Simulated Clinical Trias: some design issues

Simulation is widely used to investigate real-world systems in a large number of fields, including clinical trials for drug development, since real trials are costly, frequently fail and may lead to serious side effects. This paper is a survey of the statistical issues arising in these simulated trials. We illustrate the broad applicability of this investigation tool by means of examples selected from the literature. We discuss the aims and the peculiarities of the simulation models used in this context, including a brief mention of the use of metamodels. Of special interest is the topic of the design of the virtual experiments, stressing similarities and differences with the design of real life trials. Since it is important for a computerized model to possess a satisfactory range of accuracy consistent with its intended application, real data provided by physical experiments are used to confirm the simulator : we illustrate validating techniques through a number of examples. We end the paper with some challenging questions on the scientificity, ethics and effectiveness of simulation in the clinical research, and the interesting research problem of how to integrate simulated and physical experiments in a clinical context.Simulation models; pharmacokinetics; pharmacodynamics; model validation; experimental design, ethics. Modelli di simulazione; farmacocinetica; farmacodinamica; validazione; disegno degli esperimenti; etica.

Efficacia della fisioterapia per pazienti affetti da ernia discale: uno studio osservazionale

Fino ad alcuni anni fa, la lombosciatalgia dovuta a un’ernia discale radiologicamente comprovata era un’indicazione sicura per la rimozione chirurgica dell’ernia (discectomia), ma oggi non è più così e spesso i pazienti affetti da questo problema vengono indirizzati verso la riabilitazione fisioterapica. Ma la fisioterapia è veramente efficace? Mostriamo qui i risultati di uno studio prospettico osservazionale su un campione di pazienti sottoposti a fisioterapia in un centro medico specializzato di Bologna. Alcuni di questi pazienti avevano già subito una visita neurochirurgica e in taluni casi (che presentavano segni e sintomi più gravi degli altri, secondo gli indicatori clinici comunemente usati) avevano ricevuto l’indicazione di operarsi; però questi pazienti avevano deciso di non farlo, e di ricorrere invece a cure fisioterapiche. Come era da aspettarsi, il grado di miglioramento dei pazienti dipende da alcune caratteristiche specifiche, ma, sorprendentemente, non dal fatto che il paziente fosse o non fosse tra i “disobbedienti”. Questo risultato è confermato da un altro studio osservazionale su un piccolo campione di pazienti affetti da ernia discale visitati presso l’Ambulatorio Neurochirurgico dell’ospedale Bellaria di Bologna, alcuni dei quali sottoposti a discectomia. Nella parte conclusiva dello studio si fanno alcune considerazioni generali e un’ipotesi su possibili diversità tra i pazienti ai quali viene consigliato l’intervento chirurgico ma non vi si sottopongono e gli altri. Questa congettura è stata l’oggetto di uno studio successivo. Up to a few years ago, lower back pain and especially sciatica due to lumbar disc herniation (LDH) were indications for discectomy, whereas nowadays patients suffering from this predicament are often directed to rehabilitation by means of physiotherapy. But is physiotherapy effective? We show the results of an observational prospective study on a sample of LDH patients who underwent physiotherapy at a Bologna specialized medical centre. Prior to starting the therapy, some of the patients had been advised to resort to surgery, but had not complied, and indeed the patients with a surgical indication did present more serious signs and symptoms of LDH, according to the commonest clinical indicators. As expected, the degree of improvement appears to depend on some characteristics of the patient and his/her disease history, but, surprisingly, not on the patient being or not a non-complier. Our results are in line with the data of another small size observational study of ours, involving LDH patients who attended the out-patients Unit of the Bellaria hospital in Bologna, some of whom had surgery

Simulated Clinical Trias: some design issues

Simulation is widely used to investigate real-world systems in a large number of fields, including clinical trials for drug development, since real trials are costly, frequently fail and may lead to serious side effects. This paper is a survey of the statistical issues arising in these simulated trials. We illustrate the broad applicability of this investigation tool by means of examples selected from the literature. We discuss the aims and the peculiarities of the simulation models used in this context, including a brief mention of the use of metamodels. Of special interest is the topic of the design of the virtual experiments, stressing similarities and differences with the design of real life trials. Since it is important for a computerized model to possess a satisfactory range of accuracy consistent with its intended application, real data provided by physical experiments are used to confirm the simulator: we illustrate validating techniques through a number of examples. We end the paper with some challenging questions on the scientificity, ethics and effectiveness of simulation in the clinical research, and the interesting research problem of how to integrate simulated and physical experiments in a clinical context

Efficacia della fisioterapia per pazienti affetti da ernia discale: uno studio osservazionale

Fino ad alcuni anni fa, la lombosciatalgia dovuta a un’ernia discale radiologicamente comprovata era un’indicazione sicura per la rimozione chirurgica dell’ernia (discectomia), ma oggi non è più così e spesso i pazienti affetti da questo problema vengono indirizzati verso la riabilitazione fisioterapica. Ma la fisioterapia è veramente efficace? Mostriamo qui i risultati di uno studio prospettico osservazionale su un campione di pazienti sottoposti a fisioterapia in un centro medico specializzato di Bologna. Alcuni di questi pazienti avevano già subito una visita neurochirurgica e in taluni casi (che presentavano segni e sintomi più gravi degli altri, secondo gli indicatori clinici comunemente usati) avevano ricevuto l’indicazione di operarsi; però questi pazienti avevano deciso di non farlo, e di ricorrere invece a cure fisioterapiche. Come era da aspettarsi, il grado di miglioramento dei pazienti dipende da alcune caratteristiche specifiche, ma, sorprendentemente, non dal fatto che il paziente fosse o non fosse tra i “disobbedienti”. Questo risultato è confermato da un altro studio osservazionale su un piccolo campione di pazienti affetti da ernia discale visitati presso l’Ambulatorio Neurochirurgico dell’ospedale Bellaria di Bologna, alcuni dei quali sottoposti a discectomia. Nella parte conclusiva dello studio si fanno alcune considerazioni generali e un’ipotesi su possibili diversità tra i pazienti ai quali viene consigliato l’intervento chirurgico ma non vi si sottopongono e gli altri. Questa congettura è stata l’oggetto di uno studio successivo. Up to a few years ago, lower back pain and especially sciatica due to lumbar disc herniation (LDH) were indications for discectomy, whereas nowadays patients suffering from this predicament are often directed to rehabilitation by means of physiotherapy. But is physiotherapy effective? We show the results of an observational prospective study on a sample of LDH patients who underwent physiotherapy at a Bologna specialized medical centre. Prior to starting the therapy, some of the patients had been advised to resort to surgery, but had not complied, and indeed the patients with a surgical indication did present more serious signs and symptoms of LDH, according to the commonest clinical indicators. As expected, the degree of improvement appears to depend on some characteristics of the patient and his/her disease history, but, surprisingly, not on the patient being or not a non-complier. Our results are in line with the data of another small size observational study of ours, involving LDH patients who attended the out-patients Unit of the Bellaria hospital in Bologna, some of whom had surgery.Discectomia, Ernia al Disco, Fisioterapia, Lombalgia, Lombosciatalgia. Discectomy, Lumbar Disc Herniation, Low Back Pain, Physiotherapy, Sciatica

(U,V)-Ordering and a Duality Theorem for Risk Aversion and Lorenz-type Orderings

There is a duality theory connecting certain stochastic orderings between cumulative distribution functions F_1,F_2 and stochastic orderings between their inverses F_1^(-1),F_2^(-1). This underlies some theories of utility in the case of the cdf and deprivation indices in the case of the inverse. Under certain conditions there is an equivalence between the two theories. An example is the equivalence between second order stochastic dominance and the Lorenz ordering. This duality is generalised to include the case where there is "distortion" of the cdf of the form v(F) and also of the inverse. A comprehensive duality theorem is presented in a form which includes the distortions and links the duality to the parallel theories of risk and deprivation indices. It is shown that some well-known examples are special cases of the results, including some from the Yaari social welfare theory and the theory of majorization.Comment: 23 pages, no figures, 2 Appendice

Diagnostic and therapeutic path of breast cancer: Effectiveness, appropriateness, and costs â Results from the DOCMa study

none8noopenGiovagnoli, Maria Rosaria; Bonifacino, Adriana; Neglia, Cosimo; Benvenuto, Marco; Sambati, Francesco Vincenzo; Giolli, Lorenzo; Giovagnoli, Alessandra; Piscitelli, PriscoGiovagnoli, Maria Rosaria; Bonifacino, Adriana; Neglia, Cosimo; Benvenuto, Marco; Sambati, Francesco Vincenzo; Giolli, Lorenzo; Giovagnoli, Alessandra; Piscitelli, Prisc

Circadian Activity Rhythm in Early Relapsing-Remitting Multiple Sclerosis

While relapsing-remitting is the most prevalent course of multiple sclerosis, the prognostic/predictive markers of the worsening of symptomatology are still debated. With reference to other diseases, the study of the circadian activity rhythm, according to the theoretical framework of the two-process model of sleep regulation and applying functional linear modeling, proved to be useful to identify a possible marker. The usefulness of the study of circadian activity rhythm in multiple sclerosis is strengthened by recent findings indicating a potential involvement of circadian factors in the multifactorial etiopathology of the disorder. The aim of the present study was to verify whether circadian activity rhythm of early relapsing-remitting multiple sclerosis patients presents specific alterations, through functional linear modeling. Thirty-five relapsing-remitting multiple sclerosis patients (24 females; mean age ± SD = 31.51 ± 7.74) and 35 healthy controls (24 females; mean age ± SD = 31.29 ± 8.02) were enrolled. They wore an actigraph around the non-dominant wrist for one week. Relapsing-remitting multiple sclerosis patients showed a peak in motor activity around 5:00 a.m., higher than that of healthy controls. The timing of the peak in motor activity in the patients could be explained according to the hyperactive hypothalamus-pituitary-adrenal axis and higher cortisol awakening response reported in these patients

A Predicitive Approach to the Bayesian Design Problem with Application to Normal Regression Models

1 online resource (PDF, 20 pages

Preliminary Validation of the CI-FRA Checklist: A Simple Screening Tool for Measuring the Early Signs of Reading and Spelling Disorders in Italian Primary Students

Although several screening tests for recognizing early signs of reading and spelling difficulties have been developed, brief and methodologically grounded tools for teachers are very limited. The present study aimed to lay the foundation for a new screening tool for teachers: the Checklist for early Indicators of risk Factors in Reading Ability (CI-FRA). The proposed checklist consists of 20 items, based on a 7-point Likert scale, and it investigates five domains: reading, writing, attention, and motor skills. Six hundred sixtyseven children were evaluated by 40 teachers during the first year of primary school and, longitudinally, in the second year. Exploratory factor analysis and confirmatory factor analysis (CFA) were applied to verify structural validity. Concurrent validity was assessed by Spearman correlation to analyze the link between CI-FRA and reading and spelling standardized tests and cognitive tests. Reliability was assessed by Cronbach a and interclass correlation coefficient. The CFA reported a three-factor structure as the optimal solution, including language (reading and writing), visuospatial attention, and fine motor skills subscales. Good reliability, good internal consistency, and acceptable test\u2013 retest indices were found. Concurrent validity was confirmed by significant correlations between CI-FRA total score and standardized reading and spelling test, as well as by correlations between CI-FRA subscales and neuropsychological standardized test scores. Preliminary evaluation of sensitivity by receiver operating characteristic curves showed that the CI-FRA score has particularly high sensitivity and specificity for word reading speed deficit. In conclusion, the results confirm that CI-FRA is a theoretically grounded and statistically valid tool that could help the teachers to screen for early signs of reading and spelling difficulties