Fitness functions map large combinatorial spaces of biological sequences to properties of interest. Inferring these multimodal functions from experimental data is a central task in modern protein engineering. Global epistasis models are an effective and physically-grounded class of models for estimating fitness functions from observed data. These models assume that a sparse latent function is transformed by a monotonic nonlinearity to emit measurable fitness. Here we demonstrate that minimizing contrastive loss functions, such as the Bradley-Terry loss, is a simple and flexible technique for extracting the sparse latent function implied by global epistasis. We argue by way of a fitness-epistasis uncertainty principle that the nonlinearities in global epistasis models can produce observed fitness functions that do not admit sparse representations, and thus may be inefficient to learn from observations when using a Mean Squared Error (MSE) loss (a common practice). We show that contrastive losses are able to accurately estimate a ranking function from limited data even in regimes where MSE is ineffective. We validate the practical utility of this insight by showing contrastive loss functions result in consistently improved performance on benchmark tasks.
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We propose a framework where Fer and Wilcox expansions for the solution of differential equations are derived from two particular choices for the initial transformation that seeds the product expansion. In this scheme intermediate expansions can also be envisaged. Recurrence formulas are developed. A new lower bound for the convergence of the Wilcox expansion is provided as well as some applications of the results. In particular, two examples are worked out up to high order of approximation to illustrate the behavior of the Wilcox expansion.
Network meta-analysis combines aggregate data (AgD) from multiple randomised controlled trials, assuming that any effect modifiers are balanced across populations. Individual patient data (IPD) meta-regression is the ``gold standard'' method to relax this assumption, however IPD are frequently only available in a subset of studies. Multilevel network meta-regression (ML-NMR) extends IPD meta-regression to incorporate AgD studies whilst avoiding aggregation bias, but currently requires the aggregate-level likelihood to have a known closed form. Notably, this prevents application to time-to-event outcomes. We extend ML-NMR to individual-level likelihoods of any form, by integrating the individual-level likelihood function over the AgD covariate distributions to obtain the respective marginal likelihood contributions. We illustrate with two examples of time-to-event outcomes, showing the performance of ML-NMR in a simulated comparison with little loss of precision from a full IPD analysis, and demonstrating flexible modelling of baseline hazards using cubic M-splines with synthetic data on newly diagnosed multiple myeloma. ML-NMR is a general method for synthesising individual and aggregate level data in networks of all sizes. Extension to general likelihoods, including for survival outcomes, greatly increases the applicability of the method. R and Stan code is provided, and the methods are implemented in the multinma R package.
It is well known that for singular inconsistent range-symmetric linear systems, the generalized minimal residual (GMRES) method determines a least squares solution without breakdown. The reached least squares solution may be or not be the pseudoinverse solution. We show that a lift strategy can be used to obtain the pseudoinverse solution. In addition, we propose a new iterative method named RSMAR (minimum $\mathbf A$-residual) for range-symmetric linear systems $\mathbf A\mathbf x=\mathbf b$. At step $k$ RSMAR minimizes $\|\mathbf A\mathbf r_k\|$ in the $k$th Krylov subspace generated with $\{\mathbf A, \mathbf r_0\}$ rather than $\|\mathbf r_k\|$, where $\mathbf r_k$ is the $k$th residual vector and $\|\cdot\|$ denotes the Euclidean vector norm. We show that RSMAR and GMRES terminate with the same least squares solution when applied to range-symmetric linear systems. We provide two implementations for RSMAR. Our numerical experiments show that RSMAR is the most suitable method among GMRES-type methods for singular inconsistent range-symmetric linear systems.
Recently, addressing spatial confounding has become a major topic in spatial statistics. However, the literature has provided conflicting definitions, and many proposed definitions do not address the issue of confounding as it is understood in causal inference. We define spatial confounding as the existence of an unmeasured causal confounder with a spatial structure. We present a causal inference framework for nonparametric identification of the causal effect of a continuous exposure on an outcome in the presence of spatial confounding. We propose double machine learning (DML), a procedure in which flexible models are used to regress both the exposure and outcome variables on confounders to arrive at a causal estimator with favorable robustness properties and convergence rates, and we prove that this approach is consistent and asymptotically normal under spatial dependence. As far as we are aware, this is the first approach to spatial confounding that does not rely on restrictive parametric assumptions (such as linearity, effect homogeneity, or Gaussianity) for both identification and estimation. We demonstrate the advantages of the DML approach analytically and in simulations. We apply our methods and reasoning to a study of the effect of fine particulate matter exposure during pregnancy on birthweight in California.
We study the complexity (that is, the weight of the multiplication table) of the elliptic normal bases introduced by Couveignes and Lercier. We give an upper bound on the complexity of these elliptic normal bases, and we analyze the weight of some special vectors related to the multiplication table of those bases. This analysis leads us to some perspectives on the search for low complexity normal bases from elliptic periods.
The numerical solution of differential equations using machine learning-based approaches has gained significant popularity. Neural network-based discretization has emerged as a powerful tool for solving differential equations by parameterizing a set of functions. Various approaches, such as the deep Ritz method and physics-informed neural networks, have been developed for numerical solutions. Training algorithms, including gradient descent and greedy algorithms, have been proposed to solve the resulting optimization problems. In this paper, we focus on the variational formulation of the problem and propose a Gauss- Newton method for computing the numerical solution. We provide a comprehensive analysis of the superlinear convergence properties of this method, along with a discussion on semi-regular zeros of the vanishing gradient. Numerical examples are presented to demonstrate the efficiency of the proposed Gauss-Newton method.
The mean residual life function is a key functional for a survival distribution. It has practically useful interpretation as the expected remaining lifetime given survival up to a particular time point, and it also characterizes the survival distribution. However, it has received limited attention in terms of inference methods under a probabilistic modeling framework. In this paper, we seek to provide general inference methodology for mean residual life regression. Survival data often include a set of predictor variables for the survival response distribution, and in many cases it is natural to include the covariates as random variables into the modeling. We thus propose a Dirichlet process mixture modeling approach for the joint stochastic mechanism of the covariates and survival responses. This approach implies a flexible model structure for the mean residual life of the conditional response distribution, allowing general shapes for mean residual life as a function of covariates given a specific time point, as well as a function of time given particular values of the covariate vector. To expand the scope of the modeling framework, we extend the mixture model to incorporate dependence across experimental groups, such as treatment and control groups. This extension is built from a dependent Dirichlet process prior for the group-specific mixing distributions, with common locations and weights that vary across groups through latent bivariate beta distributed random variables. We develop properties of the proposed regression models, and discuss methods for prior specification and posterior inference. The different components of the methodology are illustrated with simulated data sets. Moreover, the modeling approach is applied to a data set comprising right censored survival times of patients with small cell lung cancer.
The degree-diameter problem consists of finding the maximum number of vertices $n$ of a graph with diameter $d$ and maximum degree $\Delta$. This problem is well studied, and has been solved for plane graphs of low diameter in which every face is bounded by a 3-cycle (triangulations), and plane graphs in which every face is bounded by a 4-cycle (quadrangulations). In this paper, we solve the degree diameter problem for plane graphs of diameter 3 in which every face is bounded by a 5-cycle (pentagulations). We prove that if $\Delta \geq 8$, then $n \leq 3\Delta - 1$ for such graphs. This bound is sharp for $\Delta$ odd.
Among semiparametric regression models, partially linear additive models provide a useful tool to include additive nonparametric components as well as a parametric component, when explaining the relationship between the response and a set of explanatory variables. This paper concerns such models under sparsity assumptions for the covariates included in the linear component. Sparse covariates are frequent in regression problems where the task of variable selection is usually of interest. As in other settings, outliers either in the residuals or in the covariates involved in the linear component have a harmful effect. To simultaneously achieve model selection for the parametric component of the model and resistance to outliers, we combine preliminary robust estimators of the additive component, robust linear $MM-$regression estimators with a penalty such as SCAD on the coefficients in the parametric part. Under mild assumptions, consistency results and rates of convergence for the proposed estimators are derived. A Monte Carlo study is carried out to compare, under different models and contamination schemes, the performance of the robust proposal with its classical counterpart. The obtained results show the advantage of using the robust approach. Through the analysis of a real data set, we also illustrate the benefits of the proposed procedure.
We introduce a single-set axiomatisation of cubical $\omega$-categories, including connections and inverses. We justify these axioms by establishing a series of equivalences between the category of single-set cubical $\omega$-categories, and their variants with connections and inverses, and the corresponding cubical $\omega$-categories. We also report on the formalisation of cubical $\omega$-categories with the Isabelle/HOL proof assistant, which has been instrumental in finding the single-set axioms.
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