Biomedical subjects
Publications and source records attributed to D M Rocke.
We introduce a model for measurement error in gene expression arrays as a function of the expression level. This model, together with analysis methods, data transformations, and weighting, allows much more precise comparisons of gene expression, and provides guidance for analysis of background, determination of confidence intervals, and preprocessing data for multivariate analysis.
In calibration experiments, an estimated relationship between covariate information for a sample and an observed response is used to infer the covariate information for unknown samples from their responses. In some situations, this covariate information comprises a nominal variable (e.g., identity of a chemical, sex of an animal) and a real-valued variable (e.g., concentration of the chemical, age of animal). If the calibrating relationship can be estimated separately for each candidate identity, the first step in analyzing unknown samples is to correctly determine their identity. A discrimination statistic is suggested for use in this situation and its asymptotic distribution is derived. The investigation is motivated by the possibility of using multiple immunoassays in environmental monitoring to identify and quantitate contaminated samples in situations where there are several candidate pollutants that cross-react significantly to single assays. An example is given of the use of a four-antibody assay for the simultaneous monitoring of the levels in water samples of several of the commonly used triazine herbicides and their derivatives.
This meta-analysis discusses the consistency, strength, dose-response, independence, and generalizability of published cohort data on accident death relative risks in smokers. To locate data, three authors independently searched MEDLINE, and bibliographies of the pertinent studies found, for data which allowed estimation of an appropriate cigarette smoker accident death relative risk (and 95% confidence interval). Relative risks and dose-response were summarized by fixed effects and Poisson modeling, respectively. Four pertinent cohort studies including eight populations were located. Cigarette smoking predicted summary accident death relative risks of 1.51 (95% confidence interval 1.27-1.78) versus never smokers and 1.35 (1.17-1.57) versus ex-smokers. Summary dose-response trends were significant (P = 0.0000) versus never or least smoking referents. In individual studies, the smoking/accident death association persisted after adjustment or, in effect stratification, for age, race, sex, and occupation; occupation and time period; or numerous cardiac risk factors. This meta-analysis found significant, consistent, dose-response, often strong and independent (of age, race, and sex), prospective associations of smoking with accident death, internationally. Further studies and warnings of the smoking/accident death associations seem merited.
There have been numerous anecdotal reports of catastrophic falls in patients with fibrodysplasia ossificans progressiva. To determine the incidence of serious morbidity and mortality associated with falls in this patient population, the authors surveyed the 135 patient members of the International Fibrodysplasia Ossificans Progressiva Association and an age and gender matched control group. Eighty-one percent of the fibrodysplasia ossificans progressiva population suffered a fall resulting in injury compared with 44% of the controls. Sixty-seven percent of the falls initiated a painful flareup of fibrodysplasia ossificans progressiva leading to permanent loss of movement in almost all patients. Fifty-four percent of all falls suffered by the fibrodysplasia ossificans progressiva group led to permanent disability compared with 4% of all falls in the control group. Although trauma to the head was a common site of injury in both groups, the injury profile in the fibrodysplasia ossificans progressiva group included traumatic brain injuries, intracranial hemorrhage and death whereas the control group suffered mostly minor soft tissue lacerations. Deficiencies in coordinate gait and protective function likely accounted for the severity of injuries especially to the head in the fibrodysplasia ossificans progressiva population. Precautions are recommended that are intended to minimize the risk of injury without compromising a patient's functional level and independence. These recommendations include limitation of high risk activities, protective head gear, safety improvements in living environments, and augmentation of stabilizing and protective functions.
Retinoids are a plausible family of therapeutic agents for fibrodysplasia ossificans progressiva due to their ability to inhibit differentiation of mesenchymal tissue into cartilage and bone. A prospective study was conducted to assess the efficacy of isotretinoin (13-cis-retinoic acid) in the prevention of heterotopic ossification in patients who had fibrodysplasia ossificans progressiva. Eleven anatomic regions were assessed in each of 21 patients by clinical examination, radiographs, and bone scans. An anatomic region was considered to be involved if there was clinical, radiographic, or radionuclide evidence of orthotopic or heterotopic ossification anywhere in the region. There were 143 involved anatomic regions and 88 uninvolved anatomic regions at the beginning of the study. Only one of the 88 anatomic regions that was completely uninvolved at the beginning of the study became involved during isotretinoin therapy. However, 16 of the 21 patients (76%) had major flare ups develop in 38 of 143 (27%) previously involved anatomic regions while administered isotretinoin therapy. Isotretinoin at steady state doses of 1 to 2 mg/kg per day decreased the incidence of heterotopic ossification at uninvolved anatomic regions compared with an external control group, as long as the medication was started before the appearance of any orthotopic or heterotopic ossification in that anatomic region. The data did not allow the determination of whether isotretinoin was effective or detrimental in preventing disease flareups in regions that had even minimal orthotopic or heterotopic ossification at the time the therapy began. Extreme caution should be exercised when using this medication in patients who have fibrodysplasia ossificans progressiva.
Progressive heterotopic ossification leads to ankylosis of the major joints in patients who have fibrodysplasia ossificans progressiva. Joint subluxation has not been recognized widely in patients with this disease. The clinical records and radiographs of 79 patients with fibrodysplasia ossificans progressiva were reviewed and, it was found that humeral to chest wall synostosis and subluxation of the glenohumeral joint had occurred in 21% of skeletally immature patients and in 74% of skeletally mature patients. In fibrodysplasia ossificans progressiva, synostosis of the humeral shaft to the chest wall commonly occurs by 7 years of age, well before the age of proximal physeal closure. The continued growth of the proximal humeral physis in the presence of a humeral to chest wall synostosis causes the humeral head to migrate superiorly, thus promoting growth related subluxation. The clinical significance of this finding for patients who have fibrodysplasia ossificans progressiva is unknown, but this unique model will be useful in the study of shoulder biomechanics and growth plate physiology.
In calibration experiments, a number of samples of known concentration are used to establish the relationship between a measured response and sample concentration; this relationship is then used to estimate the unknown concentration of further samples from their measured responses. In addition to the estimates themselves, it is useful to have available some measure of their precision, usually given in the form of confidence limits. The standard method of inverting prediction limits is found to work well in simple situations, but in nonlinear multivariate calibration it becomes intractable. The bootstrap offers an alternative methodology, but in the calibration framework its application is not obvious. We describe some considerations in bootstrapping calibration data and compare our methods with a previous attempt and with the standard method in linear, nonlinear, and multivariate situations. The bootstrap is found to be a useful tool in those situations where the standard method is difficult to implement.
OBJECTIVE: To determine the relationship of dental procedures to immediate ossification and ankylosis of the jaw in patients who have fibrodysplasia ossificans progressiva. STUDY DESIGN: A mail survey was conducted of the 60 patient-members of the International Fibrodysplasia Ossificans Progressiva Association. All 41 patients (18 males, 23 females) who responded were examined. Instantaneous exact hazard rates for ossification of the jaw were calculated by the Weibull model. RESULTS: Thirty-six patients had dental procedures performed. Twenty-one (58%) patients had received an injection of local anesthetic. Five (24%) patients had an immediate flare-up of fibrodysplasia ossificans progressiva with ossification and permanent ankylosis of the jaw (expected occurrence, 0.031; p < 0.0001). None of the 12 patients who had comparable dental work without injections developed heterotopic ossification (expected occurrence, 0.019; not significant). CONCLUSION: Injections of local anesthetic during dental procedures pose serious and immediate risk for inciting heterotopic ossification and ankylosis of the jaw in patients who have fibrodysplasia ossificans progressiva and should be assiduously avoided.
BACKGROUND: There are many ways to represent a molecule's properties, including atomic-connectivity drawings, NMR spectra, and molecular orbital models. Prior methods for predicting the biological activity of compounds have largely depended on these physical representations. Measuring a compound's binding potency against a small reference panel of diverse proteins defines a very different representation of the molecule, which we call an affinity fingerprint. Statistical analysis of such fingerprints provides new insights into aspects of binding interactions that are shared among a wide variety of proteins. These analyses facilitate prediction of the binding properties of these compounds assayed against new proteins. RESULTS: Affinity fingerprints are reported for 122 structurally-diverse compounds using a reference panel of eight proteins that collectively are able to generate unique fingerprints for about 75% of the small organic compounds tested. Application of multivariate regression techniques to this database enables the creation of computational surrogates to represent new proteins that are surprisingly effective at predicting binding potencies. We illustrate this for two enzymes with no previously recognizable similarity to each other or to any of the reference proteins. Fitting of analogous computational surrogates to four other proteins confirms the generality of the method; when applied to a fingerprinted library of 5000 compounds, several sub-micromolar hits were correctly predicted. CONCLUSIONS: An affinity fingerprint database, which provides a rich source of data defining operational similarities among proteins, can be used to test theories of cryptic homology unexpected from current understanding of protein structure. Practical applications to drug design include efficient pre-screening of large numbers of compounds against target proteins using fingerprint similarities, supplemented by a small number of empirical measurements, to select promising compounds for further study.
In patients who have fibrodysplasia ossificans progressiva, routine childhood diphtheria-tetanus-pertussis immunizations administered by intramuscular injection caused a significant risk of permanent heterotopic ossification at the site of injection (p < 10(-8)), whereas measles-mumps-rubella immunizations administered by subcutaneous injection posed no significant risk. Intramuscular injections should be avoided, if possible, once a diagnosis of fibrodysplasia ossificans progressiva has been established.
The standard implementation of enzyme-linked immunosorbent assay (ELISA) for single analytes can lead to false conclusions if cross reacting compounds are present in the sample. This paper discusses the extension of the usual four-parameter logistic model for ELISA to the case of multiple cross-reacting analytes. The use of the extended model in multianalyte analysis (MELISA) is illustrated and compared with a more simplistic approach. Data on the analysis of a binary mixture of s-triazines suggests the superiority of the proposed model. This model is also suitable for other forms of immunoassay that use the four-parameter logistic curve.
Using data from a survey of 44 patients who have fibrodysplasia ossificans progressiva, age- and joint-specific risks of new joint involvement were estimated using parametric and nonparametric statistical methods. Regions in which the risk of heterotopic ossification appears to remain constant with age include the neck, spine, shoulders, elbows, and ankles. Regions with apparently increasing risk include the jaw, wrists, hips, and knees. This analysis allows clinicians to estimate the risk of new involvement for any joint at any patient age, as well as the fraction of patients with uninvolved joints at any age. The variation of ossification risk by joint provides a clinically useful guide to the patterns of progression of the disease. Such a guide will help in planning for individual patient needs, as well as anticipating auxiliary social services and rehabilitation programs.
When balanced data are analyzed by a robust method, different weights are applied to data points depending on their apparent status as outliers. This results in the effective unbalancing of the data. Concepts developed for the analysis of unbalanced data can help to suggest robust methods of analysis for balanced data.
This paper shows how to obtain accuracy and efficiency in an ELISA analysis by allocating the wells on a 96-well microplate between calibration and determination of unknowns, and by choosing the known concentrations for calibration. The method also can determine how much is lost in precision by using a convenient but non-optimal protocol.
A number of methods have been proposed for statistical analysis of bioequivalence trials. A new method is proposed and compared to three previously suggested techniques. This comparison clarifies the relationship among the four methods and yields practical suggestions regarding statistical tests.
This paper presents a new approach to evaluating classification procedures experimentally in human service organizations. Methods of design and analysis are proposed which answer the major objections to designed experiments with human subjects and which are suited to the special character of the classification problem. One important feature of the approach recommended here is the use of EVOP, a methodology originally developed for use in industrial production facilities, which allows methods of experimental design to be applied even where variation must be restricted. It is also shown that constrained mixture designs, rather than ordinary designs such as factorials, form the appropriate class of experimental designs for use in this problem. The example of assignment of prison inmates to minimum and maximum security is used to clarify the presentation and to demonstrate the practical implications of the proposed approach.
BACKGROUND: Injury and tobacco effects represent one-quarter of the global burden of disease. Understanding the causes of injury and the effects of smoking may help reduce those burdens. Some smokers have high risks of injury. We provide an initial meta-analysis of cohort associations between smoking and fatal injury. METHODS: Three authors independently searched MEDLINE, and bibliographies of the pertinent studies found, for cigarette smoker-specific injury death data which allowed estimation of an appropriate relative risk (RR) and 95% confidence interval (CI). Relative risks and dose response were summarized by fixed effects and Poisson modeling, respectively. RESULTS: Six studies covering 10 pertinent cohorts were located. Associations between smoking and injury death have been significant after adjustment or, in effect, stratification for age, race, sex, country, and, respectively, alcohol, marriage, education, and body mass; job and time period; job, alcohol, and exercise; etc. Summary dose-response trends were significantly positive (P < 0.00005). Cigarette smoking predicted summary injury death crude RRs of 1.61 (CI 1.44-1.81) vs never smokers and 1.39 (CI 1.25-1.55) vs ex-smokers. CONCLUSIONS: Smoking has significant, consistent, dose-response, often strong and independent, prospective associations with injury death, internationally.