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Biomedical subjects

C T Falk

Publications and source records attributed to C T Falk.

At least 19 recordsLinked to original sources
PubMed1992

Preliminary ordering of multiple linked loci using pairwise linkage data.

A method is presented for the preliminary ordering of loci on a chromosome using pairwise linkage data. The method is based on the biologically reasonable assumption that the "true" order of a set of linked loci will be the one that minimizes the total length of the chromosome segment. Here the "length" is defined as the sum of adjacent recombination fractions. The method searches for the optimal order, represented by a minimum distance map (MDMAP), even when it is not possible to examine the n!/2 possible distinct orders for n loci. A computerized approach, using the simulated annealing algorithm of Kirkpatrick et al. [1983], forms the basis of the method. It can be applied to data from radiation hybrid experiments as well as that from conventional family linkage studies. The technique is applied to several sets of published data to illustrate how it performs in practice. The advantages and the disadvantages of the method are discussed so that it will be clear under what conditions it is likely to work well. When data sets are "complete," in the sense that all possible pairwise recombination fractions have estimates, and when no large clusters of extremely tightly linked loci are present, the method produces ordered sets of loci that agree well with those generated by other, more complex methods. Any discrepancies that occur are likely to be with respect to the orientation of nearest-neighbor loci, where relative order cannot be reliably established by any method. The method thus provides a simple, rapid means of obtaining a preliminary order for a set of loci known to be in the same linkage group.

Algorithms↗
PubMed1991

A simple method for ordering loci using data from radiation hybrids.

A method is presented for ordering loci on a chromosome based on data generated from radiation hybrids. All loci are tabulated as being present, absent, or not scored in a series of clones. Correlation coefficients are calculated for all pairs of loci indicating how often they are retained or lost together in the clones. On the assumption that a high positive correlation implies closely linked loci, a distance score, d, equal to one minus the correlation coefficient, is obtained for each locus pair and an order is generated that minimizes the sum of the adjacent distances [the MDMAP method of Falk ("Multipoint Mapping and Linkage Analysis Based upon Affected Pedigree Members: Genetic Analysis Workshop 6," pp. 17-22, A. R. Liss, New York, 1989)]. Two sets of data, with information on 13 and 16 loci mapped to chromosome 21q, have been ordered using this method. The results are in very good agreement with other ordering methods used on the same data and with physical mapping data.

Chromosome Mapping↗
PubMed1990

Genetic loci ordering instability: an example.

In attempting to establish the order of genetic loci by constructing a map from pairwise linkage data, one assumes that the loci satisfy a linear-order relation. If the data utilized in the construction are not consistent with the linear-order assumption, then a very small change in the data may lead to a large qualitative change in the map. An example of such an instability is presented in this paper.

Chromosome Mapping↗
PubMed1989

Characteristics of a multiplex IDDM sample: unexplained differences with other samples.

Characteristics of a multiplex sample of families with insulin-dependent diabetes mellitus (IDDM) are studied and contrasted with similar characteristics in other, more conventionally sampled data sets. Some characteristics remain consistent with earlier observations including the high frequency of human leukocyte antigen (HLA) DR3,4 in affected individuals and the greater than expected percentage of HLA haplotype sharing among affected sib pairs. In other respects, however, differences are seen between this sample and others. "Control" haplotypes, i.e., those not transmitted to the first affected offspring, had a higher frequency of DR3 and DR4 than expected, and a rather high frequency of affected parents was observed. Differences between the first affected and later affected offspring reported in other samples were absent from these families. No effect of the sampling scheme and the resulting distribution of parental phenotypes could be shown to explain this difference.

Child↗
PubMed1989

Human gene for torsion dystonia located on chromosome 9q32-q34.

Torsion dystonia is a movement disorder of unknown etiology characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Dystonic movements can be caused by lesions in the basal ganglia, drugs, or gene defects. Several hereditary forms have been described, most of which have autosomal dominant transmission with variable expressivity. In the Ashkenazi Jewish population the defective gene frequency is about 1/10,000. Here, linkage analysis using polymorphic DNA and protein markers has been used to locate a gene responsible for susceptibility to dystonia in a large, non-Jewish kinship. Affected members of this family have a clinical syndrome similar to that found in the Jewish population. This dystonia gene (ITD1) shows tight linkage with the gene encoding gelsolin, an actin binding protein, and appears by multipoint linkage analysis to lie in the q32-q34 region of chromosome 9 between ABO and D9S26, a region that also contains the locus for dopamine-beta-hydroxylase.

Calcium-Binding Proteins↗
PubMed1987

Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations.

An alternative to Woolf's (1955) relative risk (RR) statistic is proposed for use in calculating the risk of disease in the presence of particular antigens or phenotypes. This alternative uses, as the control sample, the parental antigens or haplotypes not present in the affected child. The formulation of a haplotype relative risk (HRR) thus eliminates the problems of sampling from the same homogeneous population to form both the disease sample and an appropriate control. We show that, in families selected through a single affected individual, where transmission of the four parental haplotypes can be followed unambiguously, the mathematical expectation of the HRR is identical to that of the RR. Since the sample formed from the 'non-affected' parental haplotypes is clearly from the same population as the disease sample, the HRR thus provides a reliable alternative to the RR. A further advantage obtains when family data are being collected as part of a study since the control sample is then automatically contained in the family material. Data from studies of patients with insulin dependent diabetes mellitus (IDDM) are used to obtain an estimate of the risk to those with HLA antigens or phenotypes associated with IDDM using the HRR statistic. A comparison of the HRR's and RR's for these data is also presented.

Diabetes Mellitus, Type 1↗
PubMed1986

Use of molecular haplotypes specific for the human pro alpha 2(I) collagen gene in linkage analysis of the mild autosomal dominant forms of osteogenesis imperfecta.

Autosomal dominant osteogenesis imperfecta (OI) is a heterogeneous group of disorders. Molecular haplotypes associated with the pro alpha 2(I) gene of human type I procollagen were used for genetic linkage studies in a group of 10 families with OI. The clinical phenotypes of the families studied were those of OI type I and OI type IV. Evidence for linkage was highly suggestive in the four families with OI type IV (Z = 3.91 for theta = 0). In contrast, little or no indication for linkage was found in the six families with OI type I (Z = .055 for theta = .415). Heterogeneity between the two groups of families was highly significant (chi 2 = 11.14, P = .0008), suggesting that at least two separate gene defects may be the cause of the autosomal dominant forms of OI.

Alleles↗