Measurement of admixture proportions and description of admixture structure in different U.S. populations

Variation in individual admixture proportions leads to heterogeneity within populations. Though novel methods and marker panels have been developed to quantify individual admixture, empirical data describing individual admixture distributions are limited. We investigated variation in individual admixture in four U.S. populations (European American [EA], African American [AA], Hispanics from Connecticut [East Coast, or EC], and Hispanics from California [West Coast, or WC]) assuming three‐way intermixture among Europeans, Africans, and Indigenous Americans. Admixture estimates were inferred using a panel of 36 microsatellites and one SNP, which have significant allele frequency differences between ancestral populations, and by using both a maximum likelihood (ML)‐based method and a Bayesian method implemented in the program STRUCTURE. Simulation studies showed that estimates obtained with this marker panel are within 96% of expected values. EAs had the lowest non‐European admixture with both methods, but showed greater homogeneity with STRUCTURE than with ML. All other samples showed a high degree of variation in admixture estimates with both methods, were highly concordant, and showed evidence of admixture stratification. With both methods, AA subjects had on average, 16% European and <10% Indigenous American admixture. EC Hispanics had higher mean African admixture and the WC Hispanics had higher mean Indigenous American admixture, possibly reflecting their different continental origins. Hum Mutat 30:1–11, 2009. © 2009 Wiley‐Liss, Inc.     

Distribution of ancestral chromosomal segments in admixed genomes and its implications for inferring population history and admixture mapping

The ancestral chromosomal segments in admixed genomes are of significant importance for both population history inference and admixture mapping, because they essentially provide the basic information for tracking genetic events. However, the distributions of the lengths of ancestral chromosomal segments (LACS) under some admixture models remain poorly understood. Here we introduced a theoretical framework on the distribution of LACS in two representative admixture models, that is, hybrid isolation (HI) model and gradual admixture (GA) model. Although the distribution of LACS in the GA model differs from that in the HI model, we demonstrated that the mean LACS in the HI model is approximately half of that in the GA model if both admixture proportion and admixture time in the two models are identical. We showed that the theoretical framework greatly facilitated the inference and understanding of population admixture history by analyzing African-American and Mexican empirical data. In addition, we found the peak of association signatures in the HI model was much narrower and sharper than that in the GA model, indicating that the identification of putative causal allele in the HI model is more efficient than that in the GA model. Thus admixture mapping with case-only data would be a reasonable and economical choice in the HI model due to the weak background noise. However, according to our previous studies, many populations are likely to be gradually admixed and have pretty high background linkage disequilibrium. Therefore, we suggest using a case-control approach rather than a case-only approach to conduct admixture mapping to retain the statistics power in recently admixed populations.     

Genetic structure and admixture in urban populations of the Argentine North-West

BACKGROUND: From the ethnic point of view, the Argentine North-West (ANW) constitutes one of the most noticeable areas in the country due to the cultural peculiarities that integrate it to the Andean world and the ethno-historical and demographic characteristics of how it became populated. AIM: The study analysed the genetic structure and diversity of the ANW urban populations, and the contribution of parental populations to its genetic pool.Subjects and methods: Previously reported data on allele frequencies of HLA-A and HLA-B loci of 1293 individuals from Jujuy, Salta, Tucumán, Santiago del Estero, Catamarca and La Rioja were used. Our estimates include: (a) genetic intra-population diversity; (b) genetic distances between populations; (c) linkage disequilibrium (LD); (d) admixture rates and genetic distances with respect to three parental populations (European, American Indian and African). RESULTS: Low intra-population genetic differentiation and low genetic distances between populations were found. Differential LD distribution varied according to province, with 60% variance due to intra-population differences. The Spanish contribution (50%) predominated in ANW, followed by the American Indian (40%) and African (10%) contributions, and a marked inter-population heterogeneity of genetic admixture rates was observed. The shortest genetic distance was found in the American Indian parental population, and the longest in the African parental population. CONCLUSION: Five hundred years after the Spanish conquest, urban populations at ANW that have probably been subject to the same evolutionary forces present low genetic diversity and a similar genetic structure. Genetic distances and admixture percentages observed agree with census and ethno-historical data on settlement in the region.     

Facial clefting and Amerindian admixture in populations of Santiago,Chile

Among congenital malformations, cleft lip with and/or without cleft palate has the highest relative frequencies and shows ethnic variation in prevalence. Both malformations are generally more common among the Asian than European populations. Many populations of Chile have genes of Amerindian and Spanish ancestry, with considerable variation in the degree of Amerindian admixture. Therefore, the association of clefting incidence with Amerindian admixture was investigated. The frequency of cleft lip and/or cleft palate in infants born in three private and two public maternity service clinics of Santiago, Chile, is reported. The private clinic patients have a higher socioeconomic status (SES) than those receiving the public services. They also differ in estimated Amerindian admixture. More than 200,900 consecutive birth records were reviewed. The rate of clefting malformations is 15.3 per 10,000 live births. Based on allele frequencies at the ABO and Rh blood group loci, the percentage of Amerindian admixture is higher in infants born in the public compared to those born in the private maternity service clinics. Amerindian admixture is positively correlated (Spearman's p = 0.9, P = 0.008) with clefting rate across these samples. Clefting is also associated with SES, with lower SES showing higher clefting rates. Mothers of clefting newborns also have higher estimated Amerindian admixture compared to those of normal newborns. The results support the view that in Chilean populations, susceptibility to clefting is related to Amerindian ancestry. Am. J. Hum. Biol. 9:225–232, 1997. © 1997 Wiley-Liss, Inc.     

Genetic structure and admixture in urban populations of the Argentine North-West

Background: From the ethnic point of view, the Argentine North-West (ANW) constitutes one of the most noticeable areas in the country due to the cultural peculiarities that integrate it to the Andean world and the ethno-historical and demographic characteristics of how it became populated.

Aim: The study analysed the genetic structure and diversity of the ANW urban populations, and the contribution of parental populations to its genetic pool.

Subjects and methods: Previously reported data on allele frequencies of HLA-A and HLA-B loci of 1293 individuals from Jujuy, Salta, Tucumán, Santiago del Estero, Catamarca and La Rioja were used. Our estimates include: (a) genetic intra-population diversity; (b) genetic distances between populations; (c) linkage disequilibrium (LD); (d) admixture rates and genetic distances with respect to three parental populations (European, American Indian and African).

Results: Low intra-population genetic differentiation and low genetic distances between populations were found. Differential LD distribution varied according to province, with 60% variance due to intra-population differences. The Spanish contribution (50%) predominated in ANW, followed by the American Indian (40%) and African (10%) contributions, and a marked inter-population heterogeneity of genetic admixture rates was observed. The shortest genetic distance was found in the American Indian parental population, and the longest in the African parental population.

Conclusion: Five hundred years after the Spanish conquest, urban populations at ANW that have probably been subject to the same evolutionary forces present low genetic diversity and a similar genetic structure. Genetic distances and admixture percentages observed agree with census and ethno-historical data on settlement in the region.

Résumé. Arrière plan: Du point de vue ethnique, le Nord-Ouest de l’Argentine(NOA) constitue l’une des régions les plus remarquables du pays, par ses particularités culturelles qui l’intègrent au monde andin et par les circonstances ethno-historiques et démographiques de son peuplement.

But: Cette étude analyse la structure génétique et la diversité des populations urbaines du NOA ainsi que la contribution de populations mères à son patrimoine génétique.

Sujets et méthodes:. On a utilisé les données déjà publiées des fréquences alléliques des loci HLA-A et HLA-B de 1293 individus de Jujuy, Salta, Tucuman, Santiago del Estero, Catarmarca et La Rioja. Nos estimations incluent?: (a) la diversité génétique intra-populationnelle?; (b) les distances génétiques entre populations?; (c) le déséquilibre de linkage (DL)?; (d) les taux de métissage et les distances par rapport à trois populations mères (européenne, amérindienne et africaine).

Résultats: On a trouvé une faible différenciation génétique intra-populationnelle ainsi que de faibles distances génétiques entre populations. La distribution du DL varie suivant les provinces, 60% de la variance étant dus à des différences intra-populationnelle. La contribution espagnole (50%) est prédominante dans le NOA, suivie par la composante amérindienne (40%) et africaine (10%). On a observé une forte hétérogénéité interpopulationnelle des taux de métissage. La distance génétique la plus courte a été trouvée dans la population mère amérindienne et la plus longue dans la population mère africaine.

Conclusion: Cinq cent ans après la conquête espagnole, les populations urbaines du NOA qui ont probablement été soumises aux mêmes forces évolutives, présentent une diversité génétique basse et une structure génétique similaire. Les distances génétiques et les pourcentages de métissage observés s’accordent avec les recensements et les données ethno-historiques sur la colonisation de la région.

Zusammenfassung. Hintergrund: Unter ethnischen Gesichtspunkten ist der Argentinische Nordwesten (ANW) eine der bemerkenswertesten Gegenden des Landes, und zwar aufgrund der kulturellen Besonderheiten, die ihn in die Welt der Anden integrieren, und aufgrund seiner ethnisch-historischen und demographischen Merkmale unter dem Aspekt, wie die Besiedlung stattfand.

Ziel: Die Studie analysierte die genetische Struktur und Diversität von städtischen Populationen aus dem Argentinischen Nordwesten und den Beitrag väterlicher Populationen zum genetischen Pool.

Probanden und Methoden: Es wurden früher publizierte Daten betreffend die Allelfrequenzen von HLA-A und HLA-B loci von 1293 Personen aus Jujuy, Salta, Tucumán, Santiago del Estero, Catamarca und La Rioja benutzt. Unsere Schätzungen umfassten: (a) die genetische Diversität innerhalb der Populationen; (b) den genetischen Abstand zwischen den Populationen; (c) das Kopplungsungleichgewicht (linkage disequilibrium, LD); (d) die Zumischungsraten und den genetischen Abstand unter Berücksichtigung dreier elterlicher Populationen (Europäer, Amerikanische Indianer and Afrikaner).

Ergebnisse: Es wurden eine geringe genetische Differenzierung innerhalb der Populationen und geringe genetische Abstände zwischen den Populationen gefunden. Die unterschiedliche Verteilung des Kopplungsungleichgewichts variierte je nach Provinz, mit 60% Varianz aufgrund von Unterschieden innerhalb der Populationen. Der Spanische Einfluss (50%) herrschte in ANW vor, gefolgt von Amerikanisch-Indianischen (40%) und Afrikanischen (10%) Einflüssen, und es wurde eine bedeutsame Heterogenität der genetischen Zumischungsrate zwischen den Populationen beobachtet. Der geringste genetische Abstand befand sich in der Amerikanisch-Indianischen Elternpopulation, der weiteste in der Afrikanischen Elternpopulation.

Zusammenfassung: Fünfhundert Jahre nach der Spanischen Eroberung zeigen städtische Populationen in ANW, die vermutlich denselben evolutionären Kräften ausgesetzt waren, eine niedrige genetische Diversität und eine ähnliche genetische Struktur. Die beobachteten genetischen Abstände und prozentuale Zumischung stimmen mit Zensus- und ethnisch-historischen Daten zur Besiedlung dieses Gebietes überein.

Resumen. Antecedentes: Desde el punto de vista étnico, la Argentina del Noroeste (ANW) constituye una de las áreas más notables del país debido a las peculiaridades culturales que la integran en el mundo Andino y a las características etno-históricas y demográficas de su poblamiento.

Objetivos: El estudio analizó la estructura genética y la diversidad de las poblaciones de la ANW y la contribución de las poblaciones parentales a su pool génico.

Sujetos y Métodos: Se utilizaron datos previamente reportados sobre frecuencias alélicas de los loci HLA-A y HLA-B, de 1293 individuos de Jujuy, Salta, Tucumán, Santiago del Estero, Catamarca y La Rioja. Nuestras estimaciones incluyen: a) la diversidad genética intrapoblacional, b) las distancias genética entre poblaciones, c) el desequilibrio de ligamiento (DL), d) las tasas de mezcla y las distancias genéticas respecto a tres poblaciones parentales (europea, amerindia y africana).

Resultados: Se encontró una baja diferenciación genética intrapoblacional y reducidas distancias genéticas entre poblaciones. La distribución del DL diferencial variaba según la provincia, con una varianza del 60% debida a las diferencias intrapoblacionales. En la ANW predominó la contribución española (50%), seguida de las contribuciones amerindia (40%) y africana (10%) y se observó una marcada heterogeneidad interpoblacional en las tasas de mezcla genética. La menor distancia genética se encontró en la población parental amerindia y la mayor en la población parental africana.

Conclusión: Quinientos años después de la conquista española, las poblaciones urbanas de la ANW, que han estado probablemente sometidas a las mismas fuerzas evolutivas, presentan una baja diversidad genética y una estructura genética similar. Las distancias genéticas y los porcentajes de mezcla observados concuerdan con los datos del censo y los etno-históricos existentes sobre el poblamiento de la región.     

Fragile X syndrome: linkage analysis in black and white populations

Eleven white families and 10 black families have been studied to detect racial differences in the linkage of DNA markers flanking the fragile X site (FRAXA). The differences in the recombination fractions for F9-FRAXA and DX13-FRAXA were not significant. The pair St14-FRAXA exhibited no difference between the two groups. Although the sample size was small, it would appear that these DNA markers can be used in black persons for prenatal diagnosis and genetic counseling. A larger group of families would be necessary to determine if 4D8 and cX55.7 will be equally useful since these appear to have lower heterozygote frequencies in the black population.     

Covariate-based linkage analysis: application of a propensity score as the single covariate consistently improves power to detect linkage

Successful identification of genetic risk loci for complex diseases has relied on the ability to minimize disease and genetic heterogeneity to increase the power to detect linkage. One means to account for disease heterogeneity is by incorporating covariate data. However, the inclusion of each covariate will add one degree of freedom to the allele sharing based linkage test, which may in fact decrease power. We explore the application of a propensity score, which is typically used in causal inference to combine multiple covariates into a single variable, as a means of allowing for multiple covariates with the addition of only one degree of freedom. In this study, binary trait data, simulated under various models involving genetic and environmental effects, were analyzed using a nonparametric linkage statistic implemented in LODPAL. Power and type I error rates were evaluated. Results suggest that the use of the propensity score to combine multiple covariates as a single covariate consistently improves the power compared to an analysis including no covariates, each covariate individually, or all covariates simultaneously. Type I error rates were inflated for analyses with covariates and increased with increasing number of covariates, but reduced to nominal rates with sample sizes of 1000 families. Therefore, we recommend using the propensity score as a single covariate in the linkage analysis of a trait suspected to be influenced by multiple covariates because of its potential to increase the power to detect linkage, while controlling for the increase in the type I error.     

Quantitative linkage: a statistical procedure for its detection and estimation

A new approach for detecting and estimating quantitative linkage which uses sibship data is presented. Using a nested analysis of variance design (with marker genotype nested within sibship), it is shown that under the null hypothesis of no linkage, the expected between marker genotype within sibship mean square (EMSbeta) is equal to the expected within marker genotype within sibship mean square (EMSe), while under the alternative hypothesis of linkage, the first is greater than the second. Thus the regular F-ratio, MSbeta/MSe, can be used to test for quantitative linkage. This is true for both backcross and intercross matings and whether or not there is dominance at the marker locus. A second test involving the comparison of the within marker genotype within sibship variances is available for intercross matings. A maximum likelihood procedure for the estimation for the recombination frequency is also presented.     

Development, implementation and evaluation of a unique African-American faith-based approach to increase automobile restraint use

OBJECTIVE: Despite generalized intervention programs, restraint use among African Americans remains below national levels, especially among children. This study describes the development and implementation of a community participatory faith-based youth injury prevention program. METHODS: Through a partnership with the African-American faith-based community and our injury prevention group, a unique multigenerational intervention program was developed targeting motor vehicle restraint use. Once developed, the program was initially evaluated by comparing outcomes between control and intervention churches. The main objective was to observe adult and pediatric restraint use before and after program implementation. RESULTS: Overall, there was excellent recognition and participation in the program. Following program implementation, significant improvements were observed in restraint use compared to control churches. In particular, there was a 72% reduction in unrestrained children, a 25% increase in children being secured in the rear-seat position and a nearly 20% increase in driver restraint use. CONCLUSIONS: The development and implementation of a culturally sensitive intervention program can significantly improve restraint use in a minority population. Partnering with the community in all phases of the program is essential to its success.     

Recruiting elderly African-American women in cancer prevention and control studies: a multifaceted approach and its effectiveness

Barriers to engaging African Americans as research participants may be accentuated among older single African-American women partly because of financial, social, physical, and cognitive factors. This article shows our multifaceted strategies and experiences in the recruitment of single African-American women aged 65 and older in a cancer prevention and control study. The study was conducted in 10 public housing complexes in Nashville, Tennessee. Out of 367 eligible women, 325 participated in the study, resulting in a rate of 89%. The result suggests that a strategy, which targets the cultural, perceptive, and cognitive characteristics of the population, was effective for increasing the enrollment of study subjects in this population. Because the single constitute 75% of African-American women aged 65 and older; and the incidence and mortality of cancer are especially high in elderly African Americans, our experiences are encouraging for cancer prevention and control research in the population.     

Comparison of a single case to a control or normative sample in neuropsychology: development of a Bayesian approach

Frequentist methods are available for comparison of a patient's test score (or score difference) to a control or normative sample; these methods also provide a point estimate of the percentage of the population that would obtain a more extreme score (or score difference) and, for some problems, an accompanying interval estimate (i.e., confidence limits) on this percentage. In the present paper we develop a Bayesian approach to these problems. Despite the very different approaches, the Bayesian and frequentist methods yield equivalent point and interval estimates when (a) a case's score is compared to that of a control sample, and (b) when the raw (i.e., unstandardized) difference between a case's scores on two tasks are compared to the differences in controls. In contrast, the two approaches differ with regard to point estimates of the abnormality of the difference between a case's standardized scores. The Bayesian method for standardized differences has the advantages that (a) it can directly evaluate the probability that a control will obtain a more extreme difference score, (b) it appropriately incorporates error in estimating the standard deviations of the tasks from which the patient's difference score is derived, and (c) it provides a credible interval for the abnormality of the difference between an individual's standardized scores; this latter problem has failed to succumb to frequentist methods. Computer programs that implement the Bayesian methods are described and made available.     

X-chromosome as a marker for population history: linkage disequilibrium and haplotype study in Eurasian populations

Linkage disequilibrium (LD) structure is still unpredictable because the interplay of regional recombination rate and demographic history is poorly understood. We have compared the distribution of LD across two genomic regions differing in crossing-over activity -- Xq13 (0.166 cM/Mb) and Xp22 (1.3 cM/Mb) -- in 15 Eurasian populations. Demographic events predicted to increase the LD level -- genetic drift, bottleneck and admixture - had a very strong impact on extent and patterns of regional LD across Xq13 compared to Xp22. The haplotype distribution of the DXS1225-DXS8082 microsatellites from Xq13 exhibiting strong association in all populations was remarkably influenced by population history. European populations shared one common haplotype with a frequency of 25-40%. The Volga-Ural populations studied, living at the geographic borderline of Europe, showed elevated LD as well as harboring a significant fraction of haplotypes originating from East Asia, thus reflecting their past migrations and admixture. In the young Kuusamo isolate from Finland, a bottleneck has led to allelic associations between loci and shifted the haplotype distribution, but has much less affected single microsatellite allele frequencies compared to the main Finnish population. The data show that the footprint of a demographic event is longer preserved in haplotype distribution within a region of low crossing-over rate, than in the information content of a single marker, or between actively recombining markers. As the knowledge of LD patterns is often chosen to assist association mapping of common disease, our conclusions emphasize the importance of understanding the history, structure and variation of a study population.     

Classification of human muscle stretch receptor afferents: a Bayesian approach

1. A sample of 124 human muscle afferents originating from the finger extensor muscles were recorded from the radial nerve in the upper arm. A method is described to formalize the classification of units in muscle spindle primary and secondary afferents and Golgi tendon organ afferents on the basis of a few, nonrigorous assumptions. The classification was based on experimental data that largely have been described in a series of previous papers, although some additional data were collected in the present study. 2. The units were subjected to five tests providing identification data: twitch contraction test, ramp-and-hold stretch, small-amplitude sinusoidal stretches superimposed on ramp stretch, stretch sensitization, and isometric contraction/relaxation. From these five tests the following eight response features were extracted: response to maximal isometric twitch contractions, type of stretch sensitization, correlation between discharge rate and contractile force, response to sudden isometric relaxation, presence or absence of an initial burst, deceleration response, prompt silencing at slow muscle shortening, and driving by small-amplitude sinusoidal stretches. 3. A Bayesian decision procedure was adopted to classify the units on the basis of the eight discriminators. As a first step, units were provisionally classified into muscle spindle primary and secondary afferents, and Golgi tendon organ afferents, by intuitively weighting their responses to the identification tests. Prior probabilities were estimated on the basis of the provisional classification. The eight response features were analyzed and tabulated for all afferents, and the likelihood functions of the tests were directly calculated on the basis of these data.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluating the uncertainty of risk prediction in genetic counseling: a Bayesian approach

A general method to obtain the exact point estimate and the measure of uncertainty of recurrence risks for genetic counseling is present. This method, which follows Bayesian estimation theory, can be applied without restrictions of sample size, class of risk function, or parameter dimension. As an illustration, the recurrence risks for isolated cases in two autosomal dominant disorders with incomplete penetrance (mandibulofacial and fontonasal dyostoses) are estimated.     

Efficient two-trait-locus linkage analysis through program optimization and parallelization: application to hypercholesterolemia

We have optimized and parallelized the GENEHUNTER-TWOLOCUS program that allows to perform linkage analysis with two trait loci in the multimarker context. The optimization of the serial program, before parallelization, results in a speedup of a factor of more than 10. The parallelization affects the two-locus-score calculation, which is predominant in terms of computation time. We obtain perfect speedup, that is, the computation time decreases exactly by a factor of the number of processors. In addition, two-locus LOD and NPL scores are now calculated for varying genetic positions of both disease loci, not just one locus varied and the position of the other disease locus fixed, as before. This results in easily interpretable 3-D plots. We have reanalyzed a pedigree with hypercholesterolemia using our new version of GENEHUNTER-TWOLOCUS. Whereas originally, two individuals had to be discarded due to excessive computation-time demands, the entire 17-bit pedigree could now be analyzed as a whole. We obtain a two-trait-locus LOD score of 5.49 under a multiplicative model, compared to LOD scores of 3.08 and 2.87 under a heterogeneity and additive model, respectively. This further increases evidence for linkage to both 1p36.1-p35 and 13q22-q32 regions, and corroborates the hypothesis that the two genes act in a multiplicative way on LDL cholesterol level. Furthermore, we compare the computation times for two-trait-locus analysis needed by the programs GENEHUNTER-TWOLOCUS, TLINKAGE, and SUPERLINK. Altogether, our algorithmic improvements of GENEHUNTER-TWOLOCUS allow researchers to analyze complex diseases under realistic two-trait-locus models with pedigrees of reasonable size and using many markers.     

HLA in populations: an approach for genetical susceptibility to cancer.

The geographical correlations between the incidence of various cancers and the HLA and ABO antigen frequencies are studied. There is, for example, a positive correlation between breast and colorectal carcinoma and AI, B8 and B12 antigens, and a negative one between prostate carcinoma and B12. The role of the HLA system itself or other genes involved in these associations is discussed. This study gives some evidence of a possible genetic background of susceptibility or resistance to cancer.     

Interactions between genetic admixture,ethnic identity,APOE genotype and dementia prevalence in an admixed Cuban sample; a cross-sectional population survey and nested case-control study

Background  

The prevalence and incidence of dementia are low in Nigeria, but high among African-Americans. In these populations there is a high frequency of the risk-conferring APOE-e4 allele, but the risk ratio is less than in Europeans. In an admixed population of older Cubans we explored the effects of ethnic identity and genetic admixture on APOE genotype, its association with dementia, and dementia prevalence.     

A Bayesian approach to generating tutorial hints in a collaborative medical problem-based learning system

OBJECTIVES: Today a great many medical schools have turned to a problem-based learning (PBL) approach to teaching. While PBL has many strengths, effective PBL requires the tutor to provide a high degree of personal attention to the students, which is difficult in the current academic environment of increasing demands on faculty time. This paper describes intelligent tutoring in a collaborative medical tutor for PBL. The main contribution of our work is the development of representational techniques and algorithms for generating tutoring hints in PBL group problem solving, as well as the implementation of these techniques in a collaborative intelligent tutoring system, COMET. The system combines concepts from computer-supported collaborative learning with those from intelligent tutoring systems. METHODS AND MATERIALS: The system uses Bayesian networks to model individual student clinical reasoning, as well as that of the group. The prototype system incorporates substantial domain knowledge in the areas of head injury, stroke and heart attack. Tutoring in PBL is particularly challenging since the tutor should provide as little guidance as possible while at the same time not allowing the students to get lost. From studies of PBL sessions at a local medical school, we have identified and implemented eight commonly used hinting strategies. In order to evaluate the appropriateness and quality of the hints generated by our system, we compared the tutoring hints generated by COMET with those of experienced human tutors. We also compared the focus of group activity chosen by COMET with that chosen by human tutors. RESULTS: On average, 74.17% of the human tutors used the same hint as COMET. The most similar human tutor agreed with COMET 83% of the time and the least similar tutor agreed 62% of the time. Our results show that COMET's hints agree with the hints of the majority of the human tutors with a high degree of statistical agreement (McNemar test, p=0.652, kappa=0.773). The focus of group activity chosen by COMET agrees with that chosen by the majority of the human tutors with a high degree of statistical agreement (McNemar test, p=0.774, kappa=0.823). CONCLUSION: Bayesian network clinical reasoning models can be combined with generic tutoring strategies to successfully emulate human tutor hints in group medical PBL.     

Molecular phylogenetic analysis of bovine viral diarrhoea virus: a Bayesian approach

Genetic typing of bovine viral diarrhoea virus (BVDV) is important for precise classification of viruses. Traditionally, inferring BVDV phylogeny has been performed by distance-based method, i.e. neighbor-joining for single genes. In this study, a Bayesian approach was exploited to analyze five genetic regions of BVDV genome (5′ UTR, N^pro, E2a, E2b, and NS3) for 68 taxa retrieved from GenBank. The results showed that all taxa in the consensus tree of E2a have been assigned correctly to corresponding groups, i.e. type-2 BVDV, and BVDV-1a, -1b, -1c, -1e, and -1g, supported by a high posterior probability. In contrast, subgroup 1a formed polytomies in the consensus trees of 5′ UTR and NS3. Polytomies also appeared among the subgroup 1b in the consensus trees of N^pro and E2b. Analysis of a combined dataset produced an unambiguous, well-supported phylogenetic hypothesis. The topologies found for each genetic region separately and combined were different, but the differences were mainly weakly supported by the data. Combining the data allowed the identification of well-supported clades of strains that correspond to some of the previously defined subgroups. Only a combined approach will allow the confident placement of new strains in the current classification of viruses into genotype and subgenotype.