Assessing response profiles from incomplete longitudinal clinical trial data with subject dropout under regulatory conditions

Treatment effects are often evaluated by comparing change over time in outcome measures. However, valid analyses of longitudinal data can be problematic, particularly when some data are missing for reasons related to the outcome. In choosing the primary analysis for confirmatory clinical trials, regulatory agencies have for decades favored the last observation carried forward (LOCF) approach for imputing missing values. Many advances in statistical methodology, and also in our ability to implement those methods, have been made in recent years. The characteristics of data from acute phase clinical trials can be exploited to develop an appropriate analysis for assessing response profiles in a regulatory setting. These data characteristics and regulatory considerations will be 1 reviewed. Approaches for handling missing data are compared along with options for modeling time effects and correlations between repeated measurements. Theory and empirical evidence are utilized to support the proposal that likelihood-based mixed-effects model repeated measures (MMRM) approaches, based on the missing at random assumption, provide superior control of Type I and Type II error when compared with the traditional LOCF approach, which is based on the more restrictive missing completely at random assumption. It is further reasoned that in acute phase clinical trials, unstructured modeling of time trends and within-subject error correlations may be preferred. Key words: missing data, longitudinal data, mixed-effects model

Herdabilidades de parâmetros de curvas de crescimento não-lineares em zebuínos, no estado de Pernambuco Heritabilities of nonlinear growth curve parameters in zebu breeds, in Pernambuco State, Northeastern Brazil

Objetivou-se estimar parâmetros genéticos e fenotípicos de curvas de crescimento de modelos não-lineares. Foram analisados dados de pesagem constantes no banco de dados de Controle de Desenvolvimento Ponderal da Associação Brasileira de Criadores de Zebu (ABCZ), referentes a 24.028 animais Zebu, nascidos entre 1960 e 2000, das raças Guzerá, Nelore e Nelore Mocho. As pesagens ocorreram ao nascimento e em intervalos de 90 dias até dois anos de idade. Os seguintes modelos não-lineares foram utilizados na análise dos dados de peso-idade: Brody, Gompertz, Logístico, von Bertalanffy e Richards. Os efeitos fixos estudados no modelo misto foram sexo, rebanho, ano e mês de nascimento e regime de criação. As herdabilidades para os parâmetros foram de baixa a alta magnitude, em geral, para todos os modelos. As correlações genéticas entre peso assintótico e taxa de maturidade e entre peso assintótico e velocidade de crescimento foram negativas, enquanto aquelas entre taxa de maturidade e velocidade de crescimento foram positivas. As correlações fenotípicas foram negativas entre peso assintótico e taxa de crescimento e entre peso assintótico e velocidade de crescimento e positivas entre taxa e velocidade de crescimento. Encontrou-se variabilidade possível de ser explorada em um programa de melhoramento genético, especialmente para a raça Nelore, que apresentou amostra de dados e resultados mais consistentes.<br>Weight records of 24.028 zebu animals from Guzerá, Nelore, and Polled Nelore breeds available from Brazilian Association of Zebu Breeders (ABCZ) database were used to estimate heritabilities of growth curve parameters. Non-linear Brody, Gompertz, Logistic, Mitscherlich, von Bertalanffy, Richards, and Double Logistic models including sex, farm, year of birth, month of birth, raising system, and interaction sex*raising system as fixed effects and sire and dam, as random effects were adjusted using weight-age records of animals which were born between 1960 and 2000, every three months, from birth to 24 months of age. Heritability estimates of growth curve parameters ranged from low to high values for all models and breeds. Genetic correlations between asymptotic weight and mature rate and asymptotic weight and growth rate were negative whereas those between mature rate and growth rate were positive. Phenotypic correlations between asymptotic weight and mature rate and asymptotic weight and growth rate were negative and those between mature rate and growth rate were positive. The variability observed in this study indicates the possibility of changing the growth curve by a breeding program, especially for the Nellore because more consistent records and results obtained for this breed

Análise genética da habilidade de permanência em fêmeas da raça Nelore Genetic analysis of stayability among Nelore females

O objetivo deste estudo foi verificar a possibilidade da característica habilidade de permanência (HP) de matrizes ser utilizada como critério de seleção na raça Nelore. A HP foi definida como a probabilidade de uma vaca parir, no rebanho, na idade de seis anos ou depois desta idade, dado que ela teve uma parição em data anterior. Foram analisadas informações de 55.682 animais. Utilizou-se a amostragem de Gibbs para estimar os componentes de variância e um modelo de limiar de máximo a posteriori para predizer os valores genéticos. A análise forneceu estimativa posterior de herdabilidade e desvio-padrão de 0,21 &plusmn; 0,00 e tendência genética, média por ano, de 0,14% para HP. A facilidade de mensuração da característica, a estimativa de herdabilidade e a tendência indicam que a utilização desta característica como critério de seleção pode contribuir para o aumento da fertilidade do rebanho.<br>The purpose of this study was to analyse of the stayability trait (STAY) of Nelore cows. Stayability was defined as the probability of calving at a specific age, or after that age, given that the cow calved at least one time prior to that age. The study focused specifically on six year old groups, and the information corresponding to 55,682 animals were analysed. The data were analysed based on an a posteriori maximum threshold model to predict the genetic values, while the Gibbs sample was used to estimate the variance components. The analyses provided heritability estimate and standard deviation of 0.21 &plusmn; 0.003 and average genetic tendency a year was of 0.14% for STAY. The estimates indicate that the use of this trait as a criterion for selection may contribute toward increased female fertility