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Biomedical subjects

M Haber

Publications and source records attributed to M Haber.

At least 19 recordsLinked to original sources
PubMed1992

Interpretation and estimation of vaccine efficacy under heterogeneity.

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.

Disease Susceptibility↗
PubMed1992

Soft tissue effects of the THC:YAG laser on canine vocal cords.

Recently, a laser based on a thulium-holmium-chromium (THC) doped Yttrium-aluminum-garnet (YAG) rod has been developed that produces light of 2.15 microns wavelength and can be transmitted through a low OH- silica fiberoptic cable. This wavelength falls on one of the peaks of the energy absorption spectrum of water. Thus, the THC:YAG laser eliminates the disadvantage of a cumbersome delivery system found in the CO2 laser while still providing precise cutting and minimal tissue injury inherent in lasers emitting light absorbed by water. We evaluated the soft tissue effects of this laser on canine vocal cords. Ablative lesions were produced by the THC:YAG laser and histologically examined on postoperative days 1, 7, and 28. Results indicate that the depth of tissue penetration is easily controlled and the healing response to tissue injury is comparable to that of the CO2 laser. The THC:YAG laser should prove to be a superior laser for use in otorhinolaryngology, especially when adapted to a flexible endoscope.

Aluminum Silicates↗
PubMed1992

A discrete-time model for the statistical analysis of infectious disease incidence data.

A discrete-time model is devised for the per-time-unit distribution of infectious disease cases in a sample of households. Using the time at which an individual is identified (e.g., when illness symptoms appear) as a marker for being infected, the probabilities of becoming infected from the community or from a single infectious household member are estimated for various risk factor levels. Maximum likelihood procedures for estimating the model parameters are given. An individual may be classified with regard to level of susceptibility and level of infectiousness. The model is fitted to a combination of symptom and viral culture data from a rhinovirus epidemic in Tecumseh, Michigan. In general, it is observed that decreasing risk of infection is associated with increasing age.

Adult↗
PubMed1991

Reduced drug accumulation as the mechanism of extreme clinical resistance to methotrexate in the human T-cell leukemia xenograft, LALW-2.

The mechanisms were examined that underlie the extreme resistance to methotrexate (MTX) by near diploid leukemic T-cells (LALW-2) exposed to the drug only during the course of therapy administered to the patient of origin. Despite the LALW-2 cells being highly resistant to MTX (inhibitory dose for 50% of cells, more than 10(-3) mol/l), southern blot analysis did not show any amplification of the dihydrofolate reductase gene, nor was there any evidence, by comparison with drug-sensitive CCRF-CEM cells, that the gene was overexpressed. Kinetic analysis of dihydrofolate reductase activity in the presence of MTX provided no basis for attributing resistance in LALW-2 cells to a change in enzyme structure. By contrast, studies of MTX accumulation revealed that the LALW-2 cells accumulated significantly less drug than either CCRF-CEM cells or a MTX-resistant CCRF-CEM subline with a characterized transport defect. These data suggest that extreme MTX resistance in LALW-2 cells is mediated by reduced drug accumulation in the absence of any effect on the target enzyme.

Animals↗
PubMed1991

Direct and indirect effects in vaccine efficacy and effectiveness.

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.

Environmental Exposure↗
PubMed1991

Estimation of vaccine efficacy in outbreaks of acute infectious diseases.

In a previous paper we defined the efficacy of a vaccine as 1-beta 1/beta 0, where beta 0 is the instantaneous probability of transmission of infection to an unvaccinated person exposed to a single infectious person, and beta 1 is similarly defined for a vaccinated person. We showed that under the conditions of an outbreak of an acute, directly transmitted infectious disease in a homogeneous and randomly mixing population, an estimate of this measure of vaccine efficacy is 1-[1n(1-A1)/1n(1-A0)], where A0 and A1 are the observed final attack rates among unvaccinated and vaccinated persons, respectively. In the present work we present an approximation for the standard error of this estimator, accounting for both the sampling and process variation. We extend the results of our previous paper to a stratified population, where the strata correspond to different levels of susceptibility and may have different vaccination coverage. We also consider populations that consist of small units (for example, households) where individuals mix primarily in these units. In this case, definition of vaccine efficacy is in terms of the within-unit transmission probabilities and is estimable by using transmission models for infectious diseases. We apply the estimation methods described above to data from influenza and measles outbreaks. We also examine, via a stochastic simulation study, the robustness of the vaccine efficacy estimators under various population structures and mixing patterns.

Adolescent↗
PubMed1991

Measures of the effects of vaccination in a randomly mixing population.

Vaccine efficacy in the field is often derived from the relative attack rates in the vaccinated and unvaccinated after an outbreak. In this paper, vaccine efficacy is defined in terms of the probability that the infectious agent is transmitted from an infected to a susceptible person, and a method for estimating it from the usual attack rate data is given. We explore two mechanisms of vaccine action defined by Smith et al, but include an underlying dynamic epidemic model of an acute directly transmitted disease. We show analytically that under the model in which the vaccine mechanism reduces the probability of infection given a certain exposure, vaccine efficacy based on the relative attack rates underestimates the protective effect of the vaccine based on the relative transmission probabilities. Under the other model in which the vaccine mechanism offers complete protection to a certain proportion of those vaccinated, and no protection to the other vaccinated proportion, the vaccine efficacy based on the relative attack rates will equal that based on the transmission probabilities. Parameters for the effectiveness of a vaccination programme are defined in terms of the direct and indirect benefit to a single person as well as the total and average benefit to the entire population, and derived from the dynamic model for an outbreak of an acute directly transmitted disease. These effects can also be estimated without an actual separate unvaccinated population, independent of assumptions about the vaccine mechanism. The variation of these measures as functions of the fraction of vaccinated people in the population is explored numerically.

Cohort Studies↗
PubMed1991

A generalized stochastic model for the analysis of infectious disease final size data.

A stochastic infectious disease model was developed by Ball (1986, Advances in Applied Probability 18, 289-310) in which the distribution of the length of the infectious period is allowed to have any distribution that can be described by its Laplace transform. We extend this model such that the infection can be transmitted within the population or from an unspecified source outside the population. Also, discrete heterogeneity in the population can be modeled to incorporate variable susceptibility, variable infectivity, and/or mixing behaviors. The model is fitted to serologic data from two influenza epidemics in Tecumseh, Michigan, using maximum likelihood estimation procedures. The estimates show a clustering pattern by age groups.

Adult↗
PubMed1990

Phenotypic and cytogenetic analysis of atypical multidrug resistance in human leukaemic cells selected with methotrexate at high concentration.

A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype. The mechanism(s) underlying resistance to vincristine, vinblastine and actinomycin D in the most resistant subline (CEM/MTX R3) has now been investigated. Efflux of [3H]vincristine was more rapid in CEM/MTX R3 than in either CCRF-CEM cells or a methotrexate-resistant subline not refractory to Vinca alkaloids. In addition, verapamil completely reversed resistance to vincristine, vinblastine and actinomycin D in the CEM/MTX R3 cells. While these results are suggestive of P-glycoprotein-mediated multidrug resistance, Northern analysis revealed no detectable expression of the mdr 1/gene in CEM/MTX R3 cells. Likewise, karyotypic analysis of the resistant subline, while revealing certain clonal abnormalities, provided no evidence of alteration in the mdr 1/gene locus on chromosome 7. The data suggest therefore the operation, in these cells, of a novel mechanism of resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Atypical multidrug resistance in CCRF-CEM cells selected for high level methotrexate resistance: reactivity to monoclonal antibody C219 in the absence of P-glycoprotein expression.

A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype (J.Natl.Cancer Inst.1989; 81, 1250-1254). The role of the mdr1 gene and its product (P-glycoprotein) in this atypical pattern of multidrug resistance has now been investigated. Southern and Northern analyses failed to demonstrate any amplification, rearrangement or over-expression of the mdr1 gene in the drug-resistant cells. Similarly, monoclonal antibodies MRK16 and JSB1 revealed no increase in the amount of P-glycoprotein present. By contrast, monoclonal antibody C219 detected a 170 kDa protein in all sublines, and in highest concentration in the most resistant cells. The results raise the possibility that a novel, C219-reactive protein may mediate resistance to both methotrexate and members of the multidrug resistance family.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Atypical multidrug resistance in a therapy-induced drug-resistant human leukemia cell line (LALW-2): resistance to Vinca alkaloids independent of P-glycoprotein.

Near diploid leukemic T-cells (LALW-2), exposed to cytotoxic drugs only as a consequence of therapy administered to the donor patient, have been maintained by serial xenograft in nude mice. In comparison with the leukemic line CCRF-CEM, using a growth inhibition assay, LALW-2 cells were resistant to Vinca alkaloids and actinomycin D (relative resistance, 200-fold or more), were slightly resistant to Adriamycin (relative resistance, 4-fold), and showed no resistance to daunorubicin or teniposide. By comparison, a vincristine-resistant CEM subline developed in our laboratory (CEM/VCR R) was resistant to all these agents by at least 30-fold. The VCR R subline served as a positive control, confirming the previously reported correlation between multidrug resistance and amplification of the P-glycoprotein gene. Comparison of CEM, CEM/VCR R, and LALW-2 cells establish that the P-glycoprotein gene was not amplified or overexpressed in the LALW-2 cells; neither could the gene product be detected by immunoblotting in extracts from these cells. The LALW-2 cells were further distinguished from CEM/VCR R cells due to the lack of increased vincristine efflux by the xenografted cells, an effect readily demonstrable in the CEM/VCR R cells. However, although LALW-2 cells efflux vincristine at the same rate as CCRF-CEM cells, the xenografted cells exhibited a reduced rate of vincristine accumulation. Uptake of daunorubicin by LALW-2 cells was not distinguished from that by CEM cells, consistent with similar 50% inhibitory dose levels for this drug in both cell populations, and differentiating both from CEM/VCR R cells. Thus, clinical resistance in this case appears to be an "atypical" form of multidrug resistance specifically distinguished by resistance to Vinca alkaloids and actinomycin D occurring in the absence of increased amounts of P-glycoprotein and manifesting decreased drug uptake.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Resistance to drugs associated with the multidrug resistance phenotype following selection with high-concentration methotrexate.

To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 10(2)- to greater than 10(5)-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications.

Antineoplastic Agents↗
PubMed1989

Therapy-induced drug resistance in a human leukemia line (LALW-2). A clinically relevant model.

A human leukemic T-cell line, LALW-2, established by xenografting in nude mice, has been maintained through 14 serial passages. The cells display consistent morphologic features, immunophenotype, and karyotypic aberrations (including an 11;14 translocation) and exhibit rearrangement of the T-cell receptor beta-chain gene. The growth rate of LALW-2 xenografts was differentially affected by drugs administered to host mice, the cells being resistant to cytotoxic agents (particularly methotrexate and doxorubicin) used in treatment of the donor patient. In short-term in vitro culture, LALW-2 cells exhibited extreme resistance to methotrexate and were also resistant to vincristine, vinblastine, dactinomycin, and doxorubicin. The findings differ from those obtained with laboratory-derived methotrexate or multidrug-resistant cell lines. The response of LALW-2 cells, in both the nude mouse model and in vitro, is consistent with acquisition of drug-resistance as a result of clinical treatment.

Animals↗
PubMed1989

Protecting adults with mental retardation: a model statute.

On February 1, 1985, the Abuse Investigation Division of the Office of Protection and Advocacy was created by Section 19a-458 of the Connecticut General Statutes. This division was designed to receive and investigate allegations of the abuse and neglect of adults with mental retardation and to ensure that necessary protective services are provided by appropriate agencies. The major components of the law were discussed, and data were reported concerning type of abuse and neglect, perpetrators, and locations in which it occurs.

Adult↗
PubMed1988

Statistical inference for infectious diseases. Risk-specific household and community transmission parameters.

A statistical model is presented for the analysis of infectious disease data from family studies in the community. The model partitions the sources of infection into those from within the household and those from the community at large. The parameters reflecting these sources of infection are estimated as functions of the risk factors. This new model is used to overcome problems associated with the lack of independence of observations in infectious disease data and negative confounding due to the association of unmeasured exposures and immunity. An example of how this new statistical model is used to provide a clearer and less confounded description of risk factor effects is presented for data from influenza A(H3N2) epidemic seasons in the Tecumseh Respiratory Illness Study. The risk factors examined are age and pre-epidemic season antibody level as measured by the hemagglutination-inhibition test, while the outcome is the infection rate. A standard analysis of the data indicates that the efficacy of protective antibodies is 70% in children and only 47% in adults. However, such an efficacy measurement is negatively confounded by past exposure which is age dependent. By means of the model, the true, unconfounded, efficacy of protective antibodies is shown to be 90% in both adults and children.

Adolescent↗
PubMed1988

Models for the statistical analysis of infectious disease data.

The Longini-Koopman model (1982, Biometrics 38, 115-126) describes the process underlying the transmission of an infectious disease in terms of household and community level transmission probabilities. This model is generalized by allowing for different transmission probabilities that may correspond to various levels of risk factors on both the household and community levels. Two types of models are considered: (i) models for household data, where the numbers of susceptible and infected members in each household are known along with the values of household level risk factors; and (ii) models for individual data, where the infection status and risk factor level are known for each individual in the household. Although the type (i) models can be expressed as special cases of the type (ii) models, they deserve special attention as they can be represented and analyzed as log-linear models. Both types of models can be analyzed using maximum likelihood methods, while the type (i) models, when expressed as log-linear models, can also be analyzed by the weighted least squares method. Data from influenza epidemics in Tecumseh, Michigan and Seattle, Washington are used to illustrate these methods.

Adult↗