J. Ott. Analysis of Human Genetic Linkage. Johns Hopkins University Press, Baltimore, Maryland, 1999.  Home/Search   Document Not in Database   Summary   Related Articles   Check

....determine whether there are fragments of the genome that are inherited in a pattern that is unlikely to occur purely by chance. The Mendelian laws of inheritance have been chosen by many researchers in computational genetics as the starting point in their investigations (see, e.g. the references [8,21,22]) Furthermore, a large number of traits are today known to be caused by single gene disorders [13] 5 Pedigrees In order to track the inheritance of genetic traits, geneticists use structures called pedigrees. In our setting, we shall always assume that a pedigree has some (possibly incomplete) ....

....stated. When describing genotypes, we only write one of the equivalent genotypes (e.g. AB is equivalent to BA) Consistency Checking A pedigree with associated genotype information is consistent when all observed or inferred genotypes are possible according to the Mendelian laws of inheritance [22]. There can be several reasons for inconsistencies in a pedigree and its genotype information. For instance, a family relationship could be misspecified, or there could be errors in the genotyping process or mutation. Generally it is not possible to determine the source of error; it is simply ....

J. OTT, Analysis of Human Genetic Linkage, The Johns Hopkins University Press, 3rd ed., 1999.

....determine whether there are fragments of the genome that are inherited in a pattern that is unlikely to occur purely by chance. The Mendelian laws of inheritance have been chosen by many researchers in computational genetics as the starting point in their investigations (see, e.g. the references [8,21,22]) Furthermore, a large number of traits are today known to be caused by single gene disorders [13] 5 Pedigrees In order to track the inheritance of genetic traits, geneticists use structures called pedigrees. In our setting, we shall always assume that a pedigree has some (possibly incomplete) ....

....stated. When describing genotypes, we only write one of the equivalent genotypes (e.g. AB is equivalent to BA) Consistency Checking A pedigree with associated genotype information is consistent when all observed or inferred genotypes are possible according to the Mendelian laws of inheritance [22]. There can be several reasons for inconsistencies in a pedigree and its genotype information. For instance, a family relationship could be misspecified, or there could be errors in the genotyping process or mutation. Generally it is not possible to determine the source of error; it is simply ....

J. OTT, Analysis of Human Genetic Linkage, The Johns Hopkins University Press, 3rd ed., 1999.

....ideas in combination with clique tree inference procedures. Finally, we describe experimental results that examine the effectiveness of these ideas. 2 Genetic Linkage Analysis We now briefly introduce the relevant genetic notions that are needed for the discussion below. We refer the reader to [12] for a comprehensive introduction to linkage analysis. The human genetic material consists of 22 pairs of autosomal chromosomes, and a pair of the sex chromosomes. The situation with the later pair is slightly different, and we will restrict the discussion here to the autosomal case, although ....

J. Ott. Analysis of Human Genetic Linkage. 1991.

....is not itself sufficient to define a crossover or chiasma process. One solution provided by Karlin and Liberman [14] imposes rules for obtaining multi locus probabilities from the two locus probabilities given by map functions. However, for many map functions, including the Kosambi map function [21], this results in some negative probabilities. Karlin and Liberman call map functions for which negative probabilities result from their rules multi locus infeasible. A more satisfactory approach (discussed in [22] is to derive a renewal process model that is consistent with the map function. ....

J. Ott. Analysis of Human Genetic Linkage, chapter 6, Multipoint linkage anal- ysis. John Hopkins University Press, Baltimore, 1985.

....once. This is discussed further below. The ultimate use of genetic function analysis is to aid and abet the task of linkage mapping. Current techniques of genetic mapping require the assumption of a pg mapping or at best a small number of possible pg mappings which can be parametrically encoded. [16, 17] Risch has considered the problem of linkage analysis given complex genetic traits, though the multilocus model used is simpler than the one postulated here. 21, 22, 23] Genetic function analysis (gfa) could either deduce the function of a gene once it is found or be part of the effort of ....

Jurg Ott. Analysis of Human Genetic Linkage. Johns Hopkins Univ. Press, Baltimore, 1991.

....and their analysis. In Section 4 we compare experimentally WRA and MGA wrt performance and run time. 2 Background: The loop cutset problem Pearl s method of conditioning is one of the best known inference methods for Bayesian networks. It is a method of choice in some genetic linkage programs [Ot91, BGS98]. A short overview of the method of conditioning, and definitions related to Bayesian networks, are given below. See [Pe88] for more details. We then define the loop cutset problem. Let P (u 1 ; un ) be a probability distribution where each u i draws values from a finite set called the ....

Ott J., Analysis of human genetic linkage, The Johns Hopkins University Press, 1991, revised edition.

....Such models are used in the RHMAP and RHMAPPER packages. More recently, more e#cient approximated MLE versions based on two points estimation have also been used [2] but they don t deal with unknowns and won t be considered in the sequel. The older but still widely used genetic mapping technique [10] exploits the occurrence of cross overs during meiosis. As for RH mapping, the underlying intuition is that the further apart two markers are, the most likely it is that a cross over will occur in between. Because cross overs cannot be directly observed, the indirect observation of allelic ....

Jurg Ott. Analysis of human genetic linkage. John Hopkins University Press, Baltimore, Maryland, 2nd edition, 1991.

....For example, there are situations where a disease is caused in some families by one locus and in other families by another locus. Geneticists want to test the hypothesis that the disease population is homogeneous (cf. Friedlander Leitersdorf 1995; Heiba et al. 1995; Schork et al. 1996; and Ott 1999). There has 1 also been increasing interest for researchers in mixture models in recent years, e.g. Everitt Hand (1981) Titterington et al. 1985) and Lindsay (1995) In this paper, the following problem is considered. Let f(x, #)for####IR be a probability density function (pdf) with ....

J. Ott (1999). Analysis of Human Genetic Linkage, 3rd Edition. The Johns Hopkins University Press, Baltimore, MD.

....use genetic markers to trace the pattern of inheritance of chromosomal DNA. These data can help determine shared chromosomal regions in related individuals affected by a disease, which in turn can roughly localize the causative gene on a chromosome [1] There are robust statistical methods [12,15,20,26] that are routinely used to rigorously implement this genetic localization. ffl Diagnosis of genetic disease: Clinical geneticists use genetic markers to trace the pattern of inheritance in particular affected families. This analysis can help assess the probability of transmission of the disease ....

J. Ott, Analysis of Human Genetic Linkage, Revised Edition (The Johns Hopkins University Press, Baltimore, Maryland, 1991).

....with estimated false positive and false negative rates obtained using simulation. 1 INTRODUCTION 1 1 Introduction There are two types of genetic linkage data errors to consider: pedigree error and typing error. Pedigree error generally involves misidentification of individuals and relationships [15]. Examples include non paternity, unidentified adoption and sample mix ups. Typing error includes all other types of errors such as misinterpretation of genotypes and data entry error [2] Chromosome linkage maps are becoming denser as more marker data are collected. These high resolution linkage ....

....be resolved once. Typing errors, on the other hand, are an ongoing problem in a pedigree being typed for many markers. The present paper focuses on detecting typing and pedigree errors consistent with Mendelian inheritance. The effect of typing errors has been discussed by several authors. Ott [15] illustrates the effect of errors by letting s be the misclassification frequency, the frequency with which recombinants are misclassified as nonrecombinants and nonrecombinants are misclassified as recombinants and t be the true recombination fraction. Then the apparent recombination rate is ....

J. Ott. Analysis of human genetic linkage. Johns Hopkins University, Baltimore, revised edition, 1991.

....(Dechter, 1999) This method has two conceptual phases. First to find an optimal or close to optimal loop cutset and then to perform a likelihood computation for each instance of the variables in the loop cutset. This method is routinely used by geneticists via several genetic linkage programs (Ott, 1991# Lang, 1997# Becker, Geiger, Schaffer, 1998) A variant of this method was developed by Lange and Elston (1975) Finding a minimum weight loop cutset is NP complete and thus heuristic methods have often been applied to find a reasonable loop cutset (Suermondt Cooper, 1990) Most methods in ....

Ott, J. (1991). Analysis of human genetic linkage (revisededition). The Johns Hopkins University Press.

.... algorithms combine ordering and distance estimation by either searching for an order that provides a good least squares fit to the matrix of pairwise map distances [7] or that that maximizes the likelihood of observing the mapping population, given the best fit map distances for a given order [13]. These approaches 2 are implemented in the popular software packages JoinMap [15] and MapMaker [9] respectively. Most recent computational advances in linkage mapping have been improvements in the speed and e#ciency of optimization over the space of possible orders and distances. This has been ....

J. Ott. Analysis of human genetic linkage. Johns Hopkins University Press, Baltimore, USA, 1985.

....Sections 3 through 6 describe the four improvements. Sections 7 and 8 validate the improvements. We conclude with a short discussion. 2 Summary of LINKAGE and Related Work A thorough treatment of genetic linkage analysis, including a summary of the LINKAGE programs, is given in Ott s monograph [12]. In this section we review a few facts about LINKAGE relevant to this paper. The most fundamental goal in linkage analysis is to compute the probability, that a recombination occurs between two genes G 1 and G 2 . The LINKAGE package contains four linkage analysis programs: LODSCORE, ILINK, ....

....not need to be redone (provided the results were written to a file before the crash) This explains why there is little need to use a checkpointing scheme within LINKMAP and MLINK. The basic structure of the likelihood computation is outlined in the section on Numerical and Computerized Methods in [12]. Inside the loop over pedigrees, the programs traverse a pedigree updating the probabilities of each joint genotype for each individual. There are several different updating routines, but they all start with a double nested loop over the possible genotypes for one parent and then the other ....

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J. Ott. Analysis of Human Genetic Linkage. The Johns Hopkins University Press, Baltimore and London, 1991. Revised edition.

....Management Systems accessibility to most features of the system from the wide variety of computers employed by the variety of users of GenoMap (Mac, PC, UNIX workstation, etc) 3. C, Fortran, and Pascal implementations for compute intensive applications such as multi point linkage analysis [Ott91]. While these applications may not be interoperable on all platforms, common interfaces (written in Java) can be developed to hide the machine details of the systems on which they will run. The design decisions above have been employed in the development of the first full internal release of ....

J. Ott, Analysis of Human Genetic Linkage, Johns Hopkins University Press, Baltimore, 1991, pp. 108-141.

....can be traced; it need not be part of a gene. The probability of recombination is called the recombination fraction and denoted by . Most programs in common usage estimate using a maximum likelihood approach. A thorough treatment of maximum likelihood linkage analysis is given in Ott s book [20]. In this section we highlight a few aspects of the LINKAGE FASTLINK software package that are relevant to our parallel implementation of ILINK. The recombination fraction can be generalized to more than two loci. Suppose L 1 ; L 2 ; L k 1 are different loci, conjectured to occur in that ....

J. Ott. Analysis of Human Genetic Linkage. The Johns Hopkins University Press, Baltimore and London, 1991. Revised edition.

....probability to the actual distance between the two genes on the chromosome. Two genes are said to be linked if the recombination probability between them is less than .5. The recombination probability is denoted by . A thorough treatment of genetic linkage analysis is given in Ott s monograph [22]. We review a few particulars, especially concerning the LINKAGE programs, that are relevant to our parallel implementation. The LINKAGE package contains four related programs LODSCORE, ILINK, LINKMAP, and MLINK; we shall discuss the first three. The improved sequential algorithms in [2] are ....

....are applicable to the other programs as well. Almost all the code we modified is shared by all the LINKAGE programs. 3 Review of Sequential Likelihood Algorithm The basic structure of the likelihood computation as done in LINKAGE is outlined in the section on Numerical and Computerized Methods in [22]. The following summary describes LINKAGE 5.1 [16] and its faster version [2] Given a fixed value of , the outer loop of the likelihood evaluation iterates over all the pedigrees calculating the likelihood for each one. Within a pedigree, the program visits each nuclear family and updates the ....

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J. Ott. Analysis of Human Genetic Linkage. The Johns Hopkins University Press, Baltimore and London, 1991. Revised edition.

....and connections to external databases for acquiring data on disease incidence, patterns of inheritance, mutation rates, penetrance, etc. 1. The Need for Computer Support of Genetic Counseling Although the mathematical principles of pedigree analysis are well known and widely advocated (e.g. [1, 2, 3]) their application in the genetic counseling office is difficult because of lack of easy to use tools, and therefore they are only occasionally applied and then with severe simplifications [1] As our understanding of the mechanisms of genetic disorders grows through knowledge gained in ....

J. Ott. Analysis of Human Genetic Linkage. The Johns Hopkins University Press, Baltimore, Maryland, 1985.

.... with a socketoriented, client server design employing recent applet security features [CoH97] The gene identification application supported by GenoMap is characterized by a two stage process of data gathering and verification, followed by an analysis phase known as genetic linkage analysis [Ott91, LaW96]. Java Applets provide interfaces for specifying linkage experiments, support for management of the data collection and verification process, and interacting with statistical linkage analysis packages [CoI93] One of the data collection tools is a large C Xwindows application GenoScape ....

J. Ott, Analysis of Human Genetic Linkage, Johns Hopkins University Press, Baltimore, 1991, pp. 108-141.

....cM chromosome. This map is called the original map and the order of the N markers in this map is called the original order . For each pair of adjacent markers in this original map, the recombination probability between the two markers is computed using the inverse of Haldane s mapping function (Ott 1991). The markers that are informative in each individual map are chosen as follows: first a set of N c markers is selected randomly from the N markers. The set of N Gamma N c remaining markers is randomly split in two sets with the same cardinality. These two sets, each merged with the set of ....

Ott, J. 1991. Analysis of human genetic linkage. Baltimore, Maryland: John Hopkins University Press, 2nd edition.

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J. Ott. Analysis of Human Genetic Linkage. Johns Hopkins University Press, Baltimore, Maryland, 1999.

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J. OTT, Analysis of Human Genetic Linkage, The Johns Hopkins University Press, 3rd ed., 1999.

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Jurg Ott. Analysis of Human Genetic Linkage,Third Edition. The Johns Hopkins University Press, 1999.

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Ott, J. (1991). Analysis of human genetic linkage (Revised ed.). The Johns Hopkins series in contemporary medicine and public health. Baltimore, MD, USA: Johns Hopkins University Press.

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Ott J (1991) Analysis of Human Genetic Linkage, revised edition. The Johns Hopkins University Press, Baltimore and London, 1991

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J. Ott. Analysis of human genetic linkage. Johns Hopkins University, Baltimore, revised edition, 1991.

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