Optimal designs for threshold-determining limiting dilution assays

In common with other non-linear models, the optimal design for a limiting dilution assay (LDA) depends on the value of the unknown parameter, θ$\theta$, in the model. Consequently optimal designs cannot be specified unless some assumptions are made about the possible values of θ$\theta$. If a prior distribution can be specified then a Bayesian approach can be adopted. A proper specification of the Bayesian approach requires the aim of the experiment to be described and quantified through an appropriate utility function. This paper addresses the problem of finding optimal designs for LDAs when the aim is to determine whether θ$\theta$ is above or below a specified threshold, _θ0${\theta }_0$.     

On the estimation of the most probable number in a serial dilution experiment

The purpose of this paper is to present some alternative estimates for the 'most probable number' of bacteria in a serial dilution experiment. These estimates are directed to be less biased than the ordinary maximum likelihood estimate. A numerical example illustrates the extent to which the variance and the mean square error of these estimates are generally less than those corresponding to the maximum likelihood estimate.     

Comparative characteristics of estimators of the mean responding cell density in limiting dilution assays

The statistical problems associated with estimating the mean responding cell density in the limiting dilution assay (LDA) have largely been ignored. We evaluate techniques for analyzing LDA data from multiple biological samples, assumed to follow either a normal or gamma distribution. Simulated data is used to evaluate the performance of an unweighted mean, a log transform, and a weighted mean procedure described by Taswell (1987). In general, an unweighted mean with jackknife estimates will produce satisfactory results. In some cases, a log transform is more appropriate. Taswell's weighted mean algorithm is unable to estimate an accurate variance. We also show that methods which pool samples, or LDA data, are invalid. In addition, we show that optimization of the variance in multiple sample LDA's is dependent on the estimator, the between-organism variance, the replicate well size, and the numberof biological samples. However, this optimization is generally achieved by maximizing biological samples at the expense of well replicates.     

Comparison of bias-reducing methods for estimating the parameter in dilution series

Ten different estimators of the parameter in a limiting or serial dilution assay are compared. Eight of them are constructed to reduce the bias of the commonly used maximum likelihood estimator. Extensive Monte Carlo experiments using various designs, and practical considerations, suggest that a particular jackknife version of the maximum likelihood estimator is preferred, provided that the design is not too small.     

Statistical analysis of data from dilution assays with censored correlated counts

Frequently, count data obtained from dilution assays are subject to an upper detection limit, and as such, data obtained from these assays are usually censored. Also, counts from the same subject at different dilution levels are correlated. Ignoring the censoring and the correlation may provide unreliable and misleading results. Therefore, any meaningful data modeling requires that the censoring and the correlation be simultaneously addressed. Such comprehensive approaches of modeling censoring and correlation are not widely used in the analysis of dilution assays data. Traditionally, these data are analyzed using a general linear model on a logarithmic-transformed average count per subject. However, this traditional approach ignores the between-subject variability and risks, providing inconsistent results and unreliable conclusions. In this paper, we propose the use of a censored negative binomial model with normal random effects to analyze such data. This model addresses, in addition to the censoring and the correlation, any overdispersion that may be present in count data. The model is shown to be widely accessible through the use of several modern statistical software.     

Estimation of the basic reproduction number for infectious diseases from age-stratified serological survey data

The basic reproduction number of an infection, R ₀, is the average number of secondary infections generated by a single typical infective individual in a totally susceptible population. It is directly related to the effort required to eliminate infection. We consider statistical methods for estimating R ₀ from age-stratified serological survey data. The main difficulty is indeterminacy, since the contacts between individuals of different ages are not observed. We show that, given an estimate of the average age-specific hazard of infection, a particular leading left eigenfunction is required to specify R ₀. We review existing methods of estimation in the light of this indeterminacy. We suggest using data from several infections transmitted via the same route, and we propose that the choice of model be guided by a criterion based on similarity of their contact functions. This approach also allows model uncertainty to be taken into account. If one infection induces no lasting immunity, we show that the only additional assumption required to estimate R ₀ is that the contact function is symmetric. When matched data on two or more infections transmitted by the same route are available, the methods may be extended to incorporate the effect of individual heterogeneity. The approach can also be applied in partially vaccinated populations and to populations comprising loosely linked communities. The methods are illustrated with data on hepatitis A, mumps, rubella, parvovirus, Haemophilus influenzae type b and measles infection.     

Relative efficienctes of sampling plans for selecting a small number of units from a rectangular region

We examine the efficiency of several sampling plans for use in certain agricultural, ecological and environmental studies. One concern for such studies is that plots that arephysically close might be more similar than distant plots. We considered sampling plansthat are designed to generate samples that represent the entire population while avoidingthe selection of units that provide essentially redundant information. All plans havethe property that they avoid the simultaneous selection of units that are, in some sense,neighboring units. By means of a simulation study, the efficiency of these plans iscompared to simple random Aampling Factors that influence the relative efficiencies areexamined. This is done for a number of different populations, representing variouspossible patterns for a response variable.