Understanding the consequences of mutation for molecular fitness and function is a fundamental problem in biology. Recently, generative probabilistic models have emerged as a powerful tool for estimating fitness from evolutionary sequence data, with accuracy sufficient to predict both laboratory measurements of function and disease risk in humans, and to design novel functional proteins. Existing techniques rest on an assumed relationship between density estimation and fitness estimation, a relationship that we interrogate in this article. We prove that fitness is not identifiable from observational sequence data alone, placing fundamental limits on our ability to disentangle fitness landscapes from phylogenetic history. We show on real datasets that perfect density estimation in the limit of infinite data would, with high confidence, result in poor fitness estimation; current models perform accurate fitness estimation because of, not despite, misspecification. Our results challenge the conventional wisdom that bigger models trained on bigger datasets will inevitably lead to better fitness estimation, and suggest novel estimation strategies going forward.

In this paper, we investigate the question: Given a small number of datapoints, for example N = 30, how tight can PAC-Bayes and test set bounds be made? For such small datasets, test set bounds adversely affect generalisation performance by withholding data from the training procedure. In this setting, PAC-Bayes bounds are especially attractive, due to their ability to use all the data to simultaneouslylearn a posterior and bound its generalisation risk. We focus on the case of i.i.d.

Reliable yet efficient evaluation of generalisation performance of a proposed architecture is crucial to the success of neural architecture search (NAS). Traditional approaches face a variety of limitations: training each architecture to completion is prohibitively expensive, early stopped validation accuracy may correlate poorly with fully trained performance, and model-based estimators require large training sets. We instead propose to estimate the final test performance based on a simple measure of training speed. Our estimator is theoretically motivated by the connection between generalisation and training speed, and is also inspired by the reformulation of a PAC-Bayes bound under the Bayesian setting. Our modelfree estimator is simple, efficient, and cheap to implement, and does not require hyperparameter-tuning or surrogate training before deployment. We demonstrate on various NAS search spaces that our estimator consistently outperforms other alternatives in achieving better correlation with the true test performance rankings. We further show that our estimator can be easily incorporated into both query-based and one-shot NAS methods to improve the speed or quality of the search.

To gain intuition for how p-locality functions, we will introduce another notion of locality, called Markov locality, which will use the language of Markov blankets. We will prove that under relatively relaxed conditions p-locality and Markov locality are equivalent. This will allow us to relate the notion of locality to various graph structures commonly used to represent probability distributions, and will be a key step in proving Properties 2.1 and 2.2. We start by defining the Markov boundary, M(X,S), of a random variable X contained in a set of random variables S, as a minimal set such that p(X|S) = p(X|M(X,S)). The Markov boundary defines a minimal set of variables such that, conditioned on these variables, conditioning on no additional random variables in S changes the probability of X [39]. Similarly, we define the Markov blanket, M(X,S) for X in S as any set of variables such that conditioning on M(X,S), makes X conditionally independent from all other variables [39]. In this way, the Markov boundary is a Markov blanket but not all blankets are boundaries. Markov locality: Given probability distribution p(Z) and function f: RNX+NΘ RNΘ, the update function f(Z) is Markov-local with respect to the distribution p over Z if and only if k: Z Ωs.t. AMarkov boundary can be thought of as the set of variables that'locally' communicate with the parameter Θk, thus providing a natural measure of locality. Importantly, for Markov-locality to be of use, we would like the Markov boundaries of random variables in the model of interest to be unique.

A.1 Proof of Proposition 12 Proposition 1 The historical contrastive instance discrimination (HCID) can be modelled as a3 maximum likelihood problem optimized via Expectation Maximization.4 Maximum likelihood (ML) is a concept to describe the theoretic insights of clustering algorithms.6 PN n=1 Z(kn) = 1), and the last step of derivation13 employs Jensen's inequality [6, 7, 4]. Z(kn) log p(xq,kn; θE) (5) Expectation step focuses on estimating the posterior probability p(kn; xq,θE). We first gener-17 ate keys by a historical encoder: kt mn = Et m(xt), and xt Xtgt. Then, We calculate18 p(kn; xq,θE) = p(kt mn; xq,θE) = 1 (xq,kt mn), where 1 (xq,kt mn) = 1 if both belong to the19 positive pair; otherwise, 1 (xq,kt mn) = 0.20 Please note the notation "t m" shows that the k is encoded by a historical encoder.21