The Rheumatoid Arthritis Drug Development Model: a case study in Bayesian clinical trial simulation

The development of a new drug is a major undertaking and it is important to consider carefully the key decisions in the development process. Decisions are made in the presence of uncertainty and outcomes such as the probability of successful drug registration depend on the clinical development programmme. The Rheumatoid Arthritis Drug Development Model was developed to support key decisions for drugs in development for the treatment of rheumatoid arthritis. It is configured to simulate Phase 2b and 3 trials based on the efficacy of new drugs at the end of Phase 2a, evidence about the efficacy of existing treatments, and expert opinion regarding key safety criteria. The model evaluates the performance of different development programmes with respect to the duration of disease of the target population, Phase 2b and 3 sample sizes, the dose(s) of the experimental treatment, the choice of comparator, the duration of the Phase 2b clinical trial, the primary efficacy outcome and decision criteria for successfully passing Phases 2b and 3. It uses Bayesian clinical trial simulation to calculate the probability of successful drug registration based on the uncertainty about parameters of interest, thereby providing a more realistic assessment of the likely outcomes of individual trials and sequences of trials for the purpose of decision making. In this case study, the results show that, depending on the trial design, the new treatment has assurances of successful drug registration in the range 0.044–0.142 for an ACR20 outcome and 0.057–0.213 for an ACR50 outcome. Copyright © 2009 John Wiley & Sons, Ltd.     

Paternal involvement with adolescents in intact families: The influence of fathers over the life course

We measure the quality and quantity of fathers’ involvement with adolescent children in intact families over time using longitudinal data from The National Survey of Children. We examine differentials in fathers’ involvement by children’s and family characteristics and model the long-term effects of fathers’ involvement on children’s outcomes in the transition to adulthood. Fathers are more involved with sons than with daughters and they disengage from adolescents with increasing marital conflict. We find beneficial effects for children of father’s involvement in three domains: educational and economic attainment, delinquent behavior, and psychological well-being. The course of affective relations throughout adolescence also has a beneficial effect on delinquent behavior and psychological well-being.     

Resilience of Cyber Systems with Over‐ and Underregulation

Recent cyber attacks provide evidence of increased threats to our critical systems and infrastructure. A common reaction to a new threat is to harden the system by adding new rules and regulations. As federal and state governments request new procedures to follow, each of their organizations implements their own cyber defense strategies. This unintentionally increases time and effort that employees spend on training and policy implementation and decreases the time and latitude to perform critical job functions, thus raising overall levels of stress. People's performance under stress, coupled with an overabundance of information, results in even more vulnerabilities for adversaries to exploit. In this article, we embed a simple regulatory model that accounts for cybersecurity human factors and an organization's regulatory environment in a model of a corporate cyber network under attack. The resulting model demonstrates the effect of under‐ and overregulation on an organization's resilience with respect to insider threats. Currently, there is a tendency to use ad‐hoc approaches to account for human factors rather than to incorporate them into cyber resilience modeling. It is clear that using a systematic approach utilizing behavioral science, which already exists in cyber resilience assessment, would provide a more holistic view for decisionmakers.     

ESTIMATING TEMPORAL FARM INCOME DISTRIBUTIONS USING SPATIAL SMOOTHING TECHNIQUES

The Australian Bureau of Agricultural & Resource Economics (ABARE) has conducted the annual Australian Agricultural and Grazing Industries Survey, covering the broadacre sector, in a consistent format since 1978/79. In this period the incomes of farmers have fluctuated considerably. Interest has focused on temporal income variation because of its relationship to the inherent riskiness of farming. Part of these income fluctuations can be explained by changing commodity prices and by highly variable climatic conditions. This paper outlines a method of measuring the magnitude of this income variation and how it relates to other variables. Due to rotation within the sample of farms surveyed, data are limited for determining the income variability of any particular farm. This paper, using spatial locations of surveyed farms, shows how kernel smoothing techniques can be adapted to estimate the distribution of a farm's income. This analysis uses data collected from 1978/79 to 1991/92. Summary information from these distributions is cross-tabulated against several other variables. This shows that income variability is strongly related to the production mixture of farming businesses.     

COMPONENTS OF VARIANCE MODELS WITH TRANSFORMATIONS

Power transformations are a popular way to improve the agreement between the observations and the assumptions in a statistical model. In this paper it is assumed that the data, after appropriate power transformation Λ, satisfies a variance components model, with independent Gaussian components. The focus is on inference for quantities which have an interpretation regardless of the choice of Λ (Carroll & Ruppert, 1981) – in particular the intraclass correlation coefficient ρ, the predicted probability of a new observation being less than a specified value and the predicted quantile. It is shown that, in the case Λ= 0, the asymptotic variance of ρ is the same, whether or not one treats Δ as estimated or as known. This supports an empirical conjecture of Solomon (1985). For predicted probabilities and predicted quantiles the variance when A is estimated is shown to be only slightly greater than the variance assuming Δ is known, except in the tails of the distribution where there can be substantial difference between the two variances.     

Linear Regression for Panel With Unknown Number of Factors as Interactive Fixed Effects

In this paper, we study the least squares (LS) estimator in a linear panel regression model with unknown number of factors appearing as interactive fixed effects. Assuming that the number of factors used in estimation is larger than the true number of factors in the data, we establish the limiting distribution of the LS estimator for the regression coefficients as the number of time periods and the number of cross‐sectional units jointly go to infinity. The main result of the paper is that under certain assumptions, the limiting distribution of the LS estimator is independent of the number of factors used in the estimation as long as this number is not underestimated. The important practical implication of this result is that for inference on the regression coefficients, one does not necessarily need to estimate the number of interactive fixed effects consistently.     

Social Protection and Health: Experiences in Uganda

There is an interesting and continuing debate on the nature and role of social protection in poverty reduction. Within the health sector, discussion has focussed on the drawbacks associated with fee exemption schemes and community‐based health insurance, with much less attention paid to the policy option of abolishing user fees. This paper reviews empirical evidence on the impact of the Government of Uganda's decision in 2001 to abolish user fees for health services. The paper finds that this policy intervention has had a significant positive impact on health‐seeking behaviour in Uganda and concludes that this policy measure can make an important contribution towards a more ‘promotional’ policy approach to social protection.     

Attribution of tumour lethality and estimation of the time to onset of occult tumours in the absence of cause-of-death Information

A new statistical approach is developed for estimating the carcinogenic potential of drugs and other chemical substances used by humans. Improved statistical methods are developed for rodent tumorigenicity assays that have interval sacrifices but not cause-of-death data. For such experiments, this paper proposes a nonparametric maximum likelihood estimation method for estimating the distributions of the time to onset of and the time to death from the tumour. The log-likelihood function is optimized using a constrained direct search procedure. Using the maximum likelihood estimators, the number of fatal tumours in an experiment can be imputed. By applying the procedure proposed to a real data set, the effect of calorie restriction is investigated. In this study, we found that calorie restriction delays the tumour onset time significantly for pituitary tumours. The present method can result in substantial economic savings by relieving the need for a case-by-case assignment of the cause of death or context of observation by pathologists. The ultimate goal of the method proposed is to use the imputed number of fatal tumours to modify Peto's International Agency for Research on Cancer test for application to tumorigenicity assays that lack cause-of-death data.