Predictors of adverse outcome in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy: long term experience of a tertiary care centre.

OBJECTIVE: To investigate the predictors for adverse clinical outcome in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) during long term follow up. METHODS: 61 patients with ARVD/C were studied to assess the impact of family history, clinical findings, surface ECG parameters, echocardiographic findings, and electrophysiological findings on clinical outcome. The prevalence of these risk factors were compared in two patient groups: group A (patients with adverse clinical outcome: sudden cardiac death, death from heart failure, or heart transplant) and group B (survivors excluding patients who received a heart transplant). RESULTS: Mean age at first diagnosis was 44 (14) years. The mean follow up duration was 55 (47) months. Ten patients (16%) died during follow up. The cause of death of eight of these patients was probably arrhythmic. Two patients died of advanced heart failure. Five patients underwent heart transplantation because of terminal heart failure. Risk factors significantly associated with adverse outcome were history of congestive heart failure (p < 0.001), the presence of left ventricular involvement on echocardiography (p < 0.001), left atrial dilatation (p < 0.05), prolonged PR duration (p < 0.01), prolonged QRS in V1 (p < 0.05), and bundle branch block (p < 0.05). In multivariate analysis, history of congestive heart failure and presence of left ventricular involvement were identified as independent risk predictors for an adverse outcome. CONCLUSIONS: Congestive heart failure and left ventricular involvement are independently associated with adverse outcome in patients with ARVD/C during long term follow up.

Data and models determine treatment proposals--an illustration from meta-analysis.

A relevant problem in meta-analysis concerns the possible heterogeneity between trial results. If a test of heterogeneity is not significant the trials are often considered to be "homogeneous" and the individual trial results are replaced by an overall mean effect size and its confidence interval ("equal effects model"). If the trials are heterogeneous the individual trial effect sizes are conserved ("fixed effects model"). In a more flexible approach ("random effects model"), each trial makes use of knowledge from the other trials so individual effect sizes are "shrunken" towards an overall mean effect size. The more flexible tool may be useful for doctors involved in a trial when the outcome of their individual trial differs markedly from the overall mean effect size. Where a particular trial result is opposite in direction to the overall mean result, a conflict may arise: should a new patient be treated with the new method or not? The more flexible position and a graphical comparison of the three approaches are likely to be helpful in guiding the decision. Applying different models to the same data may lead to apparently paradoxical results: an individual trial result may be interpreted to be beneficial or harmful depending on the choice of model.

[Ocular barostress and barotrauma. A study of 15 scuba divers]. / Okuläre Druckbelastung und Barotrauma. Studie an 15 Sporttauchern.

BACKGROUND: During SCUBA-diving, relative changes of the pressure in the diving mask, compared to the environmental pressure, are transmitted to the eye and to the periocular tissue. Barotrauma results from lack of pressure equilibration. MATERIAL AND METHODS: In 15 divers (6 experienced, 9 beginners) the pressure difference (delta-p) between inside and outside of the diving mask was measured every second during recreational SCUBA-diving. Data were transmitted wireless to a modified standard diving computer. An overall dive time of 323 minutes was analysed. RESULTS: Mean delta-p was 14.8 mbar (-44 to , std.dev. +/- 9), it was not dependent on the diving depth (r2 = 0.0004). Delta-p oscillated between 0 and 25 mbar (0-19 mm Hg), parallel to respiration. Negative delta-p values were 9.5 times more frequent in beginners than in experienced divers. Negative pressure peaks (changes > or = 10 mbar for more than 6 sec) occurred in the beginner group exclusively (p = 0.01). CONCLUSIONS: During SCUBA diving, ocular tissues undergo oscillating changes of environmental pressure, parallel to respiration. This may be important in eyes with previous surgery. Pressure peaks, leading to severe ocular barotrauma, are easily avoidable.

[Manifestations of the "pretherapeutic phase" of malignant melanoma of the skin in Switzerland 1996-1998]. / Erhebungen zur "prätherapeutischen Phase" des malignen Melanoms der Haut in der Schweiz in den Jahren 1996-1998.

62 patients with a histologically confirmed diagnosis of cutaneous malignant melanoma were interviewed from 1996 to 1998. Lesions were found mostly on patients backs (30.6%) and they were noted most frequently because of a change in colour (darker) (50%) and increase in size (43.5%). The median time between first noticing the melanoma and visiting a physician was one month, but for 28% of the patients it was more than three months. The median time between a medical examination and surgical removal was shorter than one month, but for 22% of the patients it was more than three months. Patients with bleeding lesions sought medical help later (14 months). Misdiagnosis led to a six months delay in treatment and if no action was taken there was a 13 months delay.

An outline of graphical Markov models in dentistry.

BACKGROUND: In the usual multiple regression model there is one response variable and one block of several explanatory variables. In contrast, in reality there may be a block of several possibly interacting response variables one would like to explain. In addition, the explanatory variables may split into a sequence of several blocks, each block containing several interacting variables. The variables in the second block are explained by those in the first block; the variables in the third block by those in the first and the second block etc. OBJECTIVE AND METHODS: During recent years methods have been developed allowing analysis of problems where the data set has the above complex structure. The models involved are called graphical models or graphical Markov models. The main result of an analysis is a picture, a conditional independence graph with precise statistical meaning, consisting of circles representing variables and lines or arrows representing significant conditional associations. The absence of a line between two circles signifies that the corresponding two variables are independent conditional on the presence of other variables in the model. EXAMPLE: An example from epidemiology is presented in order to demonstrate application and use of the models. The data set in the example has a complex structure consisting of successive blocks: the variable in the first block is year of investigation; the variables in the second block are age and gender; the variables in the third block are indices of calculus, gingivitis and mutans streptococci and the final response variables in the fourth block are different indices of caries. Since the statistical methods may not be easily accessible to dentists, this article presents them in an introductory form. CONCLUSION: Graphical models may be of great value to dentists in allowing analysis and visualisation of complex structured multivariate data sets consisting of a sequence of blocks of interacting variables and, in particular, several possibly interacting responses in the final block.

Association of salivary mutans streptococci with discoloured pits and fissures.

Experimental studies have demonstrated that mutans streptococci play a major role in caries etiology. Several previous epidemiologic studies found a positive association of salivary mutans streptococci with caries prevalence. The present epidemiologic study aimed at detecting a possible association of salivary mutans streptococci with brown discoloured pits and fissures, supposing that discolouration indicates caries. In the Canton of Zurich 1035 schoolchildren, aged 6.5-12.5, were examined with regard to caries prevalence and presence of discolourations in pits and fissures. A commercially available, semi-quantitative test was used to estimate the salivary level of mutans streptococci in each child. The salivary level (low/high) of mutans streptococci was significantly associated with the presence of slightly brown discoloured (C1), clearly brown discoloured (C2) and cavitated (C3) pits and fissures. The odds ratios were 1.5 (P<0.01) for C1, 2.5 (P<0.001) for C2 and 5.0 (P<0.001) for C3 pits and fissures. The findings are consistent with the hypothesis that brown discolouration indicates caries. Furthermore, the findings suggest that this type of discolouration at elementary school age indicates increased caries activity.

The use of generalised additive models (GAM) in dentistry.

BACKGROUND: Ordinary multiple regression and logistic multiple regression are widely applied statistical methods which allow a researcher to 'explain' or 'predict' a response variable from a set of explanatory variables or predictors. In these models it is usually assumed that quantitative predictors such as age enter linearly into the model. OBJECTIVE AND METHOD: During recent years these methods have been further developed to allow more flexibility in the way explanatory variables 'act' on a response variable. The methods are called 'generalised additive models' (GAM). The rigid linear terms characterising the association between response and predictors are replaced in an optimal way by flexible curved functions of the predictors (the 'profiles'). Plotting the 'profiles' allows the researcher to visualise easily the shape by which predictors 'act' over the whole range of values. The method facilitates detection of particular shapes such as 'bumps', 'U-shapes', 'J-shapes, 'threshold values' etc. Information about the shape of the association is not revealed by traditional methods. The shapes of the profiles may be checked by performing a Monte Carlo simulation ('bootstrapping'). CASE STUDY: After the presentation of the GAM a relevant case study is presented in order to demonstrate application and use of the method. The dependence of caries in primary teeth on a set of explanatory variables is investigated. Since GAMs may not be easily accessible to dentists, this article presents them in an introductory condensed form. It was thought that a nonmathematical summary and a worked example might encourage readers to consider the methods described. CONCLUSION: GAMs may be of great value to dentists in allowing visualisation of the shape by which predictors 'act' and obtaining a better understanding of the complex relationships between predictors and response.

Exploration of interactions between prognostic factors of stage I malignant melanoma.

While many studies have sought prognostic factors of malignant melanoma using multivariate survival models, the interaction between predictors has been much less studied. We have studied data from 1,560 patients with stage I melanoma collected at the Cancer Registry of the Canton of Zurich over the period 1980-1990 and explored interactions between predictors by identifying two separate multivariate Cox models for men and women and investigating two-way interactions between predictors in each model. Considerable differences between models for man and women were observed. In particular, in women a pronounced interaction between 'histology' and 'Clark level' was identified. Without this interaction 'histology' and 'Clark level' are not significant but when the interaction term was included both predictors become significant. Thus, omission of an interaction term may preclude the recognition of main effects ('masking'). For female patients with nodular tumours prognosis is essentially independent of Clark level. In contrast, for female patients with non-nodular tumours, prognosis was found to be strongly dependent on Clark level. In the case of Clark level 2 prognosis was extremely good: no patient was observed to die from melanoma. We conclude that it may be worth considering interaction terms. With large enough sample sizes it may be preferable to stratify patients into subgroups and to identify separate models for each stratum instead of having to cope with interactions of higher order.

Asthma and exacerbation of chronic bronchitis: sentinel and environmental data in a time series analysis.

To see whether effects of air pollutants and other environmental factors on the respiratory tract can be detected by the Swiss sentinel reporting system, two years' data of asthma bronchiale and exacerbation of chronic bronchitis were analyzed. On average, 16 cases of asthma and 9 cases of bronchitis were reported per week. The respective figures expressed as mean percentages of all consultations were 0.12% and 0.065%. Data of SO2, NO2, ozone and total suspended particles were used to measure air pollution. Additionally, meteorologic parameters such as air temperature and atmospheric pressure were used, as well as the appearance of the most important pollen groups in Switzerland: grass, birch tree and mugwort. Environmental data were summarized using the mean or sum of all measuring stations. Autocorrelations in the time series were accounted for statistically. Our analysis could not establish any relationship between reports of asthma or exacerbation of chronic bronchitis and air pollutants or other environmental data. This result, which is partly contradicted by the literature, could be explained by low numbers of reports due to patient's self administration of medication and an imprecise determination of true exposure.

Box-Jenkins modelling in medical research.

Notifications of diseases, entries in a hospital, injuries due to accidents, etc., are frequently collected in fixed equally spaced intervals. Such observations are likely to be dependent. In environmental medicine, where series such as daily concentrations of pollutants are collected and analysed, it is evident that dependence of consecutive measurements may be important. A high concentration of a pollutant today has a certain 'inertia', i.e. a tendency to be high tomorrow as well. Dependence of consecutive observations may be equally important when data such as blood glucose are recorded within a single patient. ARIMA models (autoregressive integrated moving average models, Box-Jenkins models), which allow the stochastic dependence of consecutive data to be modelled, have become well established in such fields as economics. This article reviews basic concepts of Box-Jenkins modelling. The methods are illustrated by applications. In particular, the following topics are presented: the ARIMA model, transfer function models (assessment of relations between time series) and intervention analysis (assessment of changes of time series).

Action profiles of predictors of death and survival time in stage I malignant melanoma.

BACKGROUND: Many studies have been performed to identify prognostic factors of malignant melanoma using multivariate regression models. In these models, it is generally assumed that quantitative predictors such as age or tumor thickness enter linearly into the model, or they are categorized. OBJECTIVE: The purpose of the present study is to investigate possible curvature (nonlinearity) of predictors of 'death from MM within 5 years after diagnosis' and 'survival time after diagnosis' avoiding the known shortcomings of categorizing predictors. METHODS: Our analyses are based on data of 677 patients with stage I melanoma of the skin collected at the Cancer Registry of the Canton of Zurich. In order to study non-linearity of predictors, we use 'generalized additive models' (GAM): in a GAM the usual prognostic index is replaced in an optimal way by a more flexible form where the individual linear terms are replaced by possibly curved functions of the predictors. Plotting the corresponding curves (the 'action profiles') allows one to visualize easily the shape by which predictors 'act' over the whole range of values. RESULTS: Essentially the same results emerged when studying 'death from melanoma' and 'survival time in melanoma': age and tumor thickness have a pronounced nonlinear association with both endpoints taking simultaneously into account effects of sex and tumor site. The action profile for age is J or U shaped. The action profile for thickness has a 'two-phase' pattern. It increases linearly for low thickness values and flattens for higher values. The shape of the action profiles was checked by performing a Monte Carlo simulation ('boot-strapping'). CONCLUSIONS: The best prognosis of melanoma was found within a middle age range while younger and older patients showed a poorer prognosis. In our data, the increase in thickness in the range above 2 mm is of much less clinical relevance than in the range below 2 mm. GAMs may be of great value for clinicians in providing a visualization of the shape by which predictors act and to obtain a better understanding of the complex relationships between predictors and survival. Not considering curvature of action profiles may result in excluding relevant predictors.

Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy.

BACKGROUND: Uremic small-artery disease with medial calcification and intimal hyperplasia can lead to life-threatening skin necrosis or acral gangrene. It is a distinct complication of chronic renal failure that must be differentiated from soft-tissue calcification. An increased calcium-phosphate product and secondary hyperparathyroidism are the main underlying conditions. The benefit of parathyroidectomy is controversial. OBJECTIVE: This article is based on a literature search to determine prognostic factors and, in particular, the benefit of parathyroidectomy. METHODS: The literature on uremic small-artery disease (so-called calciphylaxis) was reviewed (full data set: 104 cases, including five of our own). The therapeutic benefit of parathyroidectomy and the relation between prognostic predictors (localization, dialysis, and transplant) and outcome were analyzed. The relation between diabetes and acral gangrene was also examined. Further epidemiologic data on the reviewed group of patients were established. RESULTS: Thirty-eight of 58 patients who underwent parathyroidectomy survived compared with 13 of 37 patients who did not undergo parathyroidectomy (p = 0.007, n = 95). Forty of 53 patients with distal localization of necrosis survived compared with 11 of 42 patients with proximal pattern (p < 0.00001; n = 95). Dialysis and kidney transplantation followed by immunosuppression showed no relation to disease outcome. No association was found between diabetes and acral gangrene (p = 0.50). CONCLUSION: Uremic small-artery disease is a distinct complication of chronic renal failure. Its recognition and early diagnosis should allow more effective treatment. In our retrospective study parathyroidectomy was significantly related to survival. Only a randomized, controlled, prospective trial (parathyroidectomy vs conservative treatment of secondary hyperparathyroidism) can establish the value of parathyroidectomy in uremic small-artery disease.

Optimization of prostate carcinoma staging: comparison of imaging and clinical methods.

PURPOSE: The diagnostic value of endorectal coil MRI, body coil MRI, transrectal ultrasound, digital rectal examination and PSA levels were prospectively analysed in order to define the most accurate preoperative staging method. METHODS: 33 patients with prostate carcinoma, who underwent subsequent prostatectomy, were enrolled in the study and examined on a 1.5T system using the body coil as well as the endorectal surface coil before and after the administration of contrast material. The results were compared to digital rectal examination, prostate specific antigen levels and endorectal ultrasound. RESULTS: Staging accuracy of endorectal coil MRI was 87.9% with a sensitivity of 88.9% and specificity of 86.7%. For body coil MRI, the staging accuracy was 75.7%, the sensitivity 66.7% and the specificity 87.9%, for transrectal ultrasound 69.6%, 41.7% and 100% and for the digital rectal examination 56.6%, 33.3% and 100%, respectively. Prediction was improved by combining results of endorectal coil MRI with PSA values. CONCLUSION: Endorectal ultrasound and digital rectal examination both had a tendency to underestimate the extent of the lesion. Endorectal coil MRI proved to be the best preoperative staging method. In combination with PSA values, diagnostic accuracy could be further improved. Therefore, local staging of prostate cancer could be based on these two parameters alone.

[Multivariate analysis of clinico-pathologic predictors of axillary lymph node metastasis in invasive breast carcinoma]. / Multivariate Analyse klinisch-pathologischer Prädiktoren der axillären Lymphknotenmetastasierung beim invasiven Mammakarzinom.

UNLABELLED: The aim of this study was to find both predictors of axillary lymph node involvement and predictors of level II or III involvement. With these predictors patients should be selected who can be spared axillary lymph node dissection or who qualify for removal of only first-level lymph nodes. 239 consecutive patients with invasive breast cancer stage I-III treated with total axillary dissection were evaluated. In multiple logistic regression analysis 17 clinical and histopathological variables were included. We found 4 multivariate significant predictors for metastatic axillary involvement: Clinically positive axilla, peritumoural lymphatic vessel invasion, multicentric or multifocal tumours and a large number of past pregnancies. Multivariate significant predictors of involvement of level II or III were peritumoural lymphatic vessel invasion, younger age, larger tumour size, multicentric or multifocal tumours and postmenopausal patient. The metastatic involvement of more than 3 nodes was associated with young age and clinically positive axilla. With these easily available predictors a reliable assessment of risk of metastatic involvement of the upper levels of the axillary nodes could be defined. The binary logistic regression model to axillary node involvement had a rather unsatisfactory predictive value. CONCLUSIONS: The risk calculation of level II or III involvement with these predictors may help the surgeon to find the adequate extent of axillary clearance needed in the individual patient. Multiparity proved to be an independent predictor of metastatic axillary node involvement.

The use of logistic discrimination and receiver operating characteristics (ROC) analysis in dentistry.

Logistic regression is a statistical method which allows an investigator to 'explain' or 'predict' a binary response variable from a set of independent variables. In particular, it may be used to classify persons for example, as diseased or healthy, high risk or low risk etc. (logistic discrimination). During recent years this method has been of increasing interest and importance in dentistry. Since this demanding statistical method may not be easily accessible to dentists, a description is provided of its basic characteristics in an introductory and condensed form. A worked example, 'identification of children with high caries risk', is presented in order to demonstrate the application and use of the method. Following the presentation of the logistic model, evaluation of the performance of a classification model by means of 'receiver operating characteristic (ROC) analysis' is demonstrated. The presentation of these statistical tools here, puts more weight on verbal explanation and on graphical representations than on mathematical details. This statistical tools here, puts more weight on verbal explanation and on graphical representations than on mathematical details. This may help to make the methods accessible to readers who have insufficient time to study a more comprehensive discourse.

Fluoride varnishes (Duraphat): a meta-analysis.

In the present article we analyze a series of studies designed to detect the caries preventive effect of Duraphat by means of meta-analysis. Meta-analysis is a collection of statistical methods designed to investigate and to summarize a series of investigations. It may be a valuable tool to complement traditional narrative reviews. During the last years meta-analysis has attracted increasing interest in sociology, psychology and medicine. In order to find previous studies concerned with the clinical effects of Duraphat we applied a systematic literature search. Papers were included independent of results when they fulfilled a checklist of well defined methodological selection criteria. In order to aggregate the results of the Duraphat-studies we used different complementary statistical approaches: Firstly, the so-called file drawer problem is considered. This may help to get a better insight into the problem of underreporting non-significant results or publication bias. It was found to be very unlikely that underreporting of non-significant results could reverse the conclusion into an overall null-result. After that, the inhomogeneity between studies is investigated. The overall variation of caries reduction R is separated into two components: A between study component of variance and a variance pertaining to the individual studies (random effects model). It was found that the overall variation is dominated by the between studies variation and not by the sampling variation. Due to the pronounced variation between studies the confidence interval of the overall effect size (R = 0.38) is quite large (95%-Cl: 0.19-0.57).(ABSTRACT TRUNCATED AT 250 WORDS)

A note concerning the caries preventive effect of Duraphat.

In a previous article (1) we analyzed a series of eight studies concerned with the effect of Duraphat in the prevention of dental caries by means of meta-analysis. A random effects model was used to estimate an overall effect size of caries reduction R and the corresponding confidence interval. In the present short communication we complement this previous study by neglecting the within study variation to the overall variation which is dominated by between study variation. This allows us to include a larger number of studies and thus make fuller use of the available information. We estimate nonparametrical confidence intervals for effect sizes (caries reduction) by means of the "bootstrap method". The overall caries reduction R on permanent teeth (14 studies) was estimated to be: R = 0.38 (95%-CI: 0.25-0.50).

[The caries occurrence in 7- to 12-year-old schoolchildren in Switzerland. The results of a country-wide survey 1987-89]. / Kariesbefall bei 7- und 12jährigen Schülern in der Schweiz. Resultate einer landesweiten Erhebung 1987-89.

Between 1987 and 1989, a random sample of school children aged 7 and 12 years in Switzerland was drawn. In the first stage, districts were chosen. Within the districts, 12 children in the two specified age groups were selected. In addition, Switzerland was subdivided into two strata. The children of stratum 2 had consumed fluoridated salt since birth while those of stratum 1 had only done so during the preceding 4 to 5 years but had benefitted since the age of 5 to 7 from dental health education programs using fluorides at school. The oral examinations were carried out according to the methodology of the World Health Organization. Attendance was 94% (1115 children). 47% of the seven-year-old children were caries-free, and the average dmft was 2.20 (95% confidence limits at 1.87 and 2.52). The average dt was 1.06. These children had an average DMFT of 0.40, with 77% having DMFT = 0. At the age of 12, the average DMFT was 2.03, with confidence limits at 1.73 and 2.33. On average, they had 0.45 DT and 38% of them were caries-free (DMFT = 0). There were only minor differences between the 2 strata. These results agreed well with the data from 6 local surveys carried out during 1987 to 1989. When compared with the majority of European countries, caries experience of Swiss children was fairly low.