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Biomedical subjects

J Wakefield

Publications and source records attributed to J Wakefield.

At least 19 recordsLinked to original sources
PubMed1997

A population approach to initial dose selection.

Before a drug can be marketed, an initial dose must be established. Sheiner et al. argue that a population approach leads to the most informed and rational decision making. We discuss the choice of an initial dose from both a predictive and estimative viewpoint. Our criteria are based upon evaluating the probabilities that a patient from the specified population obtains a response that is at least of a specified size. We demonstrate the approach using a simulation study and compare estimation of population parameters and initial dose using Bayesian and likelihood-based methods.

Bayes Theorem↗
PubMed1996

The SH3 domain of Src tyrosyl protein kinase interacts with the N-terminal splice region of the PDE4A cAMP-specific phosphodiesterase RPDE-6 (RNPDE4A5).

The PDE4A (type IV) cAMP-specific, rolipram-inhibited phosphodiesterase RPDE-6 (RNPDE4A5), when transiently expressed in COS7 cells, could be complexed with the v-Src-SH3 domain expressed as a glutathione S-transferase (GST) fusion protein. RPDE-6 did not interact with GST itself. This complex was not disrupted by treatment with high NaCl concentration together with Triton X-100. Interaction was apparently determined by the N-terminal splice region of RPDE-6, as the PDE4A splice variant RPDE-39, which differs from RPDE-6 at the extreme N-terminus, failed to associate with v-Src-SH3; met26RD1 (where RD1 is rat 'dunc-like' PDE), which has the N-terminal splice region deleted, failed to associate with v-Src-SH3, and the association of RPDE-6 and v-Src-SH3 was blocked by a fusion protein formed from the N-terminal splice region. RDPE-6 showed binding to GST fusion proteins of both the intact Src kinase and an SH2-SH3 construct but did not bind to the Src-SH2 domain or to the adaptor protein Grb-2. RPDE-6 could be co-immunoprecipitated from cytosol extracts of transfected cells by using anti-Src antiserum. RPDE-6 exhibited selectivity in binding to the SH3 domains of c-Abl, Crk, Csk, Lck, Lyn, Fyn and v-Src, with binding to the SH3 regions of the Src-related tyrosyl kinases Lyn and Fyn being the most effective. The binding of RPDE-6 to the SH3 domains of Crk, Csk and Lck led to a marked reduction in PDE activity, but no change was apparent in complexes with other species. Endogenous RPDE-6 from brain, but not endogenous RPDE-39 from testis, bound to the Src-SH3 domain. We suggest that the PDE4A splice variant RPDE-6 has a propensity for interaction with selective SH3 domains, in particular those from Src and the Src-related tyrosyl kinases Lyn and Fyn. This interaction seems to be governed by alternative splicing of the PDE4A gene, because RPDE-39, a splice variant that lacks the proline-rich N-terminal splice region of RPDE-6, does not interact with these SH3 domains. It is proposed that the binding site on RPDE-6 for SH3 domains lies within the unique first 102 residues of its N-terminal splice domain, where two motifs representing Class I SH3 binding sites with selectivity for Src kinase SH3 domains can be identified and one motif for a putative Class II SH3 binding site.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Bayesian individualization via sampling-based methods.

We consider the situation where we wish to adjust the dosage regimen of a patient based on (in general) sparse concentration measurements taken on-line. A Bayesian decision theory approach is taken which requires the specification of an appropriate prior distribution and loss function. A simple method for obtaining samples from the posterior distribution of the pharmacokinetic parameters of the patient is described. In general, these samples are used to obtain a Monte Carlo estimate of the expected loss which is then minimized with respect to the dosage regimen. Some special cases which yield analytic solutions are described. When the prior distribution is based on a population analysis then a method of accounting for the uncertainty in the population parameters is described. Two simulation studies showing how the methods work in practice are presented.

Algorithms↗
PubMed1994

The hierarchical Bayesian approach to population pharmacokinetic modelling.

Compartmental models are widely used to model the profile of drug concentrations versus time from administration in an individual subject. Observed concentrations are then modelled as noisy departures from the underlying profile, the latter characterised for each individual by a small number of 'individual parameters'. When a population of individuals is studied, inter-individual variation is modelled by assuming that the individual profile parameters are drawn from a population distribution, the latter characterised by 'population parameters' describing, in effect, a mean population profile and individual variation around it. From a Bayesian statistical perspective, such models fit exactly into the so-called hierarchical modelling framework, which provides a coherent basis for individual and population inferences and prediction, as well as for decision-making (for example, the design of dosage regimens). This paper outlines the hierarchical model framework and describes how the required computations can be carried out in a straightforward manner by a Markov chain Monte Carlo technique known as Gibbs sampling, even when models involve mean-variance relationships and outliers.

Bayes Theorem↗
PubMed1987

Psychiatry and family medicine: the McMaster approach.

Family physicians may spend up to 50% of their time dealing with emotional problems but will refer less than 10% of these cases for psychiatric treatment. This paper describes an approach developed at McMaster University which emphasizes the importance of understanding the needs of family physicians and helping them make optimum use of available psychiatric services. Such an approach aims at increasing the comfort and expertise of family physicians in handling the problems they see on a regular basis, involving them actively in their patient's care after a referral, and offering relevant services that supplement those of the family physician, while monitoring and correcting problems that can arise when the two specialties work together. The implications that this has on the training of family medicine and psychiatry residents are discussed as well as ways in which continuing education can be provided for family physicians in community practice.

Education, Medical, Continuing↗
PubMed1978

Incidence of cervical cancer by marital status.

The incidence of invasive cervical cancer by age and marital status was examined, using census statistics and 1968--71 cancer registry data from women who lived in the Manchester Regional Hospital Board area. The relative rarity of the disease in the unmarried and its higher incidence in formerly married than in currently married women was confirmed. This higher incidence was shown to be mainly in widows under 50 and divorced women, suggesting that it is related to the association of the disease with number of sexual partners.

Adult↗
PubMed1976

Screening for breast cancer.

The feasibility of mass population screening for breast cancer by clinical examination and x-ray mammography was studied. The results indicate that such a programme could be conducted effectively by non-medical staff and be safe from the dangers of irradiation. The response rate of women invited for screening suggests that such a service is acceptable to the general public. The additional work load produced by screening would not overburden the existing surgical services.

Aged↗