Haplotype Inference Problem Research Articles

The complete parsimony haplotype inference problem and algorithms based on integer programming, branch-and-bound and Boolean satisfiability

Haplotype inference by pure parsimony (Hipp) is a well-known paradigm for haplotype inference. In order to assess the biological significance of this paradigm, we generalize the problem of Hipp to the problem of finding all optimal solutions, which we call Chipp. We study intrinsic haplotype features, such as backbone haplotypes and fat genotypes as well as equal columns and decomposability. We explicitly exploit these features in three computational approaches that are based on integer linear programming, depth-first branch-and-bound, and Boolean satisfiability. Further we introduce two hybrid algorithms that draw upon the diverse strengths of the approaches. Our experimental analysis shows that our optimized algorithms are significantly superior to the baseline algorithms, often with orders of magnitude faster running time. Finally, our experiments provide some useful insights into the intrinsic features of this important problem.

An improved heuristic for haplotype inference

Haplotypes include essential SNP information used for a variety of purposes such as investigating potential links between certain diseases and genetic variations. Given a set of genotypes, the haplotype inference problem based on pure parsimony is the problem of finding a minimum set of haplotypes that explains all the given genotypes. The problem is especially important because, while it is fairly inexpensive to obtain genotypes, other approaches to obtaining haplotypes are significantly expensive. There are two types of methods proposed for the problem, namely exact and inexact methods. Existing exact methods guarantee obtaining purely parsimonious solutions but have exponential time-complexities and are not practical for large number or length of genotypes. However, inexact methods are relatively fast but do not always obtain optimum solutions. In this paper, an improved heuristic is proposed, based on which new inexact and exact methods are provided. Experimental results indicate that the proposed methods replace the state-of-the-art inexact and exact methods for the problem.

Maximum-Parsimony Haplotype Inference Based on Sparse Representations of Genotypes

The haplotypes of an individual can be used to predict diseases and help designing drugs. However, experimentally determining haplotypes is expensive and time-consuming, so genotypes are usually measured instead. Given the set of genotypes for a group of unrelated individuals, it is possible to infer the haplotype pair for each subject based on the maximum parsimony principle. Finding the exact solution to this problem is NP-hard. We propose two related formulations of the haplotype inference problem that translate the maximum parsimony principle into the sparse representation of genotypes. In the first formulation we look for the set of haplotypes that explain the genotypes such that the resulting frequency vector of haplotypes is as sparse as possible. The sparseness condition is achieved by minimizing the Tsallis entropy of the frequency vector, which is still an NP-hard problem. We propose a method that enumerates all local minima with high probability by solving a set of integer linear programs of low dimensionality. The minimizer is then found by identifying the local minimum point that achieves the lowest Tsallis entropy. In the second formulation, we state the haplotypes inference as a sparse dictionary selection problem. Each genotype is reconstructed by a haplotype pair selected from a set of available haplotypes that needs to be sparse. This leads to an approximately submodular maximization problem and therefore, can be solved with a fast greedy method. We test the proposed solutions with different data sets and compare the performance with the state-of-the-art methods, achieving similar or better results.

Haplotype Inference Constrained by Plausible Haplotype Data

The haplotype inference problem (HIP) asks to find a set of haplotypes which resolve a given set of genotypes. This problem is important in practical fields such as the investigation of diseases or other types of genetic mutations. In order to find the haplotypes which are as close as possible to the real set of haplotypes that comprise the genotypes, two models have been suggested which are by now well-studied: The perfect phylogeny model and the pure parsimony model. All known algorithms up till now for haplotype inference may find haplotypes that are not necessarily plausible, i.e., very rare haplotypes or haplotypes that were never observed in the population. In order to overcome this disadvantage, we study in this paper, a new constrained version of HIP under the above-mentioned models. In this new version, a pool of plausible haplotypes H is given together with the set of genotypes G, and the goal is to find a subset H ⊆ H that resolves G. For constrained perfect phlogeny haplotyping (CPPH), we provide initial insights and polynomial-time algorithms for some restricted cases of the problem. For constrained parsimony haplotyping (CPH), we show that the problem is fixed parameter tractable when parameterized by the size of the solution set of haplotypes.

Haplotyping populations by pure parsimony based on compatible genotypes and greedy heuristics

The population haplotype inference problem based on the pure parsimony criterion (HIPP) infers an m × n genotype matrix for a population by a 2 m × n haplotype matrix with the minimum number of distinct haplotypes. Previous integer programming based HIPP solution methods are time-consuming, and their practical effectiveness remains unevaluated. On the other hand, previous heuristic HIPP algorithms are efficient, but their theoretical effectiveness in terms of optimality gaps has not been evaluated, either. We propose two new heuristic HIPP algorithms (MGP and GHI) and conduct more complete computational experiments. In particular, MGP exploits the compatible relations among genotypes to solve a reduced integer linear programming problem so that a solution of good quality can be obtained very quickly; GHI exploits a weight mechanism to selects better candidate haplotypes in a greedy fashion. The computational results show that our proposed algorithms are efficient and effective, especially for solving cases with larger recombination rates.

Mathematical properties and bounds on haplotyping populations by pure parsimony

Although the haplotype data can be used to analyze the function of DNA, due to the significant efforts required in collecting the haplotype data, usually the genotype data is collected and then the population haplotype inference (PHI) problem is solved to infer haplotype data from genotype data for a population. This paper investigates the PHI problem based on the pure parsimony criterion (HIPP), which seeks the minimum number of distinct haplotypes to infer a given genotype data. We analyze the mathematical structure and properties for the HIPP problem, propose techniques to reduce the given genotype data into an equivalent one of much smaller size, and analyze the relations of genotype data using a compatible graph. Based on the mathematical properties in the compatible graph, we propose a maximal clique heuristic to obtain an upper bound, and a new polynomial-sized integer linear programming formulation to obtain a lower bound for the HIPP problem.

Haplotype Inference by Pure Parsimony: A Survey

Given a set of genotypes from a population, the process of recovering the haplotypes that explain the genotypes is called haplotype inference. The haplotype inference problem under the assumption of pure parsimony consists in finding the smallest number of haplotypes that explain a given set of genotypes. This problem is NP-hard. The original formulations for solving the Haplotype Inference by Pure Parsimony (HIPP) problem were based on integer linear programming and branch-and-bound techniques. More recently, solutions based on Boolean satisfiability, pseudo-Boolean optimization, and answer set programming have been shown to be remarkably more efficient. HIPP can now be regarded as a feasible approach for haplotype inference, which can be competitive with other different approaches. This article provides an overview of the methods for solving the HIPP problem, including preprocessing, bounding techniques, and heuristic approaches. The article also presents an empirical evaluation of exact HIPP solvers on a comprehensive set of synthetic and real problem instances. Moreover, the bounding techniques to the exact problem are evaluated. The final section compares and discusses the HIPP approach with a well-established statistical method that represents the reference algorithm for this problem.

Solving haplotype inference problem with non-genotyped founders via integer linear programming

In Cheng et al. (Acta Math. Appl. Sin. (English Ser.), 25:475---486, 2009), the authors present a cubic time zero-recombination haplotyping algorithm that can handle some incomplete pedigrees. More specifically, the algorithm can handle pedigrees with non-genotyped founders, provided that for each nuclear family at least one parent is genotyped and each non-genotyped founder appears in at most one nuclear family. The importance of this lies in that such cases frequently happen in real data, because some founders may have passed away and their genotype data can no longer be collected. In this paper, we further generalize the above algorithm by removing the first restriction. We present a new integer linear programming based algorithm that handles pedigrees with non-genotyped founders. The new algorithm allows the pedigrees to have nuclear families where both parents are non-genotyped founders, provided that each non-genotyped founder appears in at most one nuclear family.

CollHaps: A Heuristic Approach to Haplotype Inference by Parsimony

Haplotype data play a relevant role in several genetic studies, e.g., mapping of complex disease genes, drug design, and evolutionary studies on populations. However, the experimental determination of haplotypes is expensive and time-consuming. This motivates the increasing interest in techniques for inferring haplotype data from genotypes, which can instead be obtained quickly and economically. Several such techniques are based on the maximum parsimony principle, which has been justified by both experimental results and theoretical arguments. However, the problem of haplotype inference by parsimony was shown to be NP-hard, thus limiting the applicability of exact parsimony-based techniques to relatively small data sets. In this paper, we introduce collapse rule, a generalization of the well-known Clark's rule, and describe a new heuristic algorithm for haplotype inference (implemented in a program called CollHaps), based on parsimony and the iterative application of collapse rules. The performance of CollHaps is tested on several data sets. The experiments show that CollHaps enables the user to process large data sets obtaining very "parsimonious" solutions in short processing times. They also show a correlation, especially for large data sets, between parsimony and correct reconstruction, supporting the validity of the parsimony principle to produce accurate solutions.

Haplotype inference with pseudo-Boolean optimization

The fast development of sequencing techniques in the recent past has required an urgent development of efficient and accurate haplotype inference tools. Besides being a crucial issue in genetics, haplotype inference is also a challenging computational problem. Among others, pure parsimony is a viable modeling approach to solve the problem of haplotype inference and also an interesting NP-hard problem in itself. Recently, the introduction of SAT-based methods, including pseudo-Boolean optimization (PBO) methods, has produced very efficient solvers. This paper provides a detailed description of RPoly, a PBO approach for the haplotype inference by pure parsimony (HIPP) problem. Moreover, an extensive evaluation of existent HIPP solvers, on a comprehensive set of instances, confirms that RPoly is currently the most efficient and robust HIPP approach.

AN ALMOST LINEAR TIME ALGORITHM FOR A GENERAL HAPLOTYPE SOLUTION ON TREE PEDIGREES WITH NO RECOMBINATION AND ITS EXTENSIONS

We study the haplotype inference problem from pedigree data under the zero recombination assumption, which is well supported by real data for tightly linked markers (i.e. single nucleotide polymorphisms (SNPs)) over a relatively large chromosome segment. We solve the problem in a rigorous mathematical manner by formulating genotype constraints as a linear system of inheritance variables. We then utilize disjoint-set structures to encode connectivity information among individuals, to detect constraints from genotypes, and to check consistency of constraints. On a tree pedigree without missing data, our algorithm can output a general solution as well as the number of total specific solutions in a nearly linear time O(mn . alpha(n)), where m is the number of loci, n is the number of individuals and alpha is the inverse Ackermann function, which is a further improvement over existing ones. We also extend the idea to looped pedigrees and pedigrees with missing data by considering existing (partial) constraints on inheritance variables. The algorithm has been implemented in C++ and will be incorporated into our PedPhase package. Experimental results show that it can correctly identify all 0-recombinant solutions with great efficiency. Comparisons with other two popular algorithms show that the proposed algorithm achieves 10 to 10(5)-fold improvements over a variety of parameter settings. The experimental study also provides empirical evidences on the complexity bounds suggested by theoretical analysis.

Linear-Time Haplotype Inference on Pedigrees without Recombinations and Mating Loops

In this paper, an optimal linear-time algorithm is presented to solve the haplotype inference problem for pedigree data when there are no recombinations and the pedigree has no mating loops. The approach is based on the use of graphs to capture SNP, Mendelian, and parity constraints of the given pedigree. This representation allows us to capture the constraints as the edges in a graph, rather than as a system of linear equations as in previous approaches. Graph traversals are then used to resolve the parity of these edges, resulting in an optimal running time.

A linear-time algorithm for reconstructing zero-recombinant haplotype configuration on pedigrees without mating loops

With the launch of the international HapMap project, the haplotype inference problem has attracted a great deal of attention in the computational biology community recently. In this paper, we study the question of how to efficiently infer haplotypes from genotypes of individuals related by a pedigree without mating loops, assuming that the hereditary process was free of mutations (i.e. the Mendelian law of inheritance) and recombinants. We model the haplotype inference problem as a system of linear equations as in (Xiao et al. in Proceedings of the 18th Annual ACM-SIAM Symposium on Discrete Algorithms (SODA’07), pp. 655–664, 2007) and present an (optimal) linear-time (i.e. O(mn) time) algorithm to generate a particular solution to the haplotype inference problem, where m is the number of loci (or markers) in a genotype and n is the number of individuals in the pedigree. Moreover, the algorithm also provides a general solution in O(mn 2) time, which is optimal because the descriptive size of a general solution could be as large as Θ(mn 2). The key ingredients of our construction are (i) a fast consistency checking procedure for the system of linear equations introduced in (Xiao et al. 2007) based on a careful investigation of the relationship between the equations (ii) a novel linear-time method for solving linear equations without invoking the Gaussian elimination method. Although such a fast method for solving equations is not known for general systems of linear equations, we take advantage of the underlying loop-free pedigree graph and some special properties of the linear equations.

A fast haplotype inference method for large population genotype data

With the rapid progress of genotyping techniques, many large-scale, genome-wide disease studies are now under way. One of the challenges of large disease-association studies is developing a fast and accurate computing method for haplotype inference from genotype data. In this paper, a new computing method for population-based haplotype inference problem is proposed. The designed method does not assume haplotype blocks in the population and allows each individual haplotype to have its own structure, and thus is able to accommodate recombination and obtain higher adaptivity to the genotype data, specifically in the case of long marker maps. This method develops a dynamic programming algorithm, which is theoretically guaranteed to find exact maximum likelihood solutions of the variable order Markov chain model for haplotype inference problem within linear running time. Hence, it is fast and, as a result, practicable for large genotype datasets. Through extensive computational experiments on large-scale real genotype data, the proposed method is shown to be fast and efficient.

HAPLOTYPE INFERENCE WITH BOOLEAN SATISFIABILITY

Mutation in DNA is the principal cause for differences among human beings, and Single Nucleotide Polymorphisms (SNPs) are the most common mutations. Hence, a fundamental task is to complete a map of haplotypes (which identify SNPs) in the human population. Associated with this effort, a key computational problem is the inference of haplotype data from genotype data, since in practice genotype data rather than haplotype data is usually obtained. Different haplotype inference approaches have been proposed, including the utilization of statistical methods and the utilization of the pure parsimony criterion. The problem of haplotype inference by pure parsimony (HIPP) is interesting not only because of its application to haplotype inference, but also because it is a challenging NP-hard problem, being APX-hard. Recent work has shown that a SAT-based approach is the most efficient approach for the problem of haplotype inference by pure parsimony (HIPP), being several orders of magnitude faster than existing integer linear programming and branch and bound solutions. This paper provides a detailed description of SHIPs, a SAT-based approach for the HIPP problem, and presents comprehensive experimental results comparing SHIPs with all other exact approaches for the HIPP problem. These results confirm that SHIPs is currently the most effective approach for the HIPP problem.

Stochastic local search for large-scale instances of the haplotype inference problem by pure parsimony

Haplotype Inference is a challenging problem in bioinformatics that consists in inferring the basic genetic constitution of diploid organisms on the basis of their genotype. This information allows researchers to perform association studies for the genetic variants involved in diseases and the individual responses to therapeutic agents. A notable approach to the problem is to encode it as a combinatorial problem (under certain hypotheses, such as the pure parsimony criterion) and to solve it using off-the-shelf combinatorial optimization techniques. The main methods applied to Haplotype Inference are either simple greedy heuristic or exact methods (Integer Linear Programming, Semidefinite Programming, SAT and pseudo-boolean encoding) that, at present, are adequate only for moderate size instances. In this paper, we present and discuss an approach based on the combination of local search metaheuristics and a reduction procedure based on an analysis of the problem structure. Some relevant design issues are first described, then a family of local search metaheuristics is defined to tackle the Haplotype Inference. Results on common Haplotype Inference benchmarks show that the approach achieves a good trade-off between solution quality and execution time.

An overview of the haplotype problems and algorithms

A single nucleotide polymorphism (SNP), as the most common form of genetic variation, has been widely studied to help analyze the possible association between diseases and genomes. To gain more information, SNPs on a single chromosome are usually studied together, which constitute a haplotype. Gaining haplotypes from biological experiments is usually very costly and time-consuming, which causes people to develop efficient methods to determine haplotypes from the computational angle. Many problems and algorithms about haplotypes have been proposed to reduce the cost of studies of disease association. In general, four categories of problems are widely researched: the haplotype assembly problem, the haplotype inference problem, the haplotype block partition problem, and the haplotype tagging SNP selection problem. The former two problems have been well reviewed by many researchers, whereas the latter two have not been comprehensively surveyed to our knowledge. In this paper, we try to make a detailed introduction to the four problems, especially the latter two.

Linear-time reconstruction of zero-recombinant Mendelian inheritance on pedigrees without mating loops.

With the launch of the international HapMap project, the haplotype inference problem has attracted a great deal of attention in the computational biology community recently. In this paper, we study the question of how to efficiently infer haplotypes from genotypes of individuals related by a pedigree without mating loops, assuming that the hereditary process was free of mutations (i.e. the Mendelian law of inheritance) and recombinants. We model the haplotype inference problem as a system of linear equations as in [10] and present an (optimal) linear-time (i.e. O(mn) time) algorithm to generate a particular solution (A particular solution of any linear system is an assignment of numerical values to the variables in the system which satisfies the equations in the system.) to the haplotype inference problem, where m is the number of loci (or markers) in a genotype and n is the number of individuals in the pedigree. Moreover, the algorithm also provides a general solution (A general solution of any linear system is denoted by the span of a basis in the solution space to its associated homogeneous system, offset from the origin by a vector, namely by any particular solution. A general solution for ZRHC is very useful in practice because it allows the end user to efficiently enumerate all solutions for ZRHC and performs tasks such as random sampling.) in O(mn2) time, which is optimal because the size of a general solution could be as large as Theta(mn2). The key ingredients of our construction are (i) a fast consistency checking procedure for the system of linear equations introduced in [10] based on a careful investigation of the relationship between the equations (ii) a novel linear-time method for solving linear equations without invoking the Gaussian elimination method. Although such a fast method for solving equations is not known for general systems of linear equations, we take advantage of the underlying loop-free pedigree graph and some special properties of the linear equations.

An Optimal Algorithm for Perfect Phylogeny Haplotyping

Inferring haplotype data from genotype data is a crucial step in linking SNPs to human diseases. Given n genotypes over m SNP sites, the haplotype inference (HI) problem deals with finding a set of haplotypes so that each given genotype can be formed by a combining a pair of haplotypes from the set. The perfect phylogeny haplotyping (PPH) problem is one of the many computational approaches to the HI problem. Though it was conjectured that the complexity of the PPH problem was O(nm), the complexity of all the solutions presented until recently was O(nm (2)). In this paper, we make complete use of the column-ordering that was presented earlier and show that there must be some interdependencies among the pairwise relationships between SNP sites in order for the given genotypes to allow a perfect phylogeny. Based on these interdependencies, we introduce the FlexTree (flexible tree) data structure that represents all the pairwise relationships in O(m) space. The FlexTree data structure provides a compact representation of all the perfect phylogenies for the given set of genotypes. We also introduce an ordering of the genotypes that allows the genotypes to be added to the FlexTree sequentially. The column ordering, the FlexTree data structure, and the row ordering we introduce make the O(nm) OPPH algorithm possible. We present some results on simulated data which demonstrate that the OPPH algorithm performs quiet impressively when compared to the previous algorithms. The OPPH algorithm is one of the first O(nm) algorithms presented for the PPH problem.

An Approximation Algorithm for Haplotype Inference by Maximum Parsimony

This paper studies haplotype inference by maximum parsimony using population data. We define the optimal haplotype inference (OHI) problem as given a set of genotypes and a set of related haplotypes, find a minimum subset of haplotypes that can resolve all the genotypes. We prove that OHI is NP-hard and can be formulated as an integer quadratic programming (IQP) problem. To solve the IQP problem, we propose an iterative semidefinite programming-based approximation algorithm, (called SDPHapInfer). We show that this algorithm finds a solution within a factor of O(log n) of the optimal solution, where n is the number of genotypes. This algorithm has been implemented and tested on a variety of simulated and biological data. In comparison with three other methods, (1) HAPAR, which was implemented based on the branching and bound algorithm, (2) HAPLOTYPER, which was implemented based on the expectation-maximization algorithm, and (3) PHASE, which combined the Gibbs sampling algorithm with an approximate coalescent prior, the experimental results indicate that SDPHapInfer and HAPLOTYPER have similar error rates. In addition, the results generated by PHASE have lower error rates on some data but higher error rates on others. The error rates of HAPAR are higher than the others on biological data. In terms of efficiency, SDPHapInfer, HAPLOTYPER, and PHASE output a solution in a stable and consistent way, and they run much faster than HAPAR when the number of genotypes becomes large.