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Algorithms often have tunable parameters that impact performance metrics such as runtime and solution quality. For many algorithms used in practice, no parameter settings admit meaningful worst-case bounds, so the parameters are made available for the user to tune. Alternatively, parameters may be tuned implicitly within the proof of a worst-case approximation ratio or runtime bound. Worst-case instances, however, may be rare or nonexistent in practice. A growing body of research has demonstrated that a data-driven approach to parameter tuning can lead to significant improvements in performance. This approach uses atraining setof problem instances sampled from an unknown, application-specific distribution and returns a parameter setting with strong average performance on the training set. We provide techniques for derivinggeneralization guaranteesthat bound the difference between the algorithm’s average performance over the training set and its expected performance on the unknown distribution. Our results apply no matter how the parameters are tuned, be it via an automated or manual approach. The challenge is that for many types of algorithms, performance is a volatile function of the parameters: slightly perturbing the parameters can cause a large change in behavior. Prior research [e.g.,12,16,20,62] has proved generalization bounds by employing case-by-case analyses of greedy algorithms, clustering algorithms, integer programming algorithms, and selling mechanisms. We streamline these analyses with a general theorem that applies whenever an algorithm’s performance is a piecewise-constant, piecewise-linear, or—more generally—piecewise-structuredfunction of its parameters. Our results, which are tight up to logarithmic factors in the worst case, also imply novel bounds for configuring dynamic programming algorithms from computational biology. 

Tree search algorithms, such as branch-and-bound, are the most widely used tools for solving combinatorial and non-convex problems. For example, they are the foremost method for solving (mixed) integer programs and constraint satisfaction problems. Tree search algorithms come with a variety of tunable parameters that are notoriously challenging to tune by hand. A growing body of research has demonstrated the power of using a data-driven approach to automatically optimize the parameters of tree search algorithms. These techniques use atraining setof integer programs sampled from an application-specific instance distribution to find a parameter setting that has strong average performance over the training set. However, with too few samples, a parameter setting may have strong average performance on the training set but poor expected performance on future integer programs from the same application. Our main contribution is to provide the firstsample complexity guaranteesfor tree search parameter tuning. These guarantees bound the number of samples sufficient to ensure that the average performance of tree search over the samples nearly matches its future expected performance on the unknown instance distribution. In particular, the parameters we analyze weightscoring rulesused for variable selection. Proving these guarantees is challenging because tree size is a volatile function of these parameters: we prove that, for any discretization (uniform or not) of the parameter space, there exists a distribution over integer programs such that every parameter setting in the discretization results in a tree with exponential expected size, yet there exist parameter settings between the discretized points that result in trees of constant size. In addition, we provide data-dependent guarantees that depend on the volatility of these tree-size functions: our guarantees improve if the tree-size functions can be well approximated by simpler functions. Finally, via experiments, we illustrate that learning an optimal weighting of scoring rules reduces tree size. 

The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans—that is, optimized sequences of potentially different drug combinations—providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available. 

Tree-form sequential decision making (TFSDM) extends classical one-shot decision making by modeling tree-form interactions between an agent and a potentially adversarial environment. It captures the online decision-making problems that each player faces in an extensive-form game, as well as Markov decision processes and partially-observable Markov decision processes where the agent conditions on observed history. Over the past decade, there has been considerable effort into designing online optimization methods for TFSDM. Virtually all of that work has been in the full-feedback setting, where the agent has access to counterfactuals, that is, information on what would have happened had the agent chosen a different action at any decision node. Little is known about the bandit setting, where that assumption is reversed (no counterfactual information is available), despite this latter setting being well understood for almost 20 years in one-shot decision making. In this paper, we give the first algorithm for the bandit linear optimization problem for TFSDM that offers both (i) linear-time iterations (in the size of the decision tree) and (ii) O(T−−√) cumulative regret in expectation compared to any fixed strategy, at all times T. This is made possible by new results that we derive, which may have independent uses as well: 1) geometry of the dilated entropy regularizer, 2) autocorrelation matrix of the natural sampling scheme for sequence-form strategies, 3) construction of an unbiased estimator for linear losses for sequence-form strategies, and 4) a refined regret analysis for mirror descent when using the dilated entropy regularizer.