RESUMEN
Genetic diversity generally underpins population resilience and persistence. Reductions in population size and absence of gene flow can lead to reductions in genetic diversity, reproductive fitness, and a limited ability to adapt to environmental change increasing the risk of extinction. Island populations are typically small and isolated, and as a result, inbreeding and reduced genetic diversity elevate their extinction risk. Two island populations of the platypus, Ornithorhynchus anatinus, exist; a naturally occurring population on King Island in Bass Strait and a recently introduced population on Kangaroo Island off the coast of South Australia. Here we assessed the genetic diversity within these two island populations and contrasted these patterns with genetic diversity estimates in areas from which the populations are likely to have been founded. On Kangaroo Island, we also modeled live capture data to determine estimates of population size. Levels of genetic diversity in King Island platypuses are perilously low, with eight of 13 microsatellite loci fixed, likely reflecting their small population size and prolonged isolation. Estimates of heterozygosity detected by microsatellites (H(E)= 0.032) are among the lowest level of genetic diversity recorded by this method in a naturally outbreeding vertebrate population. In contrast, estimates of genetic diversity on Kangaroo Island are somewhat higher. However, estimates of small population size and the limited founders combined with genetic isolation are likely to lead to further losses of genetic diversity through time for the Kangaroo Island platypus population. Implications for the future of these and similarly isolated or genetically depauperate populations are discussed.
RESUMEN
OBJECTIVES: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model. METHODS: One hundred seventy newly treated patients with epilepsy completed the A-B Neuropsychological Assessment Scale (ABNAS) before commencing AED therapy and were prospectively followed up for 12 months. Patients were classified as nonresponsive if they had at least 1 seizure not explained by medication noncompliance or other significant provoking factors. RESULTS: Of the 138 patients in whom a drug response phenotype at 12 months was able to be determined, nonresponsive patients (n = 45) had a higher pretreatment ABNAS score than patients whose seizures were controlled (n = 93) (p = 0.007). A lesion on MRI was also associated with a higher risk of seizure recurrence (p = 0.003). On multivariate logistic regression, the ABNAS score, the MRI results, and a genomic classifier were all independently predictive of treatment outcome. For AED pharmacoresponse, this multivariate model had diagnostic values of 91% sensitivity, 64% specificity, 84% positive predictive, and 78% negative predictive values. The predictive value of the ABNAS score was validated in a second prospective cohort of 74 newly treated patients with epilepsy (p = 0.005). CONCLUSIONS: The ABNAS provides prognostic information regarding successful seizure control in patients newly treated with AEDs. Furthermore, these results demonstrate the multifactorial nature of the determinants of AED response, with neuropsychological, structural, and genomic factors all contributing to the complex response phenotype.
Asunto(s)
Trastornos Mentales/psicología , Enfermedades del Sistema Nervioso/patología , Convulsiones/patología , Convulsiones/psicología , Anticonvulsivantes/uso terapéutico , Ansiedad/psicología , Cognición/fisiología , Estudios de Cohortes , Depresión/psicología , Resistencia a Medicamentos , Electroencefalografía , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Memoria/fisiología , Modelos Neurológicos , Pruebas Neuropsicológicas , Farmacogenética , Estudios Prospectivos , Recurrencia , Reproducibilidad de los Resultados , Convulsiones/genética , Encuestas y Cuestionarios , Análisis de SupervivenciaRESUMEN
A model for the transmission of the CGG repeat sequence associated with the fragile-X dynamic mutation in the FMR1 gene is developed. The model incorporates both haplotype and family effects on the expansion rate of the sequence. The resulting random effects model is fitted to new data, using computer-intensive Markov chain Monte Carlo methods. The results demonstrate both the FRAXAC1-DXS458 haplotype and family effects on the transmission of CGG repeats from mother to offspring.
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Teorema de Bayes , Síndrome del Cromosoma X Frágil/genética , Australia , Distribución de Chi-Cuadrado , Femenino , Variación Genética , Genética de Población , Genotipo , Haplotipos , Humanos , Masculino , Madres , Mutación , Fenotipo , Estados UnidosRESUMEN
The effect of the fragile X pre-mutation and full mutation categories, and FMRP deficits in these categories, on neurocognitive status, have been assessed in fragile X individuals from 144 extended families, which included fragile X individuals, as well as their non-fragile X relatives. Neuropsychological status was assessed by the Wechsler summary and subtest test scores. A modification of the maximum likelihood estimators for pedigree data that is resistant to outliers was used to analyze the data. The results have demonstrated the effect of large expansions of CGG repeat in the FMR1 (fragile X mental retardation 1) gene (full mutation) in decreasing full scale IQ (FSIQ), as well as several FSIQ-adjusted subtest scores in the performance domain. Moreover, the results have demonstrated significant cognitive deficits in male individuals with pre-mutation. FMRP depletion correlates strongly with neurocognitive status in the full mutation subjects. Evidence for the effect of FMRP in smaller expansions (pre-mutation) in reducing FSIQ, Performance and Verbal scores, as well as subtest scores in males, has also been obtained. The results are also suggestive of factors other than FMRP deficit which may determine some specific cognitive deficits in fragile X pre-mutation carriers. Genetic variance estimated from the models accounts for less than half of the total variance in FSIQ, and it varies widely between individual Wechsler subtests.
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Síndrome del Cromosoma X Frágil/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas de Unión al ARN , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Humanos , Masculino , Mutación , Proteínas del Tejido Nervioso/genética , LinajeRESUMEN
The effect of deficit of the FMR1-gene product (FMRP) on physical phenotype was investigated using a robust modification of the maximum likelihood estimators for pedigree data. The approach is a powerful method of examining genotype-phenotype relationships because it adjusts for intra-familial variation, and the robust modification allows violation of distributional assumptions in the data to be overcome by objectively down-weighting unusual observations. The data on 19 age- or height-adjusted physical measures including head, trunk and limb measures and height and weight from 110 extended fragile X families (including 185 fragile X males and females and 120 normal relatives) were related to the FMRP levels assessed in peripheral blood lymphocytes. A significant interaction between FMRP and age was also included in the models for some measures. The results have demonstrated a linear effect of progressively reducing levels of FMRP on the values of a majority of physical measures considered in the study. The most evident effect of FMRP deficit in sexes combined was in decreasing body height and limb length, and in increasing head height and the degree of connective tissue involvement (measured by the middle finger extension angle). Heritability estimated from the complex FMRP models showed the highest values for height and limb length, and the lowest for weight, finger extension angle and some facial measures. On the basis of the present data, a possible mechanism by which the FMRP deficit impacts physical phenotype is discussed.
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Antropometría/métodos , Síndrome del Cromosoma X Frágil/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/fisiopatología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Modelos Biológicos , Mutación , Proteínas del Tejido Nervioso/genética , FenotipoRESUMEN
Relationships between the fragile X dynamic mutation and palmar and finger epidermal ridge measures were assessed using a robust modification of the maximum likelihood estimators for pedigree data. A total of 34 extended families affected with fragile X syndrome were used. Phenotypic traits included ridge count on the thumb and ridge breadth measured in the second palmar interdigital area bilaterally. Genotypic measures were represented by the number of CGG repeats in the FMR1 gene, the levels of specific FMR1 protein (FMRP), fragile X category defined by the size of the CCG repeat, and methylation status of the gene. The results demonstrated a significant fragile X effect (related to the number of CGG repeats) in the thumb ridge count in males. This effect was more evident in ridge breadth and was found in both sexes. However, the relationship between both phenotypic traits and the level of FMRP was nonsignificant. The study makes a useful contribution to the development of methodologies for the analysis of genotype-phenotype relationships in dynamic mutations, especially in overcoming extensive variability in both the genotype and phenotype, and in approaching the statistical problems related to intergenerational changes in repeat size. The findings support the hypothesis that the fragile X mutation affects limb development during an early fetal period.
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Síndrome del Cromosoma X Frágil/genética , Linaje , Proteínas de Unión al ARN , Dermatoglifia , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Genotipo , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , FenotipoRESUMEN
Longitudinal data from twin pairs may be used to determine how the genetic effects influencing a quantitative trait change with age. Here a model for mixed longitudinal data of Huggins and Loesch [1998] on unrelated individuals is extended to twin studies. The model is fitted using robust statistical methods and a bootstrap procedure is proposed to estimate the percentiles. The method is applied to longitudinal twin data on body mass index in male and female twin pairs aged 5-18 years.
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Estudios Longitudinales , Carácter Cuantitativo Heredable , Gemelos , Adolescente , Índice de Masa Corporal , Peso Corporal/genética , Niño , Preescolar , Ambiente , Femenino , Variación Genética , Humanos , Masculino , Modelos Genéticos , Modelos EstadísticosRESUMEN
Secular changes in growth and maturation have been well documented in various world populations, with secular increase especially noticeable in the developed countries. To assess the trend in both adult size and tempo of growth we compared the data on stature and body weight obtained in 1992-1993 from 1,804 Melbourne school students aged 5 to 17 with historical data collected from white Australians during the last 100 years. We illustrate the age-dependent trend in stature and body weight by means of regression surfaces. These were constructed by fitting local regression models to historical data and by simple plots showing the overall, and per decade, secular increase in both these measures at peripubertal and adult ages. Because of limited information on sample sizes and variability provided by the historical data, statistical comparisons have been performed only between the present 1992-1993 survey and two earlier independent surveys conducted in 1985 and 1970. The results have shown secular increase in adult stature over the last century, with the rate of increase varying between 0.4 and 2.1 cm/decade in males and 0.01 and 1.6 cm/decade in females. While secular increase in stature has significantly slowed down during the last two decades, the increase in body weight is still continuing at a high rate, and this increase is more pronounced in females. The period of strong secular increase, especially in the tempo of growth, coincided both with the shift toward earlier menarche and the improvement of socioeconomic conditions of the Australian population. The need for further studies to identify factors determining the continuing increase in body weight is emphasized, and caution in using the existing national growth standards for stature and weight is recommended.
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Estatura , Peso Corporal , Desarrollo Infantil , Crecimiento , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Menarquia , Factores Sexuales , Clase SocialRESUMEN
Sleep patterns and endogenous melatonin profiles in 13 fragile X boys between the age of 4.7 and 11.0 years were compared to those of 8 age-matched, normal control boys. Parents recorded sleep patterns on a Sleep Diary Chart for 14 consecutive days. Twelve saliva samples were obtained from 8 fragile X participants and all of the controls over 48 hours for the assessment of salivary melatonin profiles. The results showed greater variability in total sleep time and difficulty in sleep maintenance in fragile X boys compared with the control participants. Nocturnal melatonin production, expressed as both peak level and area under the concentration-time curve between 20:00 h and 08:00 h, were found to be significantly larger in fragile X boys than in controls. Additionally, the mean of the minimum daytime melatonin levels recorded was significantly higher for the fragile X group. Elevated levels in some fragile X boys relative to the range seen in controls, occurring either during the day or at night, or in both segments of the secretory profile for some individuals, may be due in part to overactivity of the sympathetic nervous system. Alternative molecular mechanisms leading to changes in melatonin profiles in fragile X are also discussed.
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Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/fisiopatología , Melatonina/biosíntesis , Sueño , Factores de Edad , Índice de Masa Corporal , Niño , Preescolar , Humanos , Masculino , Melatonina/metabolismo , Proyectos Piloto , Polisomnografía , Saliva/química , Sueño/genéticaRESUMEN
A weighted martingale method, akin to a moving average, is proposed to allow the use of modified closed-population methods in the estimation of the size of a smoothly changing open population when there are frequent capture occasions. We concentrate here on modifications to martingale estimating functions for model Mt, but a wide range of closed-population estimators may be modified in this fashion. The method is motivated by and applied to weekly capture-recapture data from the Mai Po bird sanctuary in Hong Kong. Simulations show that the weighted martingale estimator compared well with the Jolly-Seber estimator when the conditions for the latter to be valid are met, and it performed far better when individuals were allowed to leave and reenter the population. Expressions are derived for the asymptotic bias and variance of the estimator in an appendix.
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Biometría , Densidad de Población , Animales , Modelos Estadísticos , Dinámica Poblacional , Pájaros CantoresRESUMEN
Mixed longitudinal growth data consists of several observations on a characteristic over a limited age range for each individual in a study. This data is then combined to model growth over the total age range of all individuals in the study. The limited data collected on each individual precludes a subject-specific approach to modelling so that a population-based approach must be used. Here we propose a method for the analysis of mixed longitudinal data using linear models constructed from cubic splines to model both the mean and variance curves of an observed characteristic. The method is illustrated on growth in height and head circumference for children in a recently collected mixed longitudinal data set concerning the growth of Victorian schoolchildren, where particular concern was the timing of growth spurts and increases in variability.
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Interpretación Estadística de Datos , Trastornos del Crecimiento/fisiopatología , Crecimiento , Estudios Longitudinales , Adolescente , Factores de Edad , Australia , Biometría/métodos , Estatura , Niño , Preescolar , Estudios de Cohortes , Femenino , Cabeza/anatomía & histología , Humanos , Masculino , Modelos Estadísticos , Caracteres SexualesRESUMEN
A non-linear time series version of a model for the transmission of fragile X previously described in Ashley & Sherman (1995) is developed. The model retains the biological features of the Ashley/Sherman model but is easier to generalize and in particular allows the inclusion of covariates such as haplotype to model different paths and random effects to model family effects. The model is fitted to data from Murray et al. (1997) and its properties are illustrated in a simulation study.
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Síndrome del Cromosoma X Frágil/genética , Modelos Genéticos , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN , Repeticiones de Trinucleótidos/genética , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Haplotipos , Humanos , Masculino , Cromosoma XRESUMEN
We utilize an extension of the variance-components models for cell lineage data in Huggins and Staudte (R.M. Huggins and R.G. Staudte, Variance components models for dependent cell populations. J. Am. Stat. Assoc. 89:19-29 (1994) to analyze NIH3T3 cells grown in two different media. This modeling approach has the advantage of a simple built-in correlation structure between familial members and allows for estimating experimental effects, rather than treating them as random effects. In addition, this methodology gives robust estimates of model parameters together with standard errors required for statistical inference. The importance of clonal heterogeneity and interexperiment variability in modeling eukaryotic cell cycles was previously pointed out by Kuczek and Axelrod (T. Kuczek and D.E. Axelrod, The importance of clonal heterogeneity and interexperimental variability in modeling the eukaryotic cell cycle. Math. Biosci. 79:87-96 (1986). This analysis confirms significantly positive sister-sister correlation when cells are grown in rich or poor medium and negative mother-daughter correlation when cells are grown in poor medium. However, for cells grown in rich medium, Kuczek and Axelrod's analysis gives negative mother-daughter correlations, whereas this analysis gives significant positive mother-daughter correlations.
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Células Clonales/citología , Modelos Biológicos , Células 3T3 , Animales , Ciclo Celular , División Celular , Senescencia Celular , Matemática , Ratones , Análisis de Regresión , Factores de TiempoRESUMEN
E. O. Powell carried out numerous experiments observing cell-generation times on bacteria. His statistical methodology, though quite advanced 40 years ago, can be enhanced by better models of dependence, by advanced computational methods, and by judicious use of robust methods. We reexamine Powell's data, focussing on his main interest in establishing whether there were indeed dependencies in generation times between cells with close filial connections.
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Biometría/métodos , Escherichia coli/crecimiento & desarrollo , Análisis de Varianza , División Celular , Interpretación Estadística de Datos , Escherichia coli/citología , Modelos Biológicos , Modelos Estadísticos , Programas Informáticos , Factores de TiempoRESUMEN
The effect of fragile X on growth in stature was estimated in individuals aged 5-20 years from 50 fragile X families. The multivariate normal model for pedigree analysis was applied to the mixed longitudinal data, which varied with regard to intervals between the measurements and their number in individual subjects, totalling 349 measurement data points from fragile X families, and 292 data points from unrelated normal subjects. The results of genetic and regression analysis showed that, in fragile X boys and girls, total pubertal height gain is impaired, whereas the rate of growth during the preadolescent period is increased, compared with the growth rate of nonfragile X subjects. Moreover, the growth parameters in fragile X males were found to be correlated with the size of CGG trinucleotide expansion. The hypothesis of premature activation of the hypothalamo-pituitary gonadal axis is postulated as the cause of growth impairment in fragile X boys and girls, which should be verified by data on the timing of pubertal stages, hormone levels, and bone maturation.
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Síndrome del Cromosoma X Frágil/fisiopatología , Trastornos del Crecimiento/genética , Adolescente , Adulto , Estatura , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , LinajeRESUMEN
We have analyzed longitudinal twin data by using a multivariate normal model to identify and quantify genetic effects over time on two main aspects of growth, height and skeletal maturity. The largest genetic contribution to the variance in both height and skeletal maturity coincided with the respective ages of peak growth velocity. The highest genetic covariance between these two traits coincided with the age of greatest acceleration of growth in height. These findings imply the existence of regulatory or structural genes that influence growth in both height and skeletal maturity. We also found sex differences in the rapport between velocities for height and skeletal maturity. These are consistent with a predominant role of estrogen in accelerating skeletal maturation in females, and the existence of additional mechanisms in males which may promote growth in height independently of the effects of gonadal sex steroids.
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Estatura/fisiología , Desarrollo Óseo/fisiología , Pubertad/fisiología , Caracteres Sexuales , Adolescente , Estatura/genética , Desarrollo Óseo/genética , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Factores de TiempoRESUMEN
Owing to the presence of outliers, an estimated 3.5% in the ridge breadth data and 1.7% in the height data, the effect of fragile X on height and ridge breadth was examined using robust statistical techniques for data collected from 54 families afflicted with this disorder. It is shown that fragile X affects ridge breadth and height in a different manner. Fragile X women had a greater mean ridge breadth than normal women, whereas there was a similar trend, but no significant difference, between normal and fragile X men. Fragile X men were shorter than normal men, but no significant difference between the mean height of normal and fragile X women was observed. However, fragile X girls were shown to grow more quickly and to stop growing earlier than normal girls. An examination of the covariance between relatives classified according to fragile X status showed that for both traits the effect of fragile X was to reduce the covariance between parents and offspring, which produced the effect of departure from an additive polygenic model of inheritance.
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Síndrome del Cromosoma X Frágil/epidemiología , Modelos Genéticos , Modelos Estadísticos , Adolescente , Adulto , Factores de Edad , Anciano , Análisis de Varianza , Estatura , Niño , Preescolar , Dermatoglifia , Femenino , Síndrome del Cromosoma X Frágil/genética , Mano , Humanos , Masculino , Persona de Mediana Edad , Distribución Normal , Linaje , Fenotipo , Análisis de Regresión , Factores SexualesRESUMEN
A random sample of 2266 women aged 50 to 69 years was used to investigate factors that predict attendance at a free Australian mammographic screening program. The most important predictor was receipt of a personal invitation letter. A letter that included an appointment time increased attendance 132-fold initially and decreased to 20 times baseline after 14 days. A letter that did not include an appointment time increased attendance 12-fold, and a second letter to nonattenders increased attendance approximately 13-fold. Attendance declined with increasing distance from the program and with increases in the percentage of non-English speaking women in a neighborhood, but was higher in areas of higher socioeconomic status.
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Mamografía/estadística & datos numéricos , Tamizaje Masivo/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Factores de Edad , Anciano , Citas y Horarios , Comunicación , Femenino , Humanos , Persona de Mediana Edad , Factores Socioeconómicos , VictoriaRESUMEN
A maximum likelihood scoring technique for analysis of pedigree data, which allows for estimation of random effects (variance components) concurrently with other "fixed" effects in a quantitative trait, was applied to establish the effect of the fragile X condition in the variation of intellectual and physical traits. In 52 fragile X families, intellectual status was represented by measures of vocabulary knowledge (PPVT) and of nonverbal visuospatial skills (BDT), and physical status by a combined physical (anthropometric) score, and jaw length. The fixed effects included fragile X and sex and their interaction on the mean and covariances between relatives for the intellectual and physical scores. The random effects included environmental (common and individual) and genetic (additive and dominance) components. Different genetic models were tested by the likelihood ratio criterion, and the maximum likelihood parameters for each of the three scores were based on the most appropriate models. The effect of fragile X on the mean values was found to be significant for all the traits, and much more conspicuous in male than in female individuals, the effects in the PPVT and the anthropometric score being intercorrelated. The effect of fragile X on growth of a single physical trait relative to height was demonstrated using jaw length as an example. We have also demonstrated an effect of fragile X on genetic (additive) variance, as well as on the mean of the BDT score, and the effect of age on the nongenetic variance of PPVT, and jaw length.
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Síndrome del Cromosoma X Frágil/genética , Inteligencia , Anomalías Maxilomandibulares/genética , Antropometría , Femenino , Síndrome del Cromosoma X Frágil/patología , Síndrome del Cromosoma X Frágil/psicología , Humanos , Pruebas del Lenguaje , Masculino , Modelos Genéticos , LinajeRESUMEN
Venous thrombosis rates were compared in 200 patients undergoing total hip arthroplasty and randomized to receive either fixed mini-dose warfarin (1 mg daily) or adjusted-dose warfarin to maintain an international normalized prothrombin ratio (INR) of 2.0-4.0. Bilateral lower limb venography was performed between days 11 and 13 inclusive. Fixed mini-dose warfarin was associated with a significantly higher rate of total thrombosis (P less than 0.05). General anaesthesia was associated with a significantly higher rate of thrombosis than spinal anaesthesia (P less than 0.05). Adjusted-dose warfarin was associated with more bleeding complications than mini-dose warfarin although these were not attributable to excessive anticoagulation. A single death from pulmonary embolus occurred in the early postoperative period in a patient receiving adjusted-dose warfarin.