Validating supervised learning approaches to the prediction of disease status in neuroimaging

Alzheimer’s disease (AD) is a serious global health problem with growing human and monetary costs. Neuroimaging data offers a rich source of information about pathological changes in the brain related to AD, but its high dimensionality makes it difficult to fully exploit using conventional methods. Automated neuroimage assessment (ANA) uses supervised learning to model the relationships between imaging signatures and measures of disease. ANA methods are assessed on the basis of their predictive performance, which is measured using cross validation (CV). Despite its ubiquity, CV is not always well understood, and there is a lack of guidance as to best practice. This thesis is concerned with the practice of validation in ANA. It introduces several key challenges and considers potential solutions, including several novel contributions. Part I of this thesis reviews the field and introduces key theoretical concepts related to CV. Part II is concerned with bias due to selective reporting of performance results. It describes an empirical investigation to assess the likely level of this bias in the ANA literature and relative importance of several contributory factors. Mitigation strategies are then discussed. Part III is concerned with the optimal selection of CV strategy with respect to bias, variance and computational cost. Part IV is concerned with the statistical analysis of CV performance results. It discusses the failure of conventional statistical procedures, reviews previous alternative approaches, and demonstrates a new heuristic solution that fares well in preliminary investigations. Though the focus of this thesis is AD ANA, the issues it addresses are of great importance to all applied machine learning fields where samples are limited and predictive performance is critical

Putting reaction-diffusion systems into port-Hamiltonian framework

Reaction-diffusion systems model the evolution of the constituents distributed in space under the influence of chemical reactions and diffusion [6], [10]. These systems arise naturally in chemistry [5], but can also be used to model dynamical processes beyond the realm of chemistry such as biology, ecology, geology, and physics. In this paper, by adopting the viewpoint of port-controlled Hamiltonian systems [7] we cast reaction-diffusion systems into the portHamiltonian framework. Aside from offering conceptually a clear geometric interpretation formalized by a Stokes-Dirac structure [8], a port-Hamiltonian perspective allows to treat these dissipative systems as interconnected and thus makes their analysis, both quantitative and qualitative, more accessible from a modern dynamical systems and control theory point of view. This modeling approach permits us to draw immediately some conclusions regarding passivity and stability of reaction-diffusion systems. It is well-known that adding diffusion to the reaction system can generate behaviors absent in the ode case. This primarily pertains to the problem of diffusion-driven instability which constitutes the basis of Turing’s mechanism for pattern formation [11], [5]. Here the treatment of reaction-diffusion systems as dissipative distributed portHamiltonian systems could prove to be instrumental in supply of the results on absorbing sets, the existence of the maximal attractor and stability analysis. Furthermore, by adopting a discrete differential geometrybased approach [9] and discretizing the reaction-diffusion system in port-Hamiltonian form, apart from preserving a geometric structure, a compartmental model analogous to the standard one [1], [2] is obtaine

Removal of antagonistic spindle forces can rescue metaphase spindle length and reduce chromosome segregation defects

Regular Abstracts - Tuesday Poster Presentations: no. 1925Metaphase describes a phase of mitosis where chromosomes are attached and oriented on the bipolar spindle for subsequent segregation at anaphase. In diverse cell types, the metaphase spindle is maintained at a relatively constant length. Metaphase spindle length is proposed to be regulated by a balance of pushing and pulling forces generated by distinct sets of spindle microtubules and their interactions with motors and microtubule-associated proteins (MAPs). Spindle length appears important for chromosome segregation fidelity, as cells with shorter or longer than normal metaphase spindles, generated through deletion or inhibition of individual mitotic motors or MAPs, showed chromosome segregation defects. To test the force balance model of spindle length control and its effect on chromosome segregation, we applied fast microfluidic temperature-control with live-cell imaging to monitor the effect of switching off different combinations of antagonistic forces in the fission yeast metaphase spindle. We show that spindle midzone proteins kinesin-5 cut7p and microtubule bundler ase1p contribute to outward pushing forces, and spindle kinetochore proteins kinesin-8 klp5/6p and dam1p contribute to inward pulling forces. Removing these proteins individually led to aberrant metaphase spindle length and chromosome segregation defects. Removing these proteins in antagonistic combination rescued the defective spindle length and, in some combinations, also partially rescued chromosome segregation defects. Our results stress the importance of proper chromosome-to-microtubule attachment over spindle length regulation for proper chromosome segregation.postprin

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin