Efficient Haplotype Inference with Pseudo-Boolean Optimization

Abstract. Haplotype inference from genotype data is a key computational problem in bioinformatics, since retrieving directly haplotype information from DNA samples is not feasible using existing technology. One of the methods for solving this problem uses the pure parsimony criterion, an approach known as Haplotype Inference by Pure Parsimony (HIPP). Initial work in this area was based on a number of different Integer Linear Programming (ILP) models and branch and bound algorithms. Recent work has shown that the utilization of a Boolean Satisfiability (SAT) formulation and state of the art SAT solvers represents the most efficient approach for solving the HIPP problem. Motivated by the promising results obtained using SAT techniques, this paper investigates the utilization of modern Pseudo-Boolean Optimization (PBO) algorithms for solving the HIPP problem. The paper starts by applying PBO to existing ILP models. The results are promising, and motivate the development of a new PBO model (RPoly) for the HIPP problem, which has a compact representation and eliminates key symmetries. Experimental results indicate that RPoly outperforms the SAT-based approach on most problem instances, being, in general, significantly more efficient

Boosting Haplotype Inference with Local Search

Abstract. A very challenging problem in the genetics domain is to infer haplotypes from genotypes. This process is expected to identify genes affecting health, disease and response to drugs. One of the approaches to haplotype inference aims to minimise the number of different haplotypes used, and is known as haplotype inference by pure parsimony (HIPP). The HIPP problem is computationally difficult, being NP-hard. Recently, a SAT-based method (SHIPs) has been proposed to solve the HIPP problem. This method iteratively considers an increasing number of haplotypes, starting from an initial lower bound. Hence, one important aspect of SHIPs is the lower bounding procedure, which reduces the number of iterations of the basic algorithm, and also indirectly simplifies the resulting SAT model. This paper describes the use of local search to improve existing lower bounding procedures. The new lower bounding procedure is guaranteed to be as tight as the existing procedures. In practice the new procedure is in most cases considerably tighter, allowing significant improvement of performance on challenging problem instances.

Quantum Speed-ups for Boolean Satisfiability and Derivative-Free Optimization

In this thesis, we have considered two important problems, Boolean satisfiability (SAT) and derivative free optimization in the context of large scale quantum computers. In the first part, we survey well known classical techniques for solving satisfiability. We compute the approximate time it would take to solve SAT instances using quantum techniques and compare it with state-of-the heart classical heuristics employed annually in SAT competitions. In the second part of the thesis, we consider a few classically well known algorithms for derivative free optimization which are ubiquitously employed in engineering problems. We propose a quantum speedup to this classical algorithm by using techniques of the quantum minimum finding algorithm. In the third part of the thesis, we consider practical applications in the fields of bio-informatics, petroleum refineries and civil engineering which involve solving either satisfiability or derivative free optimization. We investigate if using known quantum techniques to speedup these algorithms directly translate to the benefit of industries which invest in technology to solve these problems. In the last section, we propose a few open problems which we feel are immediate hurdles, either from an algorithmic or architecture perspective to getting a convincing speedup for the practical problems considered

A branch-and-price approach for Pure Parsimony haplotyping

This thesis comes as the result of a detailed study of decomposition methods for large-scale problems and their application to a particular problem arising in computational biology. The improvements on computer capabilities and programming techniques in the last decades have widened the set of problems that can be easily solved as Mixed Integer Linear programs. However, several applications still require formulations that involve a non-tractable amount of data necessary to describe the geometry of the solution space. In these cases, decomposition methods are used to reduce the size of the problems to be addressed. In this thesis we propose the application of some of these methods, as Dantzig-Wolfe reformulation, column generation and Lagrangian relaxation, to a problem related to the study of the human genome. The human DNA is made of two double chains, each of which consists in a sequence of nucleotides. Among these, the ones related to the Single Nucleotide Polymorphisms (SNPs) are interesting as they describe the differences between individuals. We define a haplotype as a sequence of nucleotides that describes a portion of the SNPs found in a particular chromosome, and a genotype as the sequence that aggregates the information on SNPs coming from the double DNA chain of an individual. The problem we address falls into the class defining the Haplotyping Inference problem, that consists in recovering the structure of the haplotypes, given the information on the genotypes. In particular, we consider the parsimony criterion, which means that we want to find the minimum number of haplotypes able to explain all the genotypes. This problem is known to be APX-hard. There are several contributions in the literature that can be divided into two main different classes of mixed integer linear formulations. The first one presents a polynomial number of both variables and constraints, thus these formulations are solved using a branch-and-cut approach. The second class consists of formulations that present an exponential number of constraints and variables, solved with a branch-and-cut-and-price approach. The scope of this thesis is to investigate how a new formulation that involves an exponential number of variables and a polynomial number of constraints can be solved by a branch-and-price approach. Its aim is to provide a competitive algorithm with respect to other formulations from the literature, in particular those with a polynomial number of constraints and variables. We start by providing a review of the state of the art on the Haplotype Inference problem, with particular focus on the Mixed Integer Linear programming approaches for the Haplotype Inference by Pure Parsimony (HIPP) problem. We then consider a new mathematical programming formulation for HIPP that includes a set of quadratic constraints. By applying Dantzig-Wolfe reformulation, we obtained a new integer linear programming formulation, presenting an exponential number of variables and a polynomial number of constraints on the input data. This model is the basis for the development of a branch-and-price approach. Due to the large number of variables involved, a column-generation approach is needed to solve the linear relaxation at a generic node of the search tree. An initial feasible solution is easily found by means of heuristics and used as starting point to build the Restricted Master Problem (RMP). In order to find variables to be added to the RMP, we solve a dedicated subproblem, the pricing problem, that in our case presents a quadratic objective function. We propose different ways of solving the pricing problem. Among the exact methods, we consider the integer linear model obtained by linearizing the quadratic objective function and a Smart Enumeration approach, that partitions the set of feasible solutions and solves the pricing problem restricted to each subset, exploiting some extra available information to further reduce the size of the subproblems. As heuristic approaches, we at first note that the pricing problem is easily solved for particular haplotypes. Then, for investigating the remaining solutions we propose a local search-based heuristic and an Early-terminated Smart Enumeration, where we stop the Smart Enumeration approach as soon as we find a variable that can be added to the RMP. The oscillatory behaviour of the dual variables involved in the definition of the pricing problem is limited by introducing a stabilization technique adapted to our formulation. In particular, we extended the proof of convergence of this procedure, that consists in using dual values obtained as convex combinations between real dual variables and a chosen stability center, to the cases in which the stabilized dual variables are feasible for the dual problem. In order to solve the integer model, the solution of the linear relaxation is embedded in a branch-and-price approach. The branching rule we present is inspired to the well-known Ryan-Foster branching rule for set-partitioning problems. The correctness of our approach has been proved. Further observations on the similarity of the formulation's constraints to multiple set-covering ones suggest that we can relax a family of constraints to obtain a new formulation similar to a multiple set-covering. However, we note that the proposed branch-and-price algorithm applied to this formulation does not provide a feasible solution for HIPP, thus we need to integrate the proposed branching rule and recover a feasible optimal solution for HIPP. This branch-and-price approach has been implemented in C++, with the aid of SCIP libraries and Cplex solver. Results have been obtained from different classes of instances found in literature, coming from real biological data and generated using ad-hoc programs, as well as newly generated ones. The branch-and-price approach proposed for our formulation proves to be competitive with state-of-the-art polynomial-sized formulations. In fact, we can note how the linear relaxation of our formulation is tighter than other linear relaxations and provides an effective starting solution for the branch-and-price algorithm. Results show how our approach is efficient, in particular on the set of instances that contain a larger number of genotypes We proved therefore that a branch-and-price procedure provides a good solution approach for a formulation with exponential number of variables and polynomial number of constraints. Further work may include enhancements on the implementation details, such as exploring different ways of ordering the genotypes or combining heuristic and exact methods in the stabilized framework to solve the pricing problem. Moreover, it is possible to investigate the generalization of the proposed approach in order to solve set-partitioning problems