal" variations during onset-phase of the 2011 outburst

The 2011 outburst of the black hole candidate IGR J17091-3624 followed the canonical track of state transitions along with the evolution of Quasi-Periodic Oscillation (QPO) frequencies before it began exhibiting various variability classes similar to GRS 1915+105. We use this canonical evolution of spectral and temporal properties to determine the mass of IGR J17091-3624, using three different methods, viz : Photon Index ($\Gamma$) - QPO frequency ($\nu$) correlation, QPO frequency ($\nu$) - Time (day) evolution and broadband spectral modelling based on Two Component Advective Flow. We provide a combined mass estimate for the source using a Naive Bayes based joint likelihood approach. This gives a probable mass range of 11.8 M$_{\odot}$ - 13.7 M$_{\odot}$. Considering each individual estimate and taking the lowermost and uppermost bounds among all three methods, we get a mass range of 8.7 M$_{\odot}$ - 15.6 M$_{\odot}$ with 90% confidence. We discuss the probable implications of our findings in the context of two component accretion flow.Comment: 10 pages, 5 figures (4 in colour), 2 tables. Accepted for publication in Ap

Musculoskeletal modelling of an ostrich (Struthio camelus) pelvic limb: influence of limb orientation on muscular capacity during locomotion

We developed a three-dimensional, biomechanical computer model of the 36 major pelvic limb muscle groups in an ostrich (Struthio camelus) to investigate muscle function in this, the largest of extant birds and model organism for many studies of locomotor mechanics, body size, anatomy and evolution. Combined with experimental data, we use this model to test two main hypotheses. We first query whether ostriches use limb orientations (joint angles) that optimize the moment-generating capacities of their muscles during walking or running. Next, we test whether ostriches use limb orientations at mid-stance that keep their extensor muscles near maximal, and flexor muscles near minimal, moment arms. Our two hypotheses relate to the control priorities that a large bipedal animal might evolve under biomechanical constraints to achieve more effective static weight support. We find that ostriches do not use limb orientations to optimize the moment-generating capacities or moment arms of their muscles. We infer that dynamic properties of muscles or tendons might be better candidates for locomotor optimization. Regardless, general principles explaining why species choose particular joint orientations during locomotion are lacking, raising the question of whether such general principles exist or if clades evolve different patterns (e.g., weighting of muscle force–length or force–velocity properties in selecting postures). This leaves theoretical studies of muscle moment arms estimated for extinct animals at an impasse until studies of extant taxa answer these questions. Finally, we compare our model’s results against those of two prior studies of ostrich limb muscle moment arms, finding general agreement for many muscles. Some flexor and extensor muscles exhibit self-stabilization patterns (posture-dependent switches between flexor/extensor action) that ostriches may use to coordinate their locomotion. However, some conspicuous areas of disagreement in our results illustrate some cautionary principles. Importantly, tendon-travel empirical measurements of muscle moment arms must be carefully designed to preserve 3D muscle geometry lest their accuracy suffer relative to that of anatomically realistic models. The dearth of accurate experimental measurements of 3D moment arms of muscles in birds leaves uncertainty regarding the relative accuracy of different modelling or experimental datasets such as in ostriches. Our model, however, provides a comprehensive set of 3D estimates of muscle actions in ostriches for the first time, emphasizing that avian limb mechanics are highly three-dimensional and complex, and how no muscles act purely in the sagittal plane. A comparative synthesis of experiments and models such as ours could provide powerful synthesis into how anatomy, mechanics and control interact during locomotion and how these interactions evolve. Such a framework could remove obstacles impeding the analysis of muscle function in extinct taxa

The lumbar spine has an intrinsic shape specific to each individual that remains a characteristic throughout flexion and extension

Peer reviewedPostprin

A novel approach for determining fatigue resistances of different muscle groups in static cases

In ergonomics and biomechanics, muscle fatigue models based on maximum endurance time (MET) models are often used to integrate fatigue effect into ergonomic and biomechanical application. However, due to the empirical principle of those MET models, the disadvantages of this method are: 1) the MET models cannot reveal the muscle physiology background very well; 2) there is no general formation for those MET models to predict MET. In this paper, a theoretical MET model is extended from a simple muscle fatigue model with consideration of the external load and maximum voluntary contraction in passive static exertion cases. The universal availability of the extended MET model is analyzed in comparison to 24 existing empirical MET models. Using mathematical regression method, 21 of the 24 MET models have intraclass correlations over 0.9, which means the extended MET model could replace the existing MET models in a general and computationally efficient way. In addition, an important parameter, fatigability (or fatigue resistance) of different muscle groups, could be calculated via the mathematical regression approach. Its mean value and its standard deviation are useful for predicting MET values of a given population during static operations. The possible reasons influencing the fatigue resistance were classified and discussed, and it is still a very challenging work to find out the quantitative relationship between the fatigue resistance and the influencing factors