Relationships between conformation traits and functional longevity in Holstein cows were evaluated using survival analysis. Functional longevity was defined as the number of days between the first calving and culling; that is, length of productive life. The data set consisted of 116,369 Holstein cows that first calved from 2003 to 2008. All cows used in the analysis were scored for conformation between d 30 and d 210 of their first lactation. The data included 48% censored records. Analyses were done separately for 20 linear descriptive type traits, 6 composite traits, and height at sacrum measured in centimeters. Cox proportional hazard models were fitted to analyze data. The hazard function was described as the product of a baseline hazard function and the time-independent effects of age at first calving and sire (random), and the time-dependent effects of stage of lactation and lactation number, herd, year and season, herd size, and 305-d milk production. The strongest relationship between a composite trait and functional longevity was for dairy form, followed by udder and final score. Among the descriptive type traits, the strongest relationships with longevity were found for body condition score, angularity, traits related to udder attachment, and udder depth. Foot and leg traits showed substantially lower effect on functional longevity, and the effect of foot angle was minimal. Functional longevity declined with decreased body condition score of cows. Cows with deep udders had significantly lower functional survival compared with cows with shallow udders. In addition, weak central ligament was associated with significant reduction of cow longevity. For dairy form and angularity, cows classified as very good were the worst with respect to longevity, whereas cows classified as poor were the best. An intermediate optimum was evident for rear legs rear view and rear legs set (side view), whereas cows with sickled legs had lower longevity than cows with straighter legs.
- MeSH
- Biometry MeSH
- Longevity genetics MeSH
- Quantitative Trait, Heritable MeSH
- Lactation genetics MeSH
- Mammary Glands, Animal anatomy & histology MeSH
- Proportional Hazards Models MeSH
- Cattle anatomy & histology genetics physiology MeSH
- Animals MeSH
- Check Tag
- Cattle anatomy & histology genetics physiology MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
Survival analysis is commonly conducted in medical and public health research to assess the association of an exposure or intervention with a hard end outcome such as mortality. The Cox (proportional hazards) regression model is probably the most popular statistical tool used in this context. However, when the exposure includes compositional covariables (that is, variables representing a relative makeup such as a nutritional or physical activity behaviour composition), some basic assumptions of the Cox regression model and associated significance tests are violated. Compositional variables involve an intrinsic interplay between one another which precludes results and conclusions based on considering them in isolation as is ordinarily done. In this work, we introduce a formulation of the Cox regression model in terms of log-ratio coordinates which suitably deals with the constraints of compositional covariates, facilitates the use of common statistical inference methods, and allows for scientifically meaningful interpretations. We illustrate its practical application to a public health problem: the estimation of the mortality hazard associated with the composition of daily activity behaviour (physical activity, sitting time and sleep) using data from the U.S. National Health and Nutrition Examination Survey (NHANES).
Statistics for biology and health
[1st ed.] xiii, 350 s.
Cíl Klinický průběh onemocnění pacientů s chronickou lymfocytární leukémií (chronic lymphocytic leukemia, CLL) je velmi variabilní; někteří pacienti mají indolentní onemocnění a nevyžadují žádnou léčbu, zatímco jiní mají agresivní onemocnění vyžadující časné léčení. Zahájení terapie se nadále řídí kritérii pro aktivní onemocnění. Provedli jsme mnohorozměrnou analýzu s cílem určit prognostické faktory spojené nezávisle s dobou do první léčby pacientů s CLL. Pacienti a metody V mnohorozměrné analýze byly vyhodnoceny tradiční laboratorní a klinické prognostické faktory a nové prognostické faktory, jimiž jsou např. fluorescenční hybridizace in situ (fluorescent in situ hybridization, FISH), mutační status IGHV a exprese ZAP-70 vyšetřené při první návštěvě v MD Anderson Cancer Center, s dobou do první léčby. Tento mnohorozměrný model byl použit k sestrojení nomogramu – statisticky váženého nástroje pro výpočet 2leté a 4leté pravděpodobnosti zahájení léčby a mediánu doby do prvního léčení. Výsledky Bylo zjištěno 930 dosud neléčených pacientů, kteří podstoupili vyšetření tradičních a nových prognostických faktorů; pacienti, kteří neměli během 3 měsíců po první návštěvě aktivní CLL vyžadující zahájení léčby, byli pozorováni k zjištění doby do prvního léčení. S kratší dobou do prvního léčení byly nezávisle spojeny následující charakteristiky: tři lokalizace postižených lymfatických uzlin, zvětšení cervikálních krčních uzlin, přítomnost delece 17p nebo delece 11q podle FISH, zvýšená koncentrace laktátdehydrogenázy v séru a mutační status IGHV bez mutace. Závěr Vytvořili jsme mnohorozměrný model, jehož součástí jsou tradiční a novější prognostické faktory, k určení pacientů s vysokým rizikem progrese vyžadující léčbu. Tento model by mohl být užitečný k určení pacientů vhodných pro zařazení do studií časných intervencí.
- MeSH
- Time Factors MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell genetics metabolism therapy MeSH
- Gene Deletion MeSH
- Adult MeSH
- Risk Assessment MeSH
- Immunohistochemistry MeSH
- Kaplan-Meier Estimate MeSH
- L-Lactate Dehydrogenase genetics metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Multivariate Analysis MeSH
- Mutation MeSH
- Biomarkers, Tumor metabolism MeSH
- Nomograms MeSH
- Odds Ratio MeSH
- Predictive Value of Tests MeSH
- Prognosis MeSH
- Proportional Hazards Models MeSH
- ZAP-70 Protein-Tyrosine Kinase metabolism MeSH
- Flow Cytometry MeSH
- Risk Factors MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Immunoglobulin Heavy Chains genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Geographicals
- Texas MeSH
Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors.
- MeSH
- Cyclooxygenase 1 metabolism MeSH
- Cyclooxygenase 2 metabolism MeSH
- Cyclooxygenase Inhibitors chemistry pharmacology MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Drug Evaluation, Preclinical MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Non-invasive, focal neurostimulation with ultrasound is a potentially powerful neuroscientific tool that requires effective transcranial focusing of ultrasound to develop. Time-reversal (TR) focusing using numerical simulations of transcranial ultrasound propagation can correct for the effect of the skull, but relies on accurate simulations. Here, focusing requirements for ultrasonic neurostimulation are established through a review of previously employed ultrasonic parameters, and consideration of deep brain targets. The specific limitations of finite-difference time domain (FDTD) and k-space corrected pseudospectral time domain (PSTD) schemes are tested numerically to establish the spatial points per wavelength and temporal points per period needed to achieve the desired accuracy while minimizing the computational burden. These criteria are confirmed through convergence testing of a fully simulated TR protocol using a virtual skull. The k-space PSTD scheme performed as well as, or better than, the widely used FDTD scheme across all individual error tests and in the convergence of large scale models, recommending it for use in simulated TR. Staircasing was shown to be the most serious source of error. Convergence testing indicated that higher sampling is required to achieve fine control of the pressure amplitude at the target than is needed for accurate spatial targeting.
- MeSH
- Time Factors MeSH
- Humans MeSH
- Numerical Analysis, Computer-Assisted MeSH
- Computer Simulation * MeSH
- Motion MeSH
- Models, Theoretical * MeSH
- Pressure MeSH
- Ultrasonic Therapy methods MeSH
- Ultrasonic Waves * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
OBJECTIVES: We present results from a secondary prevention trial of coronary heart disease (CHD) in the Czech male population from northern Bohemia with the history of myocardial infarction (MI) and high prevalence of metabolic syndrome. We compare several approaches to analyzing survival data from our study in terms of respective model assumptions. METHODS: While both the Cox and Weibull survival regression models assume proportionality of the hazard functions over time, in many instances this assumption appears incompatible with the data at hand. Gray's implementation of flexible models using penalized splines allows for a more realistic assessment of the covariate effects which may vary over time. RESULTS: Gray's model results revealed a steady decline in the age-adjusted intervention effect over time, which remained significant until about 2.7 years of follow-up. This was in contrast with the results obtained from the Cox and Weibull models which suggested an overall risk reduction due to intervention during the total follow-up of 6.7 years. Survival estimates based on the Cox and Gray models are shown for the two treatment groups and selected sample quantiles of the age distribution for illustration. CONCLUSIONS: Gray's time-varying coefficients model facilitated a more realistic assessment of the intervention effect. Using suitable historical controls with MI history the effect of intervention was found to gradully diminish over time.
- MeSH
- Survival Analysis MeSH
- Adult MeSH
- Financing, Organized MeSH
- Myocardial Infarction complications MeSH
- Coronary Disease complications prevention & control MeSH
- Middle Aged MeSH
- Humans MeSH
- Metabolic Syndrome epidemiology complications MeSH
- Prevalence MeSH
- Proportional Hazards Models MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Geographicals
- Czech Republic MeSH
A new test of the proportional hazards assumption in the Cox model is proposed. The idea is based on Neyman's smooth tests. The Cox model with proportional hazards (i.e. time-constant covariate effects) is embedded in a model with a smoothly time-varying covariate effect that is expressed as a combination of some basis functions (e.g., Legendre polynomials, cosines). Then the smooth test is the score test for significance of these artificial covariates. Furthermore, we apply a modification of Schwarz's selection rule to choosing the dimension of the smooth model (the number of the basis functions). The score test is then used in the selected model. In a simulation study, we compare the proposed tests with standard tests based on the score process.
Cíl Prozkoumat, zda populační farmakogenomika přispívá k rozdílům mezi výsledky léčby pacientů v klinických studiích provedených v Japonsku a Spojených státech amerických v případě podobného uspořádání studií, kritérií pro zařazení, stagingu a léčebných režimů. Metody Prospektivně jsme navrhli a provedli tři studie fáze III (Four-Arm Cooperative Study, LC00-03 a S0003) u pokročilého nemalobuněčného karcinomu plic, z nichž každá obsahovala větev léčby kombinací paclitaxel plus carboplatina, společnou pro všechny studie. Genomická DNA byla získána od pacientů v LC00-03 a S0003, kteří dostávali paclitaxel (225 mg/m2) a carboplatinu (plocha pod křivkou koncentrace-čas, 6). Varianty genotypu CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1 a ERCC2 byly analyzovány pomocí pyrosekvenování nebo polymerázovou řetězovou reakcí (polymerase chain reaktion, PCR) délkového polymorfismu restrikčních fragmentů. Přežití pacientů bylo analyzováno pomocí Coxova modelu a pro analýzu odpovědí a toxických účinků byla použita logistická regrese. Výsledky Pozorované klinické výsledky obou japonských studií byly podobné a současně z hlediska přežití, neutropenie, febrilní neutropenie a anémie významně odlišné od výsledků americké studie. Mezi japonskými a americkými pacienty byl zjištěn významný rozdíl v distribuci genotypů CYP3A4*1B (p = 0,01), CYP3A5*3C (p = 0,03), ERCC1 118 (p < 0,0001), ERCC2 K751Q (p < 0,001) a CYP2C8 R139K (p = 0,01). Bylo pozorováno spojení genotypu CYP3A4*1B a přežití bez progrese (poměr rizik – hazard ratio, HR = 0,36; 95% CI 0,14–0,94; p = 0,04), a genotypu ERCC2 K751Q a odpovědi (HR = 0,33; 95% CI 0,13–0,83; p = 0,02). V případě neutropenie 4. stupně byl HR pro ABCB1 3425C3T 1,84 (95% CI 0,77–4,48; p = 0,19). Závěr Mezi japonskými a americkými pacienty byly pozorovány rozdíly v distribuci alel genů ovlivňujících dispozici paclitaxelu nebo opravu DNA. V této explorační analýze byla pozorována spojení dosažených výsledků pro CYP3A4*1B a ERCC2 K751Q. uvedený přístup používající společnou větev usnadňuje prospektivní hodnocení populační farmakogenomiky v případě předpokládaného vlivu etnických rozdílů na dispozici protinádorových léků.
- MeSH
- Chemotherapy, Adjuvant MeSH
- Anemia MeSH
- Pharmacogenetics MeSH
- Financing, Organized MeSH
- Antineoplastic Agents, Phytogenic MeSH
- Carboplatin therapeutic use MeSH
- Quality of Life MeSH
- Humans MeSH
- Lung Neoplasms drug therapy mortality MeSH
- Carcinoma, Non-Small-Cell Lung mortality therapy MeSH
- Neutropenia etiology MeSH
- Paclitaxel therapeutic use MeSH
- Pneumonectomy MeSH
- Disease-Free Survival MeSH
- Survival MeSH
- Proportional Hazards Models MeSH
- Prospective Studies MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Neoplasm Staging MeSH
- Check Tag
- Humans MeSH
- Geographicals
- Japan MeSH
- United States MeSH
