Scientific discovery in a model-centric framework: Reproducibility, innovation, and epistemic diversity.

Consistent confirmations obtained independently of each other lend credibility to a scientific result. We refer to results satisfying this consistency as reproducible and assume that reproducibility is a desirable property of scientific discovery. Yet seemingly science also progresses despite irreproducible results, indicating that the relationship between reproducibility and other desirable properties of scientific discovery is not well understood. These properties include early discovery of truth, persistence on truth once it is discovered, and time spent on truth in a long-term scientific inquiry. We build a mathematical model of scientific discovery that presents a viable framework to study its desirable properties including reproducibility. In this framework, we assume that scientists adopt a model-centric approach to discover the true model generating data in a stochastic process of scientific discovery. We analyze the properties of this process using Markov chain theory, Monte Carlo methods, and agent-based modeling. We show that the scientific process may not converge to truth even if scientific results are reproducible and that irreproducible results do not necessarily imply untrue results. The proportion of different research strategies represented in the scientific population, scientists' choice of methodology, the complexity of truth, and the strength of signal contribute to this counter-intuitive finding. Important insights include that innovative research speeds up the discovery of scientific truth by facilitating the exploration of model space and epistemic diversity optimizes across desirable properties of scientific discovery.

Inference on admixture fractions in a mechanistic model of recurrent admixture.

Signatures of recent historical admixture are ubiquitous in human populations. We present a mechanistic model of admixture with two source populations, encompassing recurrent admixture periods and study the distribution of admixture fractions for finite but arbitrary genome size. We provide simulation-based methods to estimate the introgression parameters and discuss the implications of reaching stationarity on estimability of parameters when there are recurrent admixture events with different rates.

Inference from the stationary distribution of allele frequencies in a family of Wright-Fisher models with two levels of genetic variability.

The distribution of allele frequencies obtained from diffusion approximations to Wright-Fisher models is useful in developing intuition about the population level effects of evolutionary processes. The statistical properties of the stationary distributions of K-allele models have been extensively studied under neutrality or under selection. Here, we introduce a new family of Wright-Fisher models in which there are two hierarchical levels of genetic variability. The genotypes composed of alleles differing from each other at the selected level have fitness differences with respect to each other and evolve under selection. The genotypes composed of alleles differing from each other only at the neutral level have the same fitness and evolve under neutrality. We show that with an appropriate scaling of the mutation parameter with respect to the number of alleles at each level, the frequencies of alleles at the selected and the neutral level are conditionally independent of each other, conditional on knowing the number of alleles at all levels. This conditional independence allows us to simulate from the joint stationary distribution of the allele frequencies. We use these simulated frequencies to perform inference on parameters of the model with two levels of genetic variability using Approximate Bayesian Computation.

Efficient simulation and likelihood methods for non-neutral multi-allele models.

Throughout the 1980s, Simon Tavaré made numerous significant contributions to population genetics theory. As genetic data, in particular DNA sequence, became more readily available, a need to connect population-genetic models to data became the central issue. The seminal work of Griffiths and Tavaré (1994a , 1994b , 1994c) was among the first to develop a likelihood method to estimate the population-genetic parameters using full DNA sequences. Now, we are in the genomics era where methods need to scale-up to handle massive data sets, and Tavaré has led the way to new approaches. However, performing statistical inference under non-neutral models has proved elusive. In tribute to Simon Tavaré, we present an article in spirit of his work that provides a computationally tractable method for simulating and analyzing data under a class of non-neutral population-genetic models. Computational methods for approximating likelihood functions and generating samples under a class of allele-frequency based non-neutral parent-independent mutation models were proposed by Donnelly, Nordborg, and Joyce (DNJ) (Donnelly et al., 2001). DNJ (2001) simulated samples of allele frequencies from non-neutral models using neutral models as auxiliary distribution in a rejection algorithm. However, patterns of allele frequencies produced by neutral models are dissimilar to patterns of allele frequencies produced by non-neutral models, making the rejection method inefficient. For example, in some cases the methods in DNJ (2001) require 10(9) rejections before a sample from the non-neutral model is accepted. Our method simulates samples directly from the distribution of non-neutral models, making simulation methods a practical tool to study the behavior of the likelihood and to perform inference on the strength of selection.

Inference on the strength of balancing selection for epistatically interacting loci.

Existing inference methods for estimating the strength of balancing selection in multi-locus genotypes rely on the assumption that there are no epistatic interactions between loci. Complex systems in which balancing selection is prevalent, such as sets of human immune system genes, are known to contain components that interact epistatically. Therefore, current methods may not produce reliable inference on the strength of selection at these loci. In this paper, we address this problem by presenting statistical methods that can account for epistatic interactions in making inference about balancing selection. A theoretical result due to Fearnhead (2006) is used to build a multi-locus Wright-Fisher model of balancing selection, allowing for epistatic interactions among loci. Antagonistic and synergistic types of interactions are examined. The joint posterior distribution of the selection and mutation parameters is sampled by Markov chain Monte Carlo methods, and the plausibility of models is assessed via Bayes factors. As a component of the inference process, an algorithm to generate multi-locus allele frequencies under balancing selection models with epistasis is also presented. Recent evidence on interactions among a set of human immune system genes is introduced as a motivating biological system for the epistatic model, and data on these genes are used to demonstrate the methods.

Estimation of selection intensity under overdominance by Bayesian methods.

A balanced pattern in the allele frequencies of polymorphic loci is a potential sign of selection, particularly of overdominance. Although this type of selection is of some interest in population genetics, there exists no likelihood based approaches specifically tailored to make inference on selection intensity. To fill this gap, we present Bayesian methods to estimate selection intensity under k-allele models with overdominance. Our model allows for an arbitrary number of loci and alleles within a locus. The neutral and selected variability within each locus are modeled with corresponding k-allele models. To estimate the posterior distribution of the mean selection intensity in a multilocus region, a hierarchical setup between loci is used. The methods are demonstrated with data at the Human Leukocyte Antigen loci from world-wide populations.