Vascular endothelial growth factor genetic polymorphisms and haplotypes in female patients with bisphosphonate-related osteonecrosis of the jaws.

OBJECTIVE: To investigate the polymorphisms of the vascular endothelial growth factor (VEGF) gene in relation to female patients who developed bisphosphonate-related osteonecrosis of the jaws (BRONJ). METHODS: Test subjects were 30 Italian female patients with BRONJ (Group A). Control subjects were 30 female patients with a history of intravenous bisphosphonate use without any evidence of osteonecrosis (Group B) and 125 unrelated healthy volunteers (Group C). Three single-nucleotide polymorphisms were investigated: -634 G>C, occurring in 5' untranslated region (UTR); +936 C>T, occurring in 3' UTR; and -2578 C>A of the promoter region. RESULTS: The frequency of the VEGF CAC (+936/-2578/-634) haplotype was increased in patients with BRONJ, compared with female disease-negative controls [odds ratio (OR) = 2.76, 95% CI = 1.09-4.94, P = 0.039; corrected P value: P(c) = 0.117], and was also increased compared with female healthy controls (OR = 2.11, 95% CI = 1.14-3.89, P = 0.024; corrected P value: P(c) = 0.072). The CC homozygotes of -634G>C of VEGF gene and AA homozygotes of -2578C>A have also been significantly correlated in female patients who developed BRONJ compared with healthy controls (OR = 2.04, 95% CI = 1.12-3.70, P = 0.008; corrected P value: P(c) = 0.024). CONCLUSIONS: These results suggest a possible haplotype effect of VEGF polymorphisms expression in BRONJ Italian female patients. Studies with different and larger populations possibly using TagSNP to represent all haplotypes within the VEGF gene are needed to further delineate the genetic contribution of this gene to BRONJ.

The efficacy of hormone assays in the differential diagnosis of amenorrhea and menopause.

The differential diagnosis of menopause and amenorrhea is currently based on the assay of circulating follicle stimulating hormone, luteinising hormone, and estradiol. The diagnostic performance of the three hormone assays, both as single and combined tests, was evaluated considering as reference data the results from 300 subjects for either condition, and assuming menopause-amenorrhea prevalence ratios corresponding to 1 and 10. In the calculation an "allocation" scheme was adopted, and the uncertainty associated with the diagnostic performance parameters was accounted for. The results obtained clearly demonstrate that the addition of a test for luteinising hormone or estradiol (or both) to the testing for follicle stimulating hormone is not justified in terms of improvement of the diagnostic information.

The uncertainty associated with the predictive value of test results.

The uncertainty associated with predictive value of test results was taken into consideration, as concerns both sampling error (related to the size of the statistical reference samples) and analytical imprecision (unavoidably involved by the measurement itself). A software package, developed for the statistical calculations, was used for the treatment of the results obtained for serum free thyroxin in euthyroid and dysthyroid subjects, assumed as an experimental model. Examples are shown for the obtainable functions predictive value vs. estimate and the related uncertainty regions. These data could help in comparing test results and, in particular, in preparing fully informative laboratory reports. The difficulties involved by an extensive application of the procedure are discussed.

Error models and quality control performance.

As an alternative to the oversimplified error schemes currently adopted in establishing quality control (QC) strategies, a complex model was assumed implying (a) the distribution of errors (critical error is regarded as a value discriminating between "effective errors" to be detected and "subcritical errors" which do not interfere with the medical decision whose detection is considered as a false-reject signal), and (b) the possibility of simultaneous losses of precision and accuracy. The control data recorded for digoxin radioimmunoassay over a one-year period were used for (1) deriving the probability density functions of random and systematic errors, through a within-run across-level normalisation procedure; (2) obtaining the functional relationships between the critical random or systematic error and the QC performance statistics (sensitivity, specificity, predictive value), weighted for the error prevalences, through integration of the probability density functions and the power functions associated with an exemplifying control rule; and (3) describing the functions which correlate the corrected performance statistics with the allowable error (whose individual values account for all possible combinations of critical random errors and critical systematic errors), by extending to the tridimensional space the above procedures. Analysis of the resulting data shows that it is necessary to revise the criteria for the choice and optimisation of QC schemes.

Performance assessment of coupled tests: the effects of statistical non-independence.

Limited to two-test associations (series and parallel schemes), the effects of statistical non-independence were studied through a mathematical approach and an experimentally-based evaluation. Both procedures were applied to results for total hormones and free fractions in euthyroid and dysthyroid subjects. Assuming independence, the sensitivity of combined tests was found to increase in parallel coupling, and to decrease, symmetrically, in series coupling, depending critically on the degree of between-test correlation and on the value of single test sensitivity (the opposite modifications obviously occur for specificity). A more complicated situation resulted for the predictive value of test associations, where a prediction based on a mathematical model was found not to be generally valid; in this case, calculations using the correct values of conditional probabilities of coupled tests seemingly remain the safest procedure.

DECIDE: a software for computer-assisted evaluation of diagnostic test performance.

The evaluation of the performance of clinical tests is a complex problem involving different steps and many statistical tools, not always structured in an organic and rational system. This paper presents a software which provides an organic system of statistical tools helping evaluation of clinical test performance. The program allows (a) the building and the organization of a working database, (b) the selection of the minimal set of tests with the maximum information content, (c) the search of the model best fitting the distribution of the test values, (d) the selection of optimal diagnostic cut-off value of the test for every positive/negative situation, (e) the evaluation of performance of the combinations of correlated and uncorrelated tests. The uncertainty associated with all the variables involved is evaluated. The program works in a MS-DOS environment with EGA or higher performing graphic card.

The imprecision profile in immunoassay. A study using a resampling technique.

A resampling ('bootstrap') technique was applied to assess the reliability of the calculated imprecision profile (IP), as obtained from the dose/response curve and the response/error relationship (RER) using the cumulative data relative to two assays, i.e. a T4 radioimmunoassay (RIA) and a TSH immunofluorometric assay (IFMA), both run in duplicate. Mean values and the related uncertainty of the estimated dose errors were compared for different RER fitting conditions and different sizes of the duplicate response sets. The following observations were made: (a) compared to the maximum-likelihood procedure, the least-square fit proved to be unsuitable for estimating the parameters in the general RER equation variance(R) = aRb (where R indicates the response), (b) the simplifying assumption of a within-method constancy of the exponent in the RER equation, while acceptable for the T4 RIA, did not hold in the case of the TSH IFMA implying a much wider response range, (c) for both assays, response sets of ca. 100 duplicates were apparently compatible with an acceptable definition of the IP (+/- 10 to +/- 20% uncertainty).

Statistical tools in the clinical laboratory.

Method evaluation, control of data and transformation of laboratory results into diagnoses all involve a decision step. A survey of the statistical tools available to organize the information and check the congruity of decision making is provided is focused on: (a) the use of classical statistical tools (including computer based simulation and replication techniques) which enable theoretical distributions to be obtained and their optimal limits to be defined for classification purposes; (b) the analysis of multivariate distributions, which evidences the relationships among the variables involved, whatever they might be: e.g. results obtained on the same specimens with different methods (in test evaluation), different laboratory data related to the same pathophysiological situations (in making diagnoses), etc. As for the latter, the most common techniques of statistical analysis of data (discriminant and cluster analysis, principal components analysis) are also illustrated by general examples.

Assessment of response/error relationship and imprecision profile in immunoassay using computer simulation procedures.

Simulation procedures were applied to assess the response/error relationship (RER) and the imprecision profile (IP) for two model assays, a T4 RIA and a TSH IFMA both using duplicate samples. In order to define the reference functions, the mean data obtained in 10 successive experiments for dose/response curve (DR), RER and IP were employed. The following conclusions emerged from the study: (a) run sizes of ca. 100 duplicates can acceptably describe within-assay IPs, irrespective of the data distribution through the dose range; (b) the contribution of DR fitting error to the total variability of estimate can be disregarded in the case of small series but not for the larger ones; (c) the variability components related to the response error can be efficiently controlled by applying criteria based on RER parameters.

[The Chernobyl accident. Evaluation of the doses absorbed by the thyroid gland in children of a mountain community from the measurement of I131 retained activity]. / Incidente di Chernobyl. Valutazione della dose assorbita dall tiroide nei bambini di una Comunità Montana a partire dalle misure di attività ritenuta di I131.

I131 thyroid uptake after the Chernobyl's accident was sampled in a Val Pellice school. Children were grouped according to sex, age and area of residence. The procedure used in collecting data and calculating the transformation coefficients from activity counts by computer simulation is analysed, as are the errors and sensitivity of the method. The activities were then converted into doses using an intake model. The dose levels identified are lower than the estimates based on the measurement of environmental matrices. Statistical analysis revealed certain subgroups with significantly different levels of absorption: particularly groups accustomed to a different diet or living in particular areas.

[Reduction of doses in teleradiography of the spine. Criteria of radiation protection and studies of dosimetry]. / Riduzione della dose nella teleradiografia del rachide. Criteri radioprotezionistici e ricerche dosimetriche.

To reduce the radiation exposure during full spine X-ray examinations, the following techniques were instituted: 72" tube to film distance; X-ray beam collimation; fast screen-film combination (rare earth gradual screens with high speed films); additional compensation filters; shielding of the most radiation-sensitive organs. Dosimetric measurements are reported. A very high reduction in exposure, above all of breasts and gonads, was obtained, without significant loss in the quality of radiographs.

[Experimental dosimetric comparison between single tomography and multiple simultaneous tomography with Synchroplan in clinical practice]. / Confronto dosimetrico sperimentale tra tomografia singola e tomografia multipla simultanea con Synchroplan nella pratica clinica.

Reference is made to a dosimetric comparison between single tomography and simultaneous multiple tomography with Synchroplan in 10 patients subjected to nefroangiotomography. Data from several thermoluminescence dosimeters placed on different parts of the body were used in a careful statistical analysis that showed the absence of significant differences in absorbed dose in function of constitutional habitus. It was also found that the dose absorbed for 6 tomograms of the renal cavities in single tomography was about 4 times higher than with the Synchroplan (using a previously experimented set of high-sensitivity intensifying screens), which provides 6 tomograms in the same dynamic phase at different levels for the same exposure.

[A method of quality control in thermoluminescent dosimetry]. / Un metodo di controllo di qualità in dosimetria a termoluminescenza.

This work suggests a quality control method for thermoluminescent dosimetry. For each set of dosemeters, read-out has been made at increasing values of dose, on the base of predetermined conditions in different read-out techniques and from different operators. The statistical analysis of each possible group of T.L.D. permitted us to draw the error-response curves and the relative precision profiles and to select the best evaluation techniques and the best operator on the base of precision, sensitivity and useful range.

[Spontaneous changes of ventricular ectopic beats in ischemic patients and subjects without other signs of cardiopathy]. / Variabilità spontanea dei battiti ectopici ventricolari in pazienti ischemici ed in soggetti senzi altri segni di cardiopatia.

Spontaneous variability of premature ventricular complexes was evaluated by 72 hour continuous ambulatory electrocardiographic monitoring in 38 patients. Nineteen patients had coronary artery disease and 19 subjects had no documented signs of cardiac disease. Using multifactorial analysis of variance we determined the minimal percent reduction of premature ventricular complexes frequency that could not be ascribed to spontaneous variability alone in both single subject and in groups of 10 and 19 individuals and analyzed the difference between the two groups of ischemic and healthy patients. Our results show that in each subject with or without coronary artery disease the minimal reduction of premature ventricular complexes is similar: 71% and 72% respectively. On the other hand when the two groups were compared the percentage of reduction was 49% in healthy subjects and 40% in patients with coronary artery disease. Spontaneous variability of premature ventricular complexes decreases as the period of monitoring lengthens; however the improvement obtained with longer electrocardiographic monitoring doesn't justify the prolongation of the examination beyond 24 hours.

[Homogeneous dose distribution in the moving-strip technic]. / Omogeneizzazione della dose nella tecnica di moving-strip.

The moving-strip technique employing a 60Co beam, is used in radiotherapy for whole abdominal irradiation in ovarian tumours and lymphomas. With this technique the spread of received dose from single strip, around an average value, is very high. Our paper suggest a computerized method for a more homogeneous dose distribution in central strips and a lower dose in out-side tissues.