Sex-dependent Models Research Articles

Sex-dependent liver cancer xenograft models for predicting clinical data in the evaluation of anticancer drugs

BackgroundThe incidence and mortality of liver cancer show a great difference between the sexes. We established sex-dependent liver cancer xenograft models and investigated whether such sex-dependent models could be used to simultaneously evaluate the therapeutic and adverse effects of anticancer drugs for drug screening.ResultsIn the in-vitro test, the cytotoxicity of anticancer drugs (cisplatin, 5-fluorouracil, and doxorubicin) was compared between male- and female-derived liver cancer cell lines. Cisplatin and 5-fluorouracil exhibited cytotoxicity without sex-difference, but doxorubicin showed dose-dependently significant cytotoxicity only in male-derived cells. Our results showed a strong correlation between preclinical and clinical data with the use of sex-dependent liver cancer xenograft models. Moreover, the male-derived Hep3B-derived xenograft model was more sensitive than the female-derived SNU-387-derived xenograft model against doxorubicin treatment. Doxorubicin showed more severe cardiotoxicity in the male xenograft model than in the female model. We investigated the occurrence frequency of doxorubicin-related cardiotoxicity using data obtained from the Korea Institute of Drug Safety & Risk Management Database, but no significant difference was observed between the sexes.ConclusionsOur results suggest that sex-dependent xenograft models are useful tools for evaluating the therapeutic and adverse effects of anticancer drugs, because sex is an important consideration in drug development.

African Americans Demonstrate Significantly Lower Serum Alanine Aminotransferase Compared to Non-African Americans.

Normal ranges of serum alanine aminotransferase (ALT) may vary by race. However, resultsfrom research studies are contradictory, and manyof these studies have included only small numbers of African Americans. We investigated ALT values in patients without evidence of liver disease to determine whether normal ranges differ across race groups. We also evaluated whether a race- and sex-dependent upper limit of normal (ULN) would improve the ability of ALT to predict liver disease compared to the sex-dependent ULN currently in use. We identified ICD9 codes for liver conditions and diabetes in medical records from a sample of 6719 patients. Analysis of variance (ANOVA) was used to assess differences in ALT log-transformed distributions by race. Logistic regression was used to evaluate whether the addition of race to the current sex-dependent ULN improves the ability of ALT to predict liver disease (assessed by area under the receiver operating characteristic curve (AUROC)). Among 1200 patients with BMI 18.5 < 25 and no evidence of liver disease or type 2diabetesin their medical record, African Americans demonstrated significantly lower ALT (23.47IU/L; 95% CL 22.87-24.10) than a combined group of Asian American/White/Other patients (25.71IU/L; 95% CL 24.69-26.77). This difference remained across BMI categories. The race- and sex-dependent model demonstrated significantly better predictive ability than the sex-dependent model (AUROC = 66.6% versus 59.6%, respectively; p < 0.0001). In a large, racially diverse sample, African Americans demonstrated significantly lower ALT compared to non-African Americans; this difference remained as BMI increased. The establishment of race-specific normal ranges for ALT could contribute to better screening and care for African American patients.

The Influence of Mark-Recapture Sampling Effort on Estimates of Rock Lobster Survival.

Five annual capture-mark-recapture surveys on Jasus edwardsii were used to evaluate the effect of sample size and fishing effort on the precision of estimated survival probability. Datasets of different numbers of individual lobsters (ranging from 200 to 1,000 lobsters) were created by random subsampling from each annual survey. This process of random subsampling was also used to create 12 datasets of different levels of effort based on three levels of the number of traps (15, 30 and 50 traps per day) and four levels of the number of sampling-days (2, 4, 6 and 7 days). The most parsimonious Cormack-Jolly-Seber (CJS) model for estimating survival probability shifted from a constant model towards sex-dependent models with increasing sample size and effort. A sample of 500 lobsters or 50 traps used on four consecutive sampling-days was required for obtaining precise survival estimations for males and females, separately. Reduced sampling effort of 30 traps over four sampling days was sufficient if a survival estimate for both sexes combined was sufficient for management of the fishery.

Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips

BackgroundIllumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study.ResultsIn general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics.ConclusionsCRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended.

The Maintenance of Single-locus Polymorphism. V. Sex-dependent Viabilities

Since natural selection requires variation to act, the amount of genetic variation in a given population is of central theoretical and experimental importance. This amount is estimated by the genetic variationpresent in current popu- lations. Electrophoretic studies of natural populations reveal that ten to twenty percent of all loci have multiple al- leles. These multi-allelic loci may be the result of the accumulation of unselected mutations (neutral theory) or of balancing selection (selectionist theory). The neutral theory views selection as primarily eliminating variation, whereas the selectionist theory views selection as often maintaining variation. Therefore, our view of selection and evolution depends upon the question of how multiple allelic systems evolve. To address whether balancing selection increases genetic variation, we examined Owen™s model in which se- lection varies in the two sexes (sex-dependent model) and compared it to a model in which selection is constant across the two sexes (se...

A pilot Swedish twin study of affective illness including hospital- and population-ascertained subsamples: Results of model fitting

We investigated the heritability of liability to affective illness (AI) in twins ascertained through psychiatric hospitalization for AI from the Swedish Psychiatric Twin Registry and from the general population Swedish Twin Registry. Lifetime diagnoses were assessed by mailed questionnaire containing, in self-report format, DSM-III-R criteria for mania and major depression (MD). Jointly analyzing both subsamples using Mx, and assuming a multifactorial threshold model, the best-fitting twin model using narrow diagnostic criteria suggested that the liability to AI could be explained by additive genetic effects, with an estimated heritability of liability of 64%, and individual-specific environment. Using broad criteria, results were similar except that the estimated broad heritability of liability was higher (83%) and due largely to dominance genetic effects. Fitting sex-dependent models suggested that the same genetic and environmental factors influenced liability to AI in men and women to the same degree, although women had a lower threshold of manifestation. These results suggested that in Sweden, AI is a highly heritable syndrome and family resemblance is due largely or entirely to genetic factors.

Speaker-independent continuous speech dictation

In this paper we report on progress made at LIMSI in speaker-independent large vocabulary speech dictation using newspaper-based speech corpora in English and French. The recognizer makes use of continuous density HMMs with Gaussian mixtures for acoustic modeling and n-gram statistics estimated on newspaper texts for language modeling. Acoustic modeling uses cepstrum-based features, context-dependent phone models (intra and interword), phone duration models, and sex-dependent models. For English the ARPA Wall Street Journal-based CSR corpus is used and for French the BREF corpus containing recordings of texts from the French newspaper Le Monde is used. Experiments were carried out with both these corpora at the phone level and at the word level with vocabularies containing up to 20,000 words. Word recognition experiments are also described for the ARPA RM task which has been widely used to evaluate and compare systems.