One‐ and two‐stage design proposals for a phase II trial comparing three active treatments with control using an ordered categorical endpoint

Phase II clinical trials are performed to investigate whether a novel treatment shows sufficient promise of efficacy to justify its evaluation in a subsequent definitive phase III trial, and they are often also used to select the dose to take forward. In this paper we discuss different design proposals for a phase II trial in which three active treatment doses and a placebo control are to be compared in terms of a single‐ordered categorical endpoint. The sample size requirements for one‐stage and two‐stage designs are derived, based on an approach similar to that of Dunnett. Detailed computations are prepared for an illustrative example concerning a study in stroke. Allowance for early stopping for futility is made. Simulations are used to verify that the specified type I error and power requirements are valid, despite certain approximations used in the derivation of sample size. The advantages and disadvantages of the different designs are discussed, and the scope for extending the approach to different forms of endpoint is considered. Copyright © 2008 John Wiley & Sons, Ltd.     

Recombinant glycoprotein based vaccine for Chandipura virus infection

Chandipura virus (CHPV) has emerged as an important pediatric encephalitis-causing pathogen with very high mortality in India. No specific vaccine or treatment is available till date. We attempted to prepare a candidate vaccine employing recombinant CHPV Glycoprotein (rGp). The Glycoprotein gene (G-gene) of CHPV was expressed using Baculovirus expression system. The rGp was purified by HPLC and used for mice immunization, 3 doses, and 4 weeks apart. One microgram rGp was found to be optimum. Sero-conversion was observed as early as 2nd week by detecting anti-CHPV IgG antibodies. Antibody titres were immunogen-concentration dependent. Intracerebral challenge of the immunized mice with 100 LD₅₀ of the homologous strain demonstrated 90% protection. In in vitro neutralization, antibodies from the immunized mice were able to neutralize heterologous viruses. There was 60% T cell proliferation observed against rGp in immunized mice. The study shows that rGp induces both arms of immune response and represents an ideal vaccine candidate for further evaluations.     

Measurement in clinical trials: A neglected issue for statisticians?

Biostatisticians have frequently uncritically accepted the measurements provided by their medical colleagues engaged in clinical research. Such measures often involve considerable loss of information. Particularly, unfortunate is the widespread use of the so‐called ‘responder analysis’, which may involve not only a loss of information through dichotomization, but also extravagant and unjustified causal inference regarding individual treatment effects at the patient level, and, increasingly, the use of the so‐called number needed to treat scale of measurement. Other problems involve inefficient use of baseline measurements, the use of covariates measured after the start of treatment, the interpretation of titrations and composite response measures. Many of these bad practices are becoming enshrined in the regulatory guidance to the pharmaceutical industry. We consider the losses involved in inappropriate measures and suggest that statisticians should pay more attention to this aspect of their work. Copyright © 2009 John Wiley & Sons, Ltd.     

Is the political system really related to health?

We analyze whether the political system and its stability are related to cross-country differences in health. We apply factor analysis on various national health indicators for a large sample of countries over the period 2000–2005 and use the outcomes of the factor analysis to construct two new health measures, i.e., the health of individuals and the quality of the health care sector. Using a cross-country structural equation model with various economic and demographic control variables, we examine the relationship between the type of regime and political stability on the one hand and health on the other. The political variables and the control variables are measured as averages over the period 1980–1999. Our results suggest that democracy has a positive relationship with the health of individuals, while regime instability has a negative relationship with the health of individuals. Government instability is negatively related to individual health via its link with the quality of the health care sector, while democracy is positively related with individual health through its link with income. Our main findings are confirmed by the results of a panel model and various sensitivity tests.     

Foot Polydactyly and Polysyndactyly: Genetic Implications in Two Families

The purpose of this study was to determine the genetic characteristics of foot polydactyly and identify its inheritance pattern by analyzing familial pedigree. Five cases from 2 Korean families were studied: 1 is a family whose members have been affected for 4 generations and the other for 2 generations. Using peripheral blood samples, we performed chromosomal analysis using the banding technique with Giemsa stain and karyotyping. We investigated the shape and structure of 46 chromosomes, looking for translation, deletion, inversion, ring chromosome, and isochromosome abnormalities. All peripheral blood samples demonstrated no chromosomal abnormalities, though the genetic nature of foot polydactyly and a new genetic locus was identified recently by other studies. Familial pedigree analysis suggested that polydactyly was inherited as an autosomal dominant trait in the first family. The mode of inheritance for the second family could not be determined due to an insufficient number of family members. The result of this study brought us to the conclusion that, while genetic factors play a major role in polydactyly, other factors may contribute to its occurrence.     

Up-regulation of urinary UPIII mRNA levels in vesicoureteral reflux patients: Potential application as a screening test for vesicoureteral reflux

OBJECTIVES: Vesicoureteral reflux (VUR) is the most common congenital urinary tract anomaly. This disease can pose a major threat to the kidneys as twenty percent of patients with endstage renal disease are reported to have VUR. Although genetic studies for uroplakin III (UPIII) have been reported recently, no study has focused on UPIII gene expression in VUR patients. We describe here the up-regulation of UPIII mRNA in exfoliated urinary cells from primary VUR patients. METHODS: A real-time RT-PCR for UPIII mRNA was performed on exfoliated urothelial cells from 18 primary VUR and 38 control samples. UPIII mRNA copies were calculated for each sample. The statistical differences were assessed by the Mann-Whitney U test. Receiver operator characteristic curves were constructed for analysis of the diagnostic values. RESULTS: UPIII mRNA was found to be up-regulated to a greater extent in VUR than in control exfoliated urinary cells (mean +/- SE: 497.0 +/- 178.5 copies vs. 69.0 +/- 10.0 copies, respectively, P < 0.001). In evaluating the measurement of urinary UPIII mRNA as a screening test for VUR, the sensitivity was 77.8% and the specificity was 76.3% by the best diagnostic cutoff point. CONCLUSIONS: This is the first report demonstrating up-regulation of UPIII in mRNA levels in VUR patients. We submit that the quantitative measurement of urinary UPIII mRNA has a potential of developing into the first non-invasive screening test for VUR.     

Cytomorphometric analysis of vaginal cells during normal cycle, under oral contraceptive therapy or in-vitro fertilization stimulation protocol

A cytomorphometric analysis of superficial vaginal cells inwomen in three groups of different types of hormonal concentrationwas made. There were 15 women in each group. Group I was studiedduring a natural cycle, group II under oral contraceptive therapyand group III during an in-vitro fertilization (IVF) stimulationprotocol. Morphometric parameters were measured on an imageanalyser. The area, perimeter and several form factors weremeasured separately for nuclei and cytoplasm. The nucleus:cytoplasmicratio was also determined. The cytoplasmic area was significantlyreduced in group II and was associated with a statisticallysignificant reduction of the nuclear area. The nucleus:cytoplasmicratio appeared significantly increased in group II and reducedin group III. Low oestradiol impregnation obtained with an oralminidosed contraceptive interfered with vaginal cell maturation.High oestradiol concentrations obtained during IVF protocolsinduced marked nuclear pycnosis but did not induce supra-physiologicalcell enlargement. Maximal cell size is genetically regulatedaccording to Driesch's law of volume invariance and hormonalover-stimulation has no effect on cell size. The nucleus:cytoplasmicratio appears to be a powerful parameter reflecting the oppositeeffects of hormones on cell compartments.     

Analysis of the degree of precision of a computer-assisted dietary survey method

A computer-assisted method for the registration of food intakes in real time according to a concise and simple procedure was subjected to a series of controls in order to assess precision. The method employs the 'portion' of a composite dish as unit of measure. The constancy of the portion was tested. The results show that the recipes of the diet of a subject may be stored and utilized in deferred time without loss of precision: data to be recorded in real time are then very limited. The length of period of analysis was also studied. The time of investigation should not be shorter than two weeks to obtain precise information on the feeding habits of an individual subject, whereas for a group of subjects the diary of a single day provides information of sufficient precision.