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PubMed2006

Identification of Enterobacter sakazakii from closely related species: the use of artificial neural networks in the analysis of biochemical and 16S rDNA data.

BACKGROUND: Enterobacter sakazakii is an emergent pathogen associated with ingestion of infant formula and accurate identification is important in both industrial and clinical settings. Bacterial species can be difficult to accurately characterise from complex biochemical datasets and computer algorithms can potentially simplify the process. RESULTS: Artificial Neural Networks were applied to biochemical and 16S rDNA data derived from 282 strains of Enterobacteriaceae, including 189 E. sakazakii isolates, in order to identify key characteristics which could improve the identification of E. sakazakii. The models developed resulted in a predictive performance for blind (validation) data of 99.3 % correct discrimination between E. sakazakii and closely related species for both phenotypic and genotypic data. Three main regions of the partial rDNA sequence were found to be key in discriminating the species. Comparison between E. sakazakii and other strains also constitutively positive for expression of the enzyme alpha-glucosidase resulted in a predictive performance of 98.7 % for 16S rDNA sequence data and 100% for phenotypic data. CONCLUSION: The computationally based methods developed here show a remarkable ability in reducing data dimensionality and complexity, in order to eliminate noise from the system in order to facilitate the speed and reliability of a potential strain identification system. Furthermore, the approaches described are also able to provide valuable information regarding the population structure and distribution of individual species thus providing the foundations for novel assays and diagnostic tests for rapid identification of pathogens.

Cronobacter sakazakii↗

PubMed2001

A robust multipoint linkage statistic (tlod) for mapping complex trait loci.

Classical parametric two-point linkage analysis is a powerful analysis tool, however there are clear disadvantages too, including the sensitivity to allele frequency mis-specification. Conversely, multipoint linkage analysis is not sensitive to allele frequency mis-specification, but it is sensitive to genetic model mis-specification. Göring and Terwilliger [Am J Hum Genet 66:1095-106, 2000] proposed a new robust multipoint statistic that increased the robustness of multipoint analyses. In this paper we have referred to this new statistic as the tlod. We applied this new statistic to the Genetic Analysis Workshop (GAW) 12 data using affected status (AFF) as the phenotype of interest. The heterogeneity tlod and two-point hlod scores correlated highly across the genome (p < 0.0001), as expected, but the het-tlod had a lower number false positives. In addition, the tlod analysis handled missing data better, as would be expected for a multipoint method. When one-third of the genotype data was removed (dead people) the tlod analysis was less affected than the two-point analysis. When tlod scores were compared with multipoint lod scores in true gene locations, the robustness of the tlod to model mis-specification was clearly evident. When the "best" replicate from the general population was analyzed, a borderline genome-wide significant two-point hlod result (3.6) was found 4 cM from MG6 and MG7 on chromosome 6. The heterogeneity tlod score was lower than the two-point hlod score (1.8), but greater than the heterogeneity multipoint lod score (0.4). However, when replicate 1 of the isolated population was analyzed none of the true gene locations were identified with either statistic.

Chromosome Mapping↗

PubMed2005

Identification of networks of sexually transmitted infection: a molecular, geographic, and social network analysis.

BACKGROUND: Despite widespread efforts to control it, Chlamydia trachomatis remains the most frequently diagnosed bacterial sexually transmitted infection (STI). Analysis of sexual networks has been proposed as a novel tool for control of and research into STI. In the present study, we combine molecular genotype data, analysis of geographic clusters, and sociodemographic descriptors to facilitate analysis of large sexual networks. METHODS: Individual chlamydia genotypes found in Manitoba, Canada, were analyzed to identify geographic clusters, and the identified clusters were further characterized by statistical analysis of sociodemographic variables. RESULTS: A total of 10 geographic clusters of chlamydia-genotype infection were identified. Clusters in Winnipeg showed no or little geographic overlap and could be further differentiated on the basis of the sociodemographic characteristics of the individuals within a cluster. Several clusters in northern Manitoba overlapped geographically but, nonetheless, could be differentiated on the basis of the sociodemographic characteristics of the infected individuals. CONCLUSIONS: On the basis of results of the combined analyses, each geographic cluster appeared to represent a relatively distinct transmission network within the larger sexual network. The geographic analysis of the molecular data provided a basis for establishment of potential epidemiological connections between small groups of unlinked individuals. Analytic approaches of the type described here would help to decipher the patterns that exist within large social network data sets and would be applicable to many types of infectious agents.

Adolescent↗

PubMed1999

Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.

Since little is known about chromosomal locations harboring type 2 diabetes-susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q.

Age Factors↗

PubMed2005

An exact maternal-fetal genotype incompatibility (MFG) test.

The maternal-fetal genotype incompatibility (MFG) test can be used for a variety of genetic applications concerning disease risk in offspring including testing for the presence of alleles that act directly through offspring genotypes (child allelic effects), alleles that act through maternal genotypes (maternal allelic effects), or maternal-fetal genotype incompatibilities. The log-linear version of the MFG model divides the genotype data into many cells, where each cell represents one of the possible mother, father, and child genotype combinations. Currently, tests of hypotheses about different allelic effects are accomplished by an asymptotic MFG test, but it is unknown if this is appropriate under conditions that produce small cell counts. In this report, we develop an exact MFG test that is based on the permutation distribution of cell counts. We determine by simulation the type I error and power of both the exact MFG test and the asymptotic MFG test for four different biologically relevant scenarios: a test of child allelic effects in the presence of maternal allelic effects, a test of maternal allelic effects in the presence of child allelic effects, and tests of maternal-fetal genotype incompatibility with and without child allelic effects. These simulations show that, in general, the exact test is slightly conservative whereas the asymptotic test is slightly anti-conservative. However, the asymptotic MFG test produces significantly inflated type I error rates under conditions with extreme null allele frequencies and sample sizes of 75, 100, and 150. Under these conditions, the exact test is clearly preferred over the asymptotic test. Under all other conditions that we tested, the user can safely choose either the exact test or the asymptotic test.

Adult↗

PubMed2004

A collaborative database of inbred mouse strain characteristics.

UNLABELLED: A database and website (MPD: Mouse Phenome Database) have been developed to serve as a consolidated home for mouse strain characterization data being generated by the scientific community. Physiological, anatomical and behavioral data are being collected and integrated into a common framework for tabulation by strain and sex. Genotypic data are being collected as well. The current focus is on a set of 40 inbred strains. The MPD as of February 2004 contains approximately 500 phenotypic parameters relevant to human health, voluntarily contributed by several dozen investigators and laboratories. AVAILABILITY: www.jax.org/phenome

Animals↗

PubMed2026

Estimating the heritability of longitudinal rate-of-change: genetic insights into PSA velocity in prostate cancer-free individuals.

Serum prostate-specific antigen (PSA) is widely used for prostate cancer screening. While the genetics of PSA levels have been studied to enhance screening accuracy, the genetic basis of PSA velocity, the rate of PSA change over time, remains unclear. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a large, randomized study with longitudinal PSA data (15,260 cancer-free males, averaging 5.34 samples per subject) and genome-wide genotype data, provides a unique opportunity to estimate PSA velocity heritability. We developed a mixed model to jointly estimate the heritability of PSA levels at age 54 and PSA velocity. To accommodate the large dataset, we implemented 2 efficient computational approaches: a partitioning and meta-analysis strategy using average information restricted maximum likelihood (AI-REML) and a fast restricted Haseman-Elston (REHE) regression method. Simulations showed that both methods yield unbiased estimates of both heritability metrics, with AI-REML providing smaller variability in the estimation of velocity heritability than REHE. Applying AI-REML to PLCO data, we estimated heritability at 0.32 (s.e. = 0.07) for baseline PSA and 0.45 (s.e. = 0.18) for PSA velocity. These findings reveal a substantial genetic contribution to PSA velocity, supporting future genome-wide studies to identify variants affecting PSA dynamics and improve PSA-based screening.

Humans↗

PubMed2005

Lack of an association between 5-HT receptor gene polymorphisms and suicide victims.

An association between serotonergic dysfunction in the brain and suicidal behavior has previously been suggested. The high affinity of some antipsychotic and antidepressant drugs to serotonin 6 (5-HT6) receptors, and the predominant localization of 5-HT6 receptors in some limbic regions, suggest that 5-HT6 receptors play a role in the pathogenesis of suicide. The objective of the present study was to examine the association between suicide victims and two polymorphisms of the 5-HT6 receptor gene: a biallelic polymorphism (267C/T) in exon 1 and a trinucleotide repeat polymorphism ([GCC](2/3)) in the 5'-upstream region of the gene. The two polymorphisms were genotyped in 163 suicide victims and 166 controls, and the distribution of genotype and allele frequencies between the two groups were compared. Haplotype frequencies of these two polymorphisms were estimated from genotypic data by the maximum-likelihood method. In both polymorphisms, there were no significant differences in genotype or allele frequencies between the suicide victims and the controls. Moreover, there were no significant differences in the haplotype distributions of these polymorphisms between the two groups. These findings suggest that it is unlikely that the 5-HT6 receptor gene is involved in the susceptibility to suicide.

Alleles↗

PubMed1994

[Application of gene technology to clinical pathology].

Recently striking progress has been made in molecular biology. Among the newly developed techniques, PCR (polymerase chain reaction) is making an epoch in DNA diagnosis in the field of clinical pathology and laboratory medicine. In this symposium, we discussed the available PCR methods in DNA diagnosis and also the future prospect of PCR method as a routine laboratory procedure. First, Dr. Kawabata reviewed the PCR technique and analytical procedures of PCR products. Next five symposium presented the data on DNA diagnosis for particular diseases using the PCR method. Dr. Hasebe presented the HCV genotyping data from the patients. Dr. Hirose showed us the difference in accuracy in DNA typing of Chlamydia trachomatis antigen between the DNA probe method and PCR method. He also introduced the newly developed LCR method. Dr. Kondo reviewed the methods of DNA diagnosis for malignant lymphoma. Dr. Yaginuma presented the analyzed data of tumor suppressor gene p53 in some gynecological tumors. Dr. Azuma presented a case of chronic granulomatosis with a point mutation on the gp91-phox gene which had been revealed by RT-PCR. Next Dr. Yagihashi introduced the protocol for DNA typing of the HLA class II. Finally, Dr. Tanaka presented the availability of the PCR method for the convalescent screening of bone marrow transplantation. We hope this symposium is fruitful and motivating for all staffs of laboratory medicine and pathology. In closing my remarks, I express our appreciation to all symposists as well as Prof. Hisami Ikeda, president of the 27th general meeting of the Hokkaido branch, the Society of Clinical Pathology, planned this symposium.

Genetic Techniques↗

PubMed2001

A logistic regression model for measuring gene-longevity associations.

The logistic regression model is a popular model for data analysis in epidemiological research. In this paper, we use this model to analyze genetic data collected from gene-longevity association studies. This new approach models the probability of observing one genotype as a function of the age of investigated individuals. Applying the model to genotype data on the TH and 3'ApoB-VNTR loci collected from an Italian centenarian study, we show how it can be used to model the different ways that genes affect survival, including sex- and age-specific influences. We highlight the advantages of this application over other available models. The application of the model to empirical data indicates that it is an efficient and easily applicable approach for determining the influences of genes on human longevity.

Adolescent↗

PubMed2006

An evaluation of the performance of tag SNPs derived from HapMap in a Caucasian population.

The Haplotype Map (HapMap) project recently generated genotype data for more than 1 million single-nucleotide polymorphisms (SNPs) in four population samples. The main application of the data is in the selection of tag single-nucleotide polymorphisms (tSNPs) to use in association studies. The usefulness of this selection process needs to be verified in populations outside those used for the HapMap project. In addition, it is not known how well the data represent the general population, as only 90-120 chromosomes were used for each population and since the genotyped SNPs were selected so as to have high frequencies. In this study, we analyzed more than 1,000 individuals from Estonia. The population of this northern European country has been influenced by many different waves of migrations from Europe and Russia. We genotyped 1,536 randomly selected SNPs from two 500-kbp ENCODE regions on Chromosome 2. We observed that the tSNPs selected from the CEPH (Centre d'Etude du Polymorphisme Humain) from Utah (CEU) HapMap samples (derived from US residents with northern and western European ancestry) captured most of the variation in the Estonia sample. (Between 90% and 95% of the SNPs with a minor allele frequency of more than 5% have an r2 of at least 0.8 with one of the CEU tSNPs.) Using the reverse approach, tags selected from the Estonia sample could almost equally well describe the CEU sample. Finally, we observed that the sample size, the allelic frequency, and the SNP density in the dataset used to select the tags each have important effects on the tagging performance. Overall, our study supports the use of HapMap data in other Caucasian populations, but the SNP density and the bias towards high-frequency SNPs have to be taken into account when designing association studies.

Alleles↗

PubMed2026

Recall-by-genotype of neurodevelopmental disorder copy number variants in a multi-ancestry, healthcare-system biobank.

Clinical biobanks linking electronic health records (EHRs) with genotype data enable the study of genomic risk factors in real-world populations. However, recall-by-genotype (RbG) of psychiatric risk variants in diverse healthcare-system biobanks remains scarce. Leveraging BioMe, a multi-ancestry biobank within the Mount Sinai Health System, we recalled carriers of rare copy number variants (CNVs) that confer increased risk for neurodevelopmental disorders (NDDs) to establish empirical benchmarks for RbG implementation. We recontacted 892 participants: 335 NDD CNV carriers, 217 individuals with schizophrenia without NDD CNVs, and 340 neurotypical controls without NDD CNVs. Participants completed clinical and cognitive assessments. Overall, 18% of recontacted participants responded to recruitment, and 8% completed the study: 30 NDD CNV carriers, 20 individuals with schizophrenia, and 23 controls. The mean age was 48.8 years, 66% were female, and self-reported ancestry was 37% African, 34% Hispanic, and 26% European. Seventy percent of NDD CNV carriers had at least one neuropsychiatric or developmental condition, including mood or anxiety disorders (40%). Among 22 NDD CNV carriers at loci implicated in impaired cognition, performance was lower than controls on Digit Span Backward (β = -1.76, FDR = 0.04) and Digit Span Sequencing (β = -2.01, FDR = 0.04). NDD CNV carriers also outperformed the schizophrenia group on verbal learning (β = 4.5, FDR = 0.05). Recall of individuals-including those with psychiatric illness-yielded phenotypes not captured in EHRs and provides empirical benchmarks relevant to RbG implementation and precision psychiatry in diverse healthcare systems.

Journal Article↗

PubMed1988

Genetic evidence of clonal descent of Escherichia coli O157:H7 associated with hemorrhagic colitis and hemolytic uremic syndrome.

Genetic relatedness of 100 strains of Escherichia coli, isolated mostly from patients with hemorrhagic colitis or hemolytic uremic syndrome, was determined for chromosomal genotypes on the basis of allelic variation at 17 enzyme-encoding loci detected by multilocus enzyme electrophoresis. Fifteen of the 17 loci were polymorphic, with an average of 3.5 alleles per locus. Comparison of the observed combinations of alleles among strains revealed 25 distinct multilocus genotypes, which were used to define naturally occurring cell lineages or clones. Cluster analysis of the genotypic data revealed that isolates of serotype O157:H7 fall into a well-defined group of clonal genotypes that share alleles, on average, at 90% of their enzyme loci. The O157:H7 clonal group is only distantly related to other Verotoxin-producing strains belonging to other serotypes of E. coli. The results strongly support the hypothesis that isolates of E. coli O157:H7 obtained from geographically separate outbreaks and sporadic cases of hemorrhagic colitis and hemolytic uremic syndrome belong to a pathogenic clone that occurs throughout North America.

Alleles↗

PubMed2005

Response to long-term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance.

Lamivudine is effective in suppressing viral replication, normalizing alanine aminotransferase (ALT), and improving histological appearance in HBe positive and negative hepatitis. It is unclear whether hepatitis B virus (HBV) genotype influences the response to lamivudine. We report the long-term response of patients with chronic hepatitis B with and without cirrhosis at baseline treated with lamivudine according to HBV genotype. Retrospective review of charts of all patients treated with lamivudine monotherapy between 1993 and 2002. Response to therapy defined as ALT in the normal range, undetectable HBV DNA, and in the HBeAg positive group loss of HBeAg and/or the development of anti-HBe. HBV DNA measured by the Digene Hybrid capture assay (sensitivity 1.4 x 10(6) copies/mL). YMDD mutation at rtL180M and rtM204V/I measured by restriction digest of amplified products. Genotyping performed by sequencing and phylogenetic tree analysis of the preS region of the virus genome. Seventy-one patients treated with lamivudine for 6 months or more, 53 (75%) were male, average age 47 years, 38 (54%) were HBeAg+ and 33 (46%) HBeAg-. Mean baseline HBV DNA viral titre was 1280.2 copies/mL and 518 copies/mL respectively. Cirrhosis was present in 30 (42%). Sera were examined for YMDD mutations at last patient visit in 61 (86%), and were detected in 45 (74%), there being no association with a particular genotype. Data from up to 5 years on lamivudine indicated no difference in biochemical or virological response between genotypes. Cirrhosis was more prevalent with specific genotypes. We found no influence of HBV genotype on the development of resistance to lamivudine, however liver disease severity was influenced by genotype.

Alanine Transaminase↗

PubMed2001

Heterogeneity and compartmentalization of Pneumocystis carinii f. sp. hominis genotypes in autopsy lungs.

The extent and importance of genotype heterogeneity of Pneumocystis carinii f. sp. hominis within lungs have not previously been investigated. Two hundred forty PCR clones obtained from respiratory specimens and lung segments from three patients with fatal P. carinii pneumonia were investigated to detect genetic diversity in the internal transcribed spacer (ITS) region of the nuclear rRNA operon, the mitochondrial large-subunit (mtLSU) rRNA gene, and the dihydropteroate synthase-encoding gene. For two of the three examined patients, a mixture of different mtLSU rRNA and ITS genotypes was observed. Not all genotypes present in the lungs at autopsy were detected in the diagnostic respiratory samples. Compartmentalization of specific ITS and mtLSU rRNA sequence types was observed in different lung segments. In conclusion, the interpretation of genotype data and in particular ITS sequence types in the assessment of epidemiological questions should be cautious since genotyping done on respiratory samples cannot a priori be assumed to represent all genotypes present within the lung.

AIDS-Related Opportunistic Infections↗

PubMed2000

Factor VII gene polymorphism, factor VII levels, and prevalent cardiovascular disease: the Framingham Heart Study.

Elevated factor VII levels have been associated with increased cardiovascular risk in some studies. The arginine/glutamine (Arg/Gln) polymorphism of the factor VII gene has been previously shown to modify factor VII levels. However, the presence of a gene/environment interaction on factor VII levels or a link with cardiovascular disease (CVD) remains uncertain. We studied subjects from the Framingham Heart Study to determine (1) the extent to which this genetic polymorphism affects factor VII levels; (2) whether interactions exist between this polymorphism and environmental factors on factor VII levels; and (3) the association between the polymorphism and CVD. Genotype data and factor VII antigen levels were available in 1816 subjects. Factor VII levels differed significantly among genotypes in an additive fashion: Gln homozygous, 82.7+/-2.5%; heterozygous, 92.2+/-0.7%; and Arg homozygous, 100. 5+/-0.4% (P<0.0001). The polymorphism was the strongest, single predictor of factor VII levels, explaining 7.7% of the total variance of factor VII levels, whereas other traditional risk factors combined explained an additional 11.5% of the variance. There was an interaction (P=0.02) between the genotype and total cholesterol on factor VII levels, such that the correlation coefficient and slope (factor VII level/total cholesterol) were greatest in Gln/Gln subjects. Among 3204 subjects characterized for genotype and CVD, there was no significant relationship between the genotype and CVD (P=0.12). In the Framingham Heart Study, the Arg/Gln polymorphism was significantly associated with factor VII antigen levels. The strength of the association suggests that genetic variation plays an important role in determining factor VII levels. However, despite being associated with factor VII levels, the Arg/Gln polymorphism was not associated with prevalent CVD.

Amino Acid Sequence↗

PubMed2001

Identification of quantitative trait loci affecting reproduction in pigs.

The objective of this research was to identify chromosomal regions harboring QTL affecting reproduction in pigs. A three-generation resource population was developed by crossing low-indexing pigs from a randomly selected control line (C) with high-indexing pigs of a line selected for increased index of ovulation rate and embryonic survival (I). Differences between Lines I and C at Generation 10 were 6.7 ova and 3.3 fetuses at 50 d of gestation and 3.1 fully formed and 1.6 live pigs at birth. Phenotypic data were collected on F2 females, born in three replicates, for ovulation rate (n = 423), age at puberty (n = 295), litter size (n = 370), and number of nipples (n = 428). Litter-size data included number of fully formed, live, stillborn, and mummified pigs. Grandparent, F1, and F2 animals were genotyped for 151 microsatellite markers distributed across all 18 autosomes and the X chromosome. Genotypic data were available on 423 F2 females. Average spacing between markers was 19.3 Kosambi centimorgans. Calculations of logarithms of odds (LOD) scores were by least squares, and fixed effects for sire-dam combination and replicate were included in the models. Genome-wide significance level thresholds of 5% and 10% were calculated using a permutation approach. There was evidence (P < 0.05) for QTL affecting ovulation rate on SSC9, age at puberty on SSC7 and SSC8, number of nipples on SSC8 and SSC11, number of stillborn pigs on SSC5 and SSC13, and number of fully formed pigs on SSC11. There was evidence (P < 0.10) for additional QTL affecting age at puberty on SSC7, SSC8, and SSC12, number born live on SSC11, and number of nipples on SSC1, SSC6, and SSC7. Litter size is lowly heritable and sex-limited. Therefore, accuracy of selection for litter size may be enhanced by marker-assisted selection. Ovulation rate and age at puberty are laborious to measure, and thus marker-assisted selection may provide a practical and efficient method of selection.

Animals↗

PubMed1994

Linkage disequilibrium relationships among four polymorphisms within the human fibrinogen gene cluster.

The extent of linkage equilibrium was estimated among four recently characterized human fibrinogen restriction fragment length polymorphisms (RFLPs) using a randomly selected group of 110 individuals from California. Two coding region RFLPs, RsaI and MnlI (FGA codon 312 and FGB codon 448, respectively), and two RFLPs located in the 5' flanking region of the FGB gene, AluI (HindIII) and HaeIII, were analyzed. Maximum likelihood estimates based on genotypic data indicated that the RsaI polymorphism in the FGA gene was at apparent linkage equilibrium with the MnlI, AluI, and HaeIII sites in the FGB gene, but strong linkage disequilibrium was noted for the MnlI-AluI, MnlI-HaeIII, and AluI-HaeIII RFLP pairs within the latter gene. The discrepancy in disequilibrium relationships among these closely linked RFLPs may indicate a region of increased recombination between the FGA and FGB RFLP loci. The FGA RsaI polymorphism, when used in conjunction with any of the FGB sites examined, will provide more detailed linkage or association data than analyses that would utilize only FGB sites. Effective use of polymorphisms within the fibrinogen locus will aid analysis of the relationships between fibrinogen genotype, plasma fibrinogen levels, and risk of cardiovascular disease.

Alleles↗