Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.
In 1915, Greenwood and Yule noted that for valid vaccine efficacy studies, exposure to infection in the vaccinated and the unvaccinated must be equal (Proc R Soc Med 1915;8(part 2):113-94). The direct effect of a vaccine, however, needs to be defined by the protection it confers given a specific amount of exposure to infection, not just a comparable exposure. In this paper, two classes of parameters are distinguished along lines differing from the conventional distinction between efficacy and effectiveness. Efficacy parameters attempt to control for exposure to infection and represent direct effects on individuals. Direct effectiveness parameters represent a mixture of direct effects on individuals and indirect effects in the population.
Interpretation and estimation of vaccine efficacy is complicated when the vaccine effect is heterogeneous across vaccinated strata. If a person has a certain susceptibility, or probability of becoming infected conditional on a specified exposure to infection, then one effect of a vaccine would be to reduce that susceptibility, possibly to zero. Vaccine efficacy is a function of the relative susceptibilities in the vaccinated and unvaccinated persons. Under heterogeneity of vaccine effect, a general expression for a summary vaccine efficacy parameter is a function of the vaccine efficacy in the different vaccinated strata weighted by the fraction of the vaccinated subpopulations in each stratum. Interpretation and estimability of the summary vaccine efficacy parameter depends on whether the strata are identifiable, and whether the heterogeneity is host- or vaccine-related. Bounds are derived for the summary vaccine efficacy when the strata are not identifiable for the case of an outbreak of an acute infectious disease. The upper bound assumes that everyone is equally affected by the vaccine, and the lower bound assumes that some are completely protected while others have no protection. The biologic interpretation of the two bounds is different.
There are many different effects to consider when evaluating vaccines in the field. In this review, we have covered some of the various measures and issues related to study design and interpretation of the different measures. We emphasize that in designing and understanding vaccine studies, it is necessary to be specific about what the effect of interest is and about the assumptions underlying the interpretation of the results. Halloran et al. (81) present design, analysis, and interpretation of vaccine studies in more detail.
We use a staged Markov model to estimate the distribution and mean length of the incubation period for acquired immunodeficiency syndrome (AIDS) from a cohort of 603 human immunodeficiency virus (HIV) infected individuals who have been followed through various stages of infection. The model partitions the infected period into four progressive stages: (1) infected but antibody-negative; (2) antibody-positive but asymptomatic; (3) pre-AIDS symptoms and/or abnormal haematologic indicator; and (4) clinical AIDS. We also model a fifth stage: death due to AIDS. The estimated mean (median) waiting times in each stage of infection are stage 1, 2.2 (1.5) months; stage 2, 52.6 (36.5) months; stage 3, 62.9 (43.6) months; and stage 4, 23.6(16.3) months. We estimate the mean AIDS incubation period (from infection to development of clinical AIDS) as 9.8 years with a 95 per cent confidence interval of [8.4, 11.2] years. The paper also considers the estimated density function of the AIDS incubation period and the estimated survival functions for individuals in each stage of infection. This work represents one of the most complete statistical descriptions to date of the natural history of HIV infection.
The authors consider estimability and interpretation of vaccine efficacy based on time to event data, allowing that some of the population might have a very low probability of acquiring disease, and the rest have partial, possibly continuously distributed, susceptibility. The efficacy parameters of interest in the frailty mixing model include the fraction highly unlikely to acquire the infection or disease due to the vaccine, the degree of partial protection in those still susceptible, and the average protection or summary measure of efficacy under heterogeneity. The efficacy estimates can still be usefully interpreted when the heterogeneity results from heterogeneity in contact patterns, contact rates, or infectiousness of the contacts, as long as these are equal in the vaccinated and unvaccinated groups. A likelihood-based method allows estimation of the efficacy parameters of interest from grouped time to event data. Simulated vaccine studies assuming different levels and distributions of efficacy demonstrate that ignoring heterogeneity in susceptibility or exposure to infection generally results in underestimation of vaccine efficacy as well as incorrect interpretation of the estimates. The approach is also applicable to other covariates affecting susceptibility or exposure to infection in infectious diseases. Exploitation of the dependent happening structure of infectious diseases to obtain a shape for the baseline hazard may help identifiability. The authors recommend fitting several models to time to event data in vaccine studies.
The keratin phenotype of 15 cases of basal cell carcinoma was assayed immunohistochemically using a panel of monospecific antibodies to single keratin polypeptides. Whilst tumour tissue strongly expressed primary keratins 5 and 14 (normally synthesized in basal keratinocytes) no expression of secondary keratins 1 and 10 (characteristic of skin-type differentiation) was detected. Keratin 17, characteristic of the outer hair root sheath, was strongly expressed in all tumours. Keratin 19 was also normally expressed in parts of the hair follicle and was detected in four cases. The 'high cell turnover' keratin 16 was frequently induced in the overlying epidermis, but was rare within tumour tissue. No expression of simple epithelial keratins 8 and 18 was detected. Whilst the keratin phenotype of tumour cells is similar to that of basal cells within part of the hair root sheath, in keeping with suggestions of a follicular origin for basal cell carcinomas, the findings are also compatible with an origin from interfollicular pluripotent stem cells differentiating towards follicular structures.
Current Phase III trials are designed to assess only a vaccine candidate's ability to reduce susceptibility to infection or disease, that is, vaccine efficacy for susceptibility (VES). Human immunodeficiency virus (HIV) vaccination, however, may reduce the level of infectiousness of vaccinees who become infected, producing an important indirect reduction in HIV transmission even if the vaccine confers only modest protection against infection. We propose two approaches for augmenting the information of a classic trial for estimating protective efficacy that enable the additional estimation of the vaccine's effect on infectiousness, that is, vaccine efficacy for infectiousness (VEI). In the first augmentation, steady sexual partners of trial participants are recruited but not randomized to vaccine or placebo. Their infection status is monitored throughout the trial. In the second augmentation, the sexual partners are randomized. Through computer simulations and analytic methods, we investigate the feasibility and statistical properties of the augmented designs. Phase III prophylactic HIV-1 vaccines trials are currently being planned. Employment of the augmented designs described in this paper would not only provide estimation of VEI but also increase the precision of the VES estimator and the power to reject the null hypothesis of no vaccine effect.
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