Widespread unexplained variations in clinical practices and patient outcomes, together with rapidly growing availability of data, suggest major opportunities for improving the quality of medical care. One way that healthcare practitioners try to do that is by participating in organized healthcare quality improvement collaboratives (QICs). In QICs, teams of practitioners from different hospitals exchange information on clinical practices, with the aim of improving health outcomes at their own institutions. However, what works in one hospital may not work in others with different local contexts, due to non-linear interactions among various demographics, treatments, and practices. I.e., the clinical landscape is a complex socio-technical system that is difficult to search. In this dissertation we develop methods for analysis and modeling of complex systems, and apply them to the problem of healthcare improvement. Searching clinical landscapes is a multi-objective dynamic problem, as hospitals simultaneously optimize for multiple patient outcomes. We first discuss a general method we developed for finding which changes in features may be associated with various changes in outcomes at different points in time with different delays in affect. This method correctly inferred interactions on synthetic data, however the complexity and incompleteness of the real hospital dataset available to us limited the usefulness of this approach. We then discuss an agent-based model (ABM) of QICs to show that teams comprising individuals from similar institutions outperform those from more diverse institutions, under nearly all conditions, and that this advantage increases with the complexity of the landscape and the level of noise in assessing performance. We present data from a network of real hospitals that provides encouraging evidence of a high degree of similarity in clinical practices among hospitals working together in QIC teams. Based on model outcomes, we propose a secure virtual collaboration system that would allow hospitals to efficiently identify potentially better practices in use at other institutions similar to theirs, without any institutions having to sacrifice the privacy of their own data. To model the search for quality improvement in clinical fitness landscapes, we need benchmark landscapes with tunable feature interactions. NK landscapes have been the classic benchmarks for modeling landscapes with epistatic interactions, but the ruggedness is only tunable in discrete jumps. Walsh polynomials are more finely tunable than NK landscapes, but are only defined on binary alphabets and, in general, have unknown global maximum and minimum. We define a different subset of interaction models that we dub as NM landscapes. NM landscapes are shown to have smoothly tunable ruggedness and difficulty and known location and value of global maxima. With additional constraints, we can also determine the location and value of the global minima. The proposed NM landscapes can be used with alphabets of any arity, from binary to real-valued, without changing the complexity of the landscape. NM landscapes are thus useful models for simulating clinical landscapes with binary or real decision variables and varying number of interactions. NM landscapes permit proper normalization of fitnesses so that search results can be fairly averaged over different random landscapes with the same parameters, and fairly compared between landscapes with different parameters. In future work we plan to use NM landscapes as benchmarks for testing various algorithms that can discover epistatic interactions in real world datasets.

Sequence divergence of orthologous proteins enables adaptation to a plethora of environmental stresses and promotes evolution of novel functions. As one of the most common motifs in biology capable of diverse enzymatic functions, the TIM barrel represents an ideal model system for mapping the phenotypic manifestations of protein sequence. Limits on evolution imposed by constraints on sequence and structure were investigated using a model TIM barrel protein, indole-3-glycerol phosphate synthase (IGPS). Exploration of fitness landscapes of phylogenetically distant orthologs provides a strategy for elucidating the complex interrelationship in the context of a protein fold. Fitness effects of point mutations in three phylogenetically divergent IGPS proteins during adaptation to temperature stress were probed by auxotrophic complementation of yeast with prokaryotic, thermophilic IGPS. Significant correlations between the fitness landscapes of distant orthologues implicate both sequence and structure as primary forces in defining the TIM barrel fitness landscape. These results suggest that fitness landscapes of point mutants can be successfully translocated in sequence space, where knowledge of one landscape may be predictive for the landscape of another ortholog. Analysis of a surprising class of beneficial mutations in all three IGPS orthologs pointed to a long-range allosteric pathway towards the active site of the protein. Biophysical and biochemical analyses provided insights into the molecular mechanism of these beneficial fitness effects. Epistatic interactions suggest that the helical shell may be involved in the observed allostery. Taken together, knowledge of the fundamental properties of the TIM protein architecture will provide new strategies for de novo protein design of a highly targeted protein fold.

Affordability of products and services is an economic benefit that should accrue to consumers, whether they are corporations, government agencies or individuals. This concept of affordability goes beyond conventional wisdom that considers affordability as the ability to pay the price of a product or service. This dissertation defines and explores a broader concept of affordability – one of fitness to perform at the level of quality required by the consumer, to perform at that level whenever the product or service is used, and to do so with minimum consumption of resources. This concept of affordability is applied to technological systems by using the complexity sciences concept of fitness as the metaphor for technological systems' fitness. During a system design evolution, the specific design outcome is determined by that set of design search paths followed – it is path dependent. Dynamic mechanisms create, dictate and maintain path dependence. Initial conditions define the start and direction of a path. During subsequent design steps, positive feedback influences the designer to continue on that path. This dissertation describes underlying mechanisms that create, dictate and maintain path dependence; discusses the effects of path dependence on system design and system affordability; models these effects using system dynamics modeling; and suggests actions to address its effects. This dissertation also addresses several types of fitness landscapes, and suggests that the Data Envelopment Analysis (DEA) solution space is a form of fitness landscape suitable for evaluating the efficiency, and thus the fitness, of research and development (R&D) projects. It describes the use of DEA to evaluate and select Department of Defense (D0D) R&D projects as a new application of DEA. / Ph. D.

abstract: This thesis consists of three projects employing complexity economics methods to explore firm dynamics. The first is the Firm Ecosystem Model, which addresses the institutional conditions of capital access and entrenched competitive advantage. Larger firms will be more competitive than smaller firms due to efficiencies of scale, but the persistence of larger firms is also supported institutionally through mechanisms such as tax policy, capital access mechanisms and industry-favorable legislation. At the same time, evidence suggests that small firms innovate more than larger firms, and an aggressive firm-as-value perspective incentivizes early investment in new firms in an attempt to capture that value. The Ecological Firm Model explores the effects of the differences in innovation and investment patterns and persistence rates between large and small firms. The second project is the Structural Inertia Model, which is intended to build theory around why larger firms may be less successful in capturing new marketshare than smaller firms, as well as to advance fitness landscape methods. The model explores the possibility that firms with larger scopes may be less effective in mitigating the costs of cooperation because conditions may arise that cause intrafirm conflicts. The model is implemented on structured fitness landscapes derived using the maximal order of interaction (NM) formulation and described using local optima networks (LONs), thus integrating these novel techniques. Finally, firm dynamics can serve as a proxy for the ease at which people can voluntarily enter into the legal cooperative agreements that constitute firms. The third project, the Emergent Firm model, is an exploration of how this dynamic of voluntary association may be affected by differing capital institutions, and explores the macroeconomic implications of the economies that emerge out of the various resulting firm populations. / Dissertation/Thesis / Doctoral Dissertation Applied Mathematics for the Life and Social Sciences 2018

Avec la révolution moléculaire en biologie, une compréhension des mécanismes de la relation génotype-phénotype est devenue possible. Récemment, les progrès réalisés dans la synthèse et le séquençage de l’ADN ont permis le développement d’expériences de deep-mutational scanning capable de quantifier divers phénotypes pour un ensemble de génotypes sur toute la longueur d’un gène. Ces ensembles de données sont non seulement intéressants en eux-mêmes, mais permettent également de tester de manière rigoureuse des modèles phénotypiques quantitatifs. Nous avons utilisé cette technologie pour caractériser les cartes séquence-fitness de 3 systèmes bactériens modèles: un régulateur global, la CRP, une enzyme de résistance aux antibiotiques, la β-lactamase, et une petite voie métabolique constituée des enzymes AraA et AraB. Ces systèmes ont été choisis pour éclairer les rôles de différentes caractéristiques dans la formation de la relation génotype-fitness (réseaux de régulations, stabilité des protéines et flux métabolique). Nous constatons que la tendance globale des effets sur le fitness semble prévaloir sur les tendances spécifiques. Ceci nous conduit à penser qu’une grande partie de la relation entre le génotype et le fitness pourrait être expliquée à partir de la forme des fonctions de phénotype-fitness. Par ailleurs, nous voyons que la caractérisation de la relation génotype-fitness dans différents systèmes peut être un moyen puissant d’obtenir des informations sur les phénotypes pertinents. / With the molecular revolution in Biology, a mechanistic understanding of the genotype-phenotype relationship became possible. Recently, advances in DNA synthesis and sequencing have enabled the development of deep-mutational scanning experiments, capable of scoring comprehensive libraries of genotypes for a variety of phenotypes over the length of entire genes. Such datasets are not only interesting in themselves, but also allow rigorous testing of quantitative phenotypic models. We used this technology to characterise sequence-fitness maps for 3 model bacterial systems: a global regulator, CRP, an antibiotic-resistance enzyme, β-lactamase, and a small metabolic pathway, consisting of the enzymes AraA and AraB. These different systems were chosen to illuminate the roles of different mechanistic features in shaping the genotype-fitness relationship (regulatory wiring, protein stability and metabolic flux). We find that smooth patterns of fitness effects tend to prevail over idiosyncrasy, indicating that much of the genotype-fitness relationship could be understood from the global shape of smooth underlying phenotype-fitness functions. On the flip side, we see that characterising the genotype-fitness relationship in different systems can be a powerful way to glean phenotypic insights.

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The evolution of metabolism regulation is an intertwined process, where different strategies are constantly being developed towards a cognitive ability to perceive and respond to an environment. Organisms depend on an orchestration of a complex set of chemical reactions: maintaining homeostasis with a changing environment, while simultaneously sending material and energetic resources to where they are needed. The success of an organism requires efficient metabolic regulation, highlighting the connection between evolution, population dynamics and the underlying biochemistry. In this work, I represent organisms as coupled information-processing networks, that is, gene-regulatory networks receiving signals from the environment and acting on chemical reactions, eventually affecting material flows. I discuss the mechanisms through which metabolism control is improved during evolution and how the nonlinearities of competition influence this solution-searching process. The propagation of the populations through the resulting landscapes generally point to the role of the rhythm of cell division as an essential phenotypic feature driving evolution. Subsequently, as it naturally follows, different representations of organisms as oscillators are constructed to indicate more precisely how the interplay between competition, maturation timing and cell-division synchronisation affects the expected evolutionary outcomes, not always leading to the \"survival of the fastest\".

The evolution of metabolism regulation is an intertwined process, where different strategies are constantly being developed towards a cognitive ability to perceive and respond to an environment. Organisms depend on an orchestration of a complex set of chemical reactions: maintaining homeostasis with a changing environment, while simultaneously sending material and energetic resources to where they are needed. The success of an organism requires efficient metabolic regulation, highlighting the connection between evolution, population dynamics and the underlying biochemistry. In this work, I represent organisms as coupled information-processing networks, that is, gene-regulatory networks receiving signals from the environment and acting on chemical reactions, eventually affecting material flows. I discuss the mechanisms through which metabolism control is improved during evolution and how the nonlinearities of competition influence this solution-searching process. The propagation of the populations through the resulting landscapes generally point to the role of the rhythm of cell division as an essential phenotypic feature driving evolution. Subsequently, as it naturally follows, different representations of organisms as oscillators are constructed to indicate more precisely how the interplay between competition, maturation timing and cell-division synchronisation affects the expected evolutionary outcomes, not always leading to the \"survival of the fastest\".