Medical Plausibility Research Articles

Automated sex and age partitioning for the estimation of reference intervals using a regression tree model

Abstract Objectives Reference intervals (RI) play a decisive role in the interpretation of medical laboratory results. An important step in the determination of RI is age- and sex specific partitioning, which is usually based on an empirical approach by graphical representation. In this study, we evaluate an automated machine learning approach. Methods This study uses pediatric data from the CALIPER RI (Canadian Laboratory Initiative on Pediatric Reference Intervals) study. The calculation of potential partitions is carried out using a regression tree model included in the rpart package of the statistical programming language R. The Harris & Boyd method is used to compare the corresponding partitions suggested by rpart and CALIPER. For better comparability, the reference ranges of the partitions of both approaches are then calculated using reflimR. Results Most of the partitions suggested by rpart or CALIPER show sufficient heterogeneity among themselves to justify age- and/or sex-specific RI partitioning. With only few individual exceptions, both methods yield comparable results. The partitions of both approaches for albumin and γ-glutamyltransferase are very similar to each other. For creatinine rpart suggests a slightly earlier distinction between the sexes. Alkaline phosphatase shows the most pronounced differences. In addition to a considerable earlier sex split, rpart suggests different age intervals for both sexes, resulting in three partitions for females and four partitions for males. Conclusions Our findings indicate that the automated analysis provided by rpart yields results that comparable to traditional methods. Nevertheless, the medical plausibility of the automatic suggestions needs to be validated by human experts.

Advancing rare disease treatment: EMA’s decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation

Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency’s Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.

A Generative Pretrained Transformer (GPT)-Powered Chatbot as a Simulated Patient to Practice History Taking: Prospective, Mixed Methods Study.

Communication is a core competency of medical professionals and of utmost importance for patient safety. Although medical curricula emphasize communication training, traditional formats, such as real or simulated patient interactions, can present psychological stress and are limited in repetition. The recent emergence of large language models (LLMs), such as generative pretrained transformer (GPT), offers an opportunity to overcome these restrictions. The aim of this study was to explore the feasibility of a GPT-driven chatbot to practice history taking, one of the core competencies of communication. We developed an interactive chatbot interface using GPT-3.5 and a specific prompt including a chatbot-optimized illness script and a behavioral component. Following a mixed methods approach, we invited medical students to voluntarily practice history taking. To determine whether GPT provides suitable answers as a simulated patient, the conversations were recorded and analyzed using quantitative and qualitative approaches. We analyzed the extent to which the questions and answers aligned with the provided script, as well as the medical plausibility of the answers. Finally, the students filled out the Chatbot Usability Questionnaire (CUQ). A total of 28 students practiced with our chatbot (mean age 23.4, SD 2.9 years). We recorded a total of 826 question-answer pairs (QAPs), with a median of 27.5 QAPs per conversation and 94.7% (n=782) pertaining to history taking. When questions were explicitly covered by the script (n=502, 60.3%), the GPT-provided answers were mostly based on explicit script information (n=471, 94.4%). For questions not covered by the script (n=195, 23.4%), the GPT answers used 56.4% (n=110) fictitious information. Regarding plausibility, 842 (97.9%) of 860 QAPs were rated as plausible. Of the 14 (2.1%) implausible answers, GPT provided answers rated as socially desirable, leaving role identity, ignoring script information, illogical reasoning, and calculation error. Despite these results, the CUQ revealed an overall positive user experience (77/100 points). Our data showed that LLMs, such as GPT, can provide a simulated patient experience and yield a good user experience and a majority of plausible answers. Our analysis revealed that GPT-provided answers use either explicit script information or are based on available information, which can be understood as abductive reasoning. Although rare, the GPT-based chatbot provides implausible information in some instances, with the major tendency being socially desirable instead of medically plausible information.

The medical plausibility of Osvald’s disease

The medical plausibility of Osvald’s disease

Regulatory Standards in Orphan Medicinal Product Designation in the EU.

Twenty years of orphan regulation in Europe have now elapsed, with almost 2,400 orphan designated medicinal products and more than 190 orphan products authorised in the EU. Alongside the evolution in understanding of rare diseases, considerable regulatory knowledge has also been accumulated regarding the level of evidence that would support inclusion of products into the framework. This article reviews publications and regulatory documents pertaining to orphan medicinal product designation in the EU and discusses the general expectations in submitted applications as reflected in the current regulatory practise. Important elements to recommend granting a European orphan designation are the key considerations of orphan condition, medical plausibility, seriousness, and prevalence, while significant benefit is also assessed when there are authorised medicinal products for the sought indication. This review attempts to clarify the specific concepts currently used in that regard and discusses how the available data can be used to justify the criteria for designation. Moving away from theoretical expectations or assumptions, it stresses that the applications have to be complemented with nosological and epidemiological justifications pertaining to the proposed condition, as well as relevant data in specific non-clinical in vivo models or in affected patients to support inclusion into the orphan scheme.

Pseudonymization of PHI Items in German Clinical Reports.

We describe the adaptation of a non-clinical pseudonymization system, originally developed for a German email corpus, for clinical use. This tool replaces previously identified Protected Health Information (PHI) items as carriers of privacy-sensitive information (original names for people, organizations, places, etc.) with semantic type-conformant, yet, fictitious surrogates. We evaluate the generated substitutes for grammatical correctness, semantic and medical plausibility and find particularly low numbers of error instances (less than 1%) on all of these dimensions.

The translational value of animal models in orphan medicines designations for rare paediatric neurological diseases

Rare diseases are characterized by a substantial unmet need mostly because the majority have limited, or no treatment options and a large number also affect children. Appropriate animal models, based on the knowledge of the molecular pathology of the human disease, are a significant element to support the medical plausibility of an orphan designation during the development of orphan medicines for rare neurological diseases.This observational, retrospective study aims to investigate the clinical or nonclinical nature of data submitted to support medical plausibility of orphan designations in the EU (2001–2019), for a group of rare and paediatric neurological diseases. From our sample of 30 diseases, 70% are rare with paediatric onset and 37% have approved orphan designations. The use of nonclinical data was significantly higher than clinical data (65% vs. 35%, p = 0.013) to support medical plausibility. Examples of diseases, with orphan designations based only in nonclinical data, are also discussed: Aicardi–Goutières syndrome and Centronuclear myopathy animal disease models, potentially used to support medical plausibility of medicines.Nonclinical appropriate models, assessing disease relevant endpoints, may contribute to increase the translational value of animal models, in paediatric and rare neurological area, to accelerate research and the effective development of treatment options.

Orphan drug designation in Europe: A booster for the research and development of drugs in rare diseases

The research and drug development process in rare diseases is challenging in addition to those for common diseases. To stimulate its development, the orphan drug designation (ODD) was introduced in in European Union in 2000. In the present paper, we describe the main characteristics of ODD in European Union in particular the requested criteria for ODD, the overview of the general procedure and the main incentives for Sponsors and finally the predicted factors related to successful development and marketing approval of orphan drugs after designation. In accordance with regulation, an application for ODD must be submitted to European Agency including a scientific part based on relevant scientific literature related to the condition and results on experimental studies with the specific product (and clinical studies if available). Three following criteria are a central position in this application: medical plausibility, rarity and medical significant benefit. The Committee for Orphan Medicinal Products (COMP) is the European Medicines Agency's (EMA) committee responsible for recommending orphan designation of medicines for rare diseases. Even if pre-submission meetings are not mandatory, EMA strongly encourages sponsors to request a pre-submission meeting with the Agency prior to filing an application. Experience has shown that they have a positive impact on the success rate of the applications. The full application should be submitted in English via secure online portal. ODD makes the sponsor eligible for a number of orphan incentives including the 10-year market exclusivity and the protocol assistance by COMP. Based on literature and on the experience accumulated by our team ORPHANDEV F-CRIN-labelled platform the successful translation of rare disease research into orphan drug discovery is dependent of a clearly justified medical significant benefit, the disease class, its prevalence and the disease-specific scientific output, previous experience of the sponsor with a previous successful orphan drug to the market increased.

Abstract TMIM-082: OVACURE - BRINGING PERSONALIZED TREATMENT TO WOMEN WITH OVARIAN CANCER

Abstract Immunotherapy has revolutionized the treatment of many types of cancer and is now undergoing testing in ovarian cancer (OC). Several immunotherapeutic approaches are currently being developed for OC treatment; including tumor infiltrating lymphocytes based adoptive cell therapy (TIL based ACT), chimeric antigen receptor–modified T-cells (CAR T-cell), personalized vaccines and immune checkpoint blockade. Additionally, the importance of using combination of therapies and obtaining information on different group of patients (treatment responsive and unresponsive) prior to designing new approaches, has been widely identified. Although being able to choose a more targeted combination therapy can potentially be lifesaving for OC patients; identifying the successful treatment combination is challenging due to the low mutation frequency in this cancer and the variability observed patient to patient. Our goal is to support OC patients from a synergetic point of view. OvaCure portfolio contributes to almost all the immunotherapeutic approaches mentioned above; as well as to understanding how patients respond to different treatment combinations and how this information can be used to improve patient care. OvaCure's T-cell Immune Therapy Branch consist in three parallel trials that build in and complement each other, and that aim to make a meaningful impact by moving forward TIL based ACT. Our first clinical trial is led by Prof. Svane - Denmark, and has already contributed to state-of-the-art of stablishing the medical plausibility of treating recurrent OC with TIL based ACT. The clinical Phase I/II - Immunotherapy by adoptive T-cell infusion in the event of advanced ovarian cancer (stage III/IV), will be completed in 2019 and will provide an overview of the clinical efficacy of TIL based ACT in combination with anti-CTLA-4 antibody Ipilimumab and PD-1 antibody. The second trial, clinical Phase I - Combined chemo- and adoptive T-cell therapy (ACT) as treatment for recurrent epithelial ovarian carcinoma, is led by Ass. Prof. Verdegaal - The Netherlands. Patient enrolment commenced early 2018, and the trial will provide insight on the role of interferon alfa in enhancement of T-cell survival, improvement of TILs persistence and effectiveness, and in lowering toxicity for patients. The third project in our T-cell Immune Therapy Branch is led by Prof. Coukos – Switzerland, and aims to identify the human tumour cells expressed antigenic determinants. The coming Clinical Phase I will assess the clinical efficacy of utilizing the selected tumor-specific T-cells against OC. Tumour-match: Combination of immune therapy with a next generation patient selection platform to improve treatment outcomes is also part of our portfolio. Herein, Dr. Mirza combines two breakthroughs in cancer: immune therapy with a next generation patient selection platform using RNA sequencing. This study strives to develop gene expression signatures that could guide treatment decisions, can be used to monitor disease progression and open the window to diagnostic opportunities. OvaCure's core focus is to make a positive impression on society by supporting experimental, bold and risk-taking research; as well as, promoting awareness through public outreach. Visit our website (www.ovacure.org) for more information about our research and activities. Citation Format: Adoracion Pegalajar-Jurado. OVACURE - BRINGING PERSONALIZED TREATMENT TO WOMEN WITH OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-082.

Collectively ill: a preliminary case that groups can have psychiatric disorders

In the 2000s, several psychiatrists cited the lack of relational disorders (what I call “collective disorders”—disorders of groups rather than individuals) in the DSM-IV as one of the two most glaring gaps in psychiatric nosology, and campaigned for their inclusion in the DSM-5. This campaign failed, however, presumably in part due to serious “ontological concerns” haunting such disorders. Here, I offer a path to quell such ontological concerns, adding to previous conceptual work by Jerome Wakefield and Christian Perring. Specifically, I adduce reasons to think that collective disorders are compatible with key metaphysical commitments of contemporary scientific psychiatry, and argue that if one accepts the existence of mental disorders in individuals as medical, then one has good reasons to accept the existence of collective disorders as medical. First, I outline how collective disorders are reconcilable with both the harmful dysfunction model of disorder and a denial of mind-body dualism. I then identify some potential weaknesses in the main pre-existing example of a collective disorder, offering my own examples as supplements. These examples’ medical plausibility is bolstered by: (1) work in philosophy of biology on the generalized selected effects theory of function (largely from Justin Garson), and (2) work in analytic philosophy of mind on collective mentality (largely from Bryce Huebner). Finally, after offering preliminary responses to the objection that the recognition of collective disorders may lead to an overpathologization of everyday life, I spell out ways in which this recognition may have empowering effects for some would-be patients; for example, by providing substance to the notion of a “sane response to an insane world.”

Cerebrospinal fluid data compilation and knowledge-based interpretation of bacterial, viral, parasitic, oncological, chronic inflammatory and demyelinating diseases. Diagnostic patterns not to be missed in neurology and psychiatry.

The analysis of intrathecal IgG, IgA and IgM synthesis in cerebrospinal fluid (CSF) and evaluation in combined quotient diagrams provides disease-related patterns. The compilation with complementary parameters (barrier function, i.e., CSF flow rate, cytology, lactate, antibodies) in a cumulative CSF data report allows a knowledge-based interpretation and provides analytical and medical plausibility for the quality assessment in CSF laboratories. The diagnostic relevance is described for neurological and psychiatric diseases, for which CSF analysis can't be replaced by other diagnostic methods without loss of information. Dominance of intrathecal IgM, IgA or three class immune responses give a systematic approach for Facial nerve palsy, Neurotrypanosomiasis, Opportunistic diseases, lymphoma, Neurotuberculosis, Adrenoleucodystrophy or tumor metastases. Particular applications consider the diagnostic power of the polyspecific antibody response (MRZ-antibodies) in multiple sclerosis, a CSF-related systematic view on differential diagnostic of psychiatric diseases and the dynamics of brain- derived compared to blood-derived molecules in CSF for localization of paracytes.

Development of Masitinib for the Treatment of Peripheral T-Cell Lymphoma

Increasing resistance to chemotherapy means that approximately 30% of patients afflicted with peripheral T-cell lymphoma will develop a relapsed/refractory form and eventually succumb to the disease. To date there is no clearly established second-line therapy and investigation of new therapies is necessary to address this unmet medical need.Masitinib is an oral tyrosine kinase inhibitor that potently and selectively targets c-Kit and platelet-derived growth factor receptor (PDGFR). Studies in human T-cell lymphoma have identified aberrant expression of PDGFR-alpha and that this kinase fosters peripheral T-cell lymphoma cell proliferation via an autocrine loop. Masitinib may therefore exert an antiproliferative and pro-apoptotic action on abnormal T-cells. In addition to this direct mechanism of action, masitinib can elicit antitumor effects by acting on mast cells and macrophages. By inhibiting mast cells, masitinib reduces the release of pro-tumoral M2-polarizing cytokines as well as factors favoring metastasis and angiogenesis. Masitinib can also promote macrophage infiltration into tumors, inducing an anti-tumoral Th1 immune response.Inhibition of cell proliferation was observed following single-agent masitinib treatment in the OSW canine T-cell lymphoma line, with an IC50 of 0.005 μM, suggesting that it could be used efficiently for the treatment of T-cell lymphoma. This hypothesis was further substantiated by a case study in a companion dog with T-cell lymphoma treated with masitinib monotherapy 12 mg/kg/day, reporting a complete response following 3 weeks of treatment with increased quality of life. This preliminary observation was repeated in two separate independent studies, each comprised of 11 dogs with T-cell lymphoma. A first study reported an overall response rate (ORR) of 73%, including 3/11 dogs with complete response (CR) and 5/11 dogs with partial response (PR) after 3 months of treatment. A second study reported an ORR of 45%, including 2/11 dogs with CR and 3/11 dogs with PR after 3 months of treatment. Meta-analysis of these data (n=23) showed that masitinib treatment of canine T-cell lymphoma resulted in a CR in 6/23 dogs (26%) and in a PR 8/23 dogs (35%), resulting in an ORR of 61%. Naturally occurring tumors in dogs have more clinical and biological similarities to human cancers than any other animal cancer model, hence these data provide strong medical plausibility for masitinib in the treatment of human peripheral T-cell lymphoma.The above in vitro and in vivo data led to initiation of a multicenter, randomized, open-label, three-parallel group, phase 2 study to evaluate the combination of masitinib plus dexamethasone with or without gemcitabine in patients with relapsed or refractory peripheral T-cell lymphoma. A recent decision to accelerate to a phase 3 study was based on an observed survival benefit for masitinib treated patients when compared with the control arm, and an acceptable safety profile; passage to phase 3 was validated by the independent Data Safety Monitoring Board with data blinded to sponsor and investigator. Specifically, pooled data from all masitinib-treated patients in the phase 2 stage (n=34) estimated a median overall survival (OS) of 9.0 months, which compares favorably against the literature benchmark median OS of 5.5 months for documented chemotherapy in this indication.This phase 3 study is currently open for patient recruitment in at least 14 countries and has OS as the primary endpoint. If successful, masitinib could provide a new treatment option in relapsed or refractory peripheral T-cell lymphoma. DisclosuresOff Label Use: Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells and macrophages, important cells for immunity, through inhibiting a limited number of kinases. Based on its unique mechanism of action, masitinib can be developed in a large number of conditions in oncology, in inflammatory diseases, and in certain diseases of the central nervous system. In oncology due to its immunotherapy effect, masitinib can have an effect on survival, alone or in combination with chemotherapy. Through its activity on mast cells and consequently the inhibition of the activation of the inflammatory process, masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.. Marçais:AB Science: Consultancy. Dubreuil:AB Science: Consultancy. Moussy:AB Science: Other: CEO.

Establishing medical plausibility in the context of orphan medicines designation in the European Union.

In the European Union, sponsors have the responsibility to demonstrate the “intention to diagnose, prevent or treat” a serious and rare condition before the Committee of Orphan Medicinal Products (COMP), for a medicinal product to meet the criteria for Orphan Designation. This requirement is commonly referred to as “medical plausibility” and the justification of this intention is assessed on the merits of each application by the COMP, which deliberates over the scientific evaluation of the evidence submitted. The scientific assessment of the applications for orphan designation by the Committee is based on the review of non-clinical (such as in vitro and in vivo) and/or clinical data submitted by the sponsor. Several challenges regarding the evidence provided emerge when the sponsor is applying for a designation at an early stage of development. Herein we discuss specific examples from the experience of the COMP, in order to elaborate on the type and level of evidence generally considered necessary for the purpose of justification of the intention to treat an orphan condition. Importantly, it is pointed out that bridging of data from other products, irrespectively of how comparable they may be, or from settings not directly associated with the condition as applied for designation, is by and large not a successful exercise and may only be exceptionally considered. It is further exemplified that, as reflected in the updated ‘Guideline on the format and context of the applications for designation’ and the guidance document ‘Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation’ available on the EMA website, the sponsor should provide data with the specific product as applied for in specific models of the condition or in patients affected by the same condition subject of each application.

Evolving medical and surgical management of infants with trisomy 18

To review the evolving management of infants/children with trisomy 18, the prognosis with and without medical intervention, the factors that have contributed to the evolving management strategies, and an approach to the formulation of healthcare management plans for newborns with trisomy 18. There has been a trend from nonintervention for infants/children with trisomy 18 toward management to prolong life. It has become clear that the prognosis for infants/children with trisomy 18 is not as 'hopeless' as was once asserted. However, case series of patients with trisomy 18 managed with a goal of prolonging life are not adequate to evaluate the efficacy of these interventions. They are also not adequate to support the contention that they have no efficacy. In fact, anecdotal evidence and medical plausibility suggest that treatment can prolong life in some cases. This trend has been supported by a change in emphasis from a largely physician-directed model of medical decision-making to a collaborative model, which respects parents' rights to make healthcare decisions for their children and recognizes that judgments about outcomes are often subjective, and social networks, which support and advocate for children with trisomy 18 and their families. An approach to collaborative medical decision-making that is goal-directed is recommended. Healthcare management approaches or policies that reject out of hand the goal of prolonging the life of any infant/child with trisomy 18 are not defensible. Management plans should be goal-directed, based on the physician-parent evaluation of the benefits and burdens of care options for the individual child.

Haptic Palpation for Medical Simulation in Virtual Environments

Palpation is a physical examination technique where objects, e.g., organs or body parts, are touched with fingers to determine their size, shape, consistency and location. Many medical procedures utilize palpation as a supplementary interaction technique and it can be therefore considered as an essential basic method. However, palpation is mostly neglected in medical training simulators, with the exception of very specialized simulators that solely focus on palpation, e.g., for manual cancer detection. In this article we propose a novel approach to enable haptic palpation interaction for virtual reality-based medical simulators. The main contribution is an extensive user study conducted with a large group of medical experts. To provide a plausible simulation framework for this user study, we contribute a novel and detailed interaction algorithm for palpation with tissue dragging, which utilizes a multi-object force algorithm to support multiple layers of anatomy and a pulse force algorithm for simulation of an arterial pulse. Furthermore, we propose a modification for an off–the–shelf haptic device by adding a lightweight palpation pad to support a more realistic finger grip configuration for palpation tasks. The user study itself has been conducted on a medical training simulator prototype with a specific procedure from regional anesthesia, which strongly depends on palpation. The prototype utilizes a co-rotational finite-element approach for soft tissue simulation and provides bimanual interaction by combining the aforementioned techniques with needle insertion for the other hand. The results of the user study suggest reasonable face validity of the simulator prototype and in particular validate medical plausibility of the proposed palpation interaction algorithm.

Designation, plausibility, protocol assistance, clinical benefit, similarity, reassessment: Rules and experiences

Orphan legislation provides incentives to industry to investigate rare conditions that otherwise would be unlikely to be investigated. These incentives include, free access to scientific advice during the development of their clinical programs (‘protocol assistance’); reduction in fees payable to EMA for review of the marketing authorisation and subsequent licence maintenance fees; sustained market protection in the form of market exclusivity in addition to a range of national incentives. To qualify for these incentives companies must apply for orphan designation confirming the seriousness of the condition which has inadequate alternative therapeutic options (for the diagnosis, prevention or treatment) and that the condition qualifies in terms of low prevalence in the European community. The company must also provide evidence of medical plausibility including likely significant medical benefit for patients to be treated with the product for the proposed orphan indication. If an application for orphan designation is not accepted then a company is able to appeal providing detailed grounds for reassessment and will receive a second opinion from the PDCO. The period of market exclusivity awarded by orphan designation will require that future applications received by the EMA for the same condition have to undergo an assessment of similarity to ensure that no variations or new applications for ‘similar’ medicinal products are granted licences during this ten year period. Products gaining orphan designation provide regular/annual reports regarding their development status, status of global regulatory submissions and any change likely financial returns predicted for the indication.

How to overcome the hurdles of running a clinical trial?

The statistical method is an integral part of clinical trials, because clinical trials are scientific experiments involving human subjects and are to produce objective inferences as to the benefit of intervention – including more narrowly defined medical regiment – under evaluation. Many interventions with reputed anecdotal evidence of plausible benefit turn out to be not so useful if not outright harmful. Furthermore, a treatment good for one group of patients may not be necessarily good for another group of patients receiving a placebo. Clinical trial data are complex and rarely complete. Recently, behavior modifications such as smoking cessation and diet are being evaluated by clinical trial methods. People believed beta-carotene and vitamin C would prevent cancer, but clinical trials have shown no benefit. This points out that the medical plausibility should not be accepted blindly. I will explain the role of statisticians in planning, designing and analyzing clinical trials mainly from my experience.

Reality and Fiction Cues in Medical Patient Simulation: An Interview Study with Anesthesiologists

Following the framework of ecological validity, and taking into account the social character of simulation, we investigated how six anesthesiologists each experienced three patient simulation scenarios. Using content analysis, we describe factors mentioned in the 18 half-structured interviews that were relevant for the perceived realism of the scenarios: overall impression and medical plausibility, participants' own actions, role play of the simulator team, workload, technical aspects, group dynamics, and anticipations. Further, we describe the circumstances under which these relevant elements were experienced as fiction cues (emphasizing differences between scenarios and clinical cases) or as reality cues (emphasizing similarities between scenarios and clinical cases). The experience of the scenarios among the anesthesiologists was dynamic over time and differed among participants. Considering the described elements and their character as either fiction or reality cues improves the understanding of the still-unanswered question of why simulators and simulations “work.” Simulators and simulations help in designing, optimizing, conducting, and analyzing patient simulation scenarios in a goal-oriented fashion.

Be skeptical about unexpected large apparent treatment effects:: the case of an MRC AML12 randomization

The preliminary results of the twelfth Medical Research Council acute myeloid leukemia trial show no evidence of a survival advantage for five courses of therapy compared to four courses in a randomized comparison involving 1078 patients (hazard ratio 1.09, 95% confidence interval [CI] 0.87–1.37, p=0.4). However, the data presented to the independent data monitoring and ethics committee (DMEC) at both its reviews in 1998 suggested large benefits for the additional course with hazard ratios of 0.47 and 0.55 (95% CIs 0.29–0.77 and 0.38–0.80, p=0.003 and p=0.002, respectively). Despite these highly significant findings, the DMEC did not recommend closure of the randomization, a decision vindicated by the subsequent reversion to a null result. The main reason for not closing the randomization was that the treatment effects observed in 1998 (53% and 45% reductions in the odds of death) were considered too large to be clinically plausible, despite the p-values associated with them. Investigations have not identified any clinical explanations, such as different types of patients in the early and later parts of the trial, to explain the loss of benefit as the trial progressed. Thus, the most likely current explanation for the large benefit observed early on is the play of chance. Lessons to be learned from this example are that: fixed stopping rules based on some predetermined p-value should not be used and the decision to close a randomization or not should take account of other factors such as the medical plausibility of the magnitude of the treatment effect; chance effects do occur and happen more frequently than many clinicians realize; it is important that DMEC members are experienced in the interpretation of clinical trial evidence and aware of the dangers of early stopping without wholly convincing evidence.

Measuring potentially avoidable hospital readmissions

The objectives of this study were to develop a computerized method to screen for potentially avoidable hospital readmissions using routinely collected data and a prediction model to adjust rates for case mix. We studied hospital information system data of a random sample of 3,474 inpatients discharged alive in 1997 from a university hospital and medical records of those (1,115) readmitted within 1 year. The gold standard was set on the basis of the hospital data and medical records: all readmissions were classified as foreseen readmissions, unforeseen readmissions for a new affection, or unforeseen readmissions for a previously known affection. The latter category was submitted to a systematic medical record review to identify the main cause of readmission. Potentially avoidable readmissions were defined as a subgroup of unforeseen readmissions for a previously known affection occurring within an appropriate interval, set to maximize the chance of detecting avoidable readmissions. The computerized screening algorithm was strictly based on routine statistics: diagnosis and procedures coding and admission mode. The prediction was based on a Poisson regression model. There were 454 (13.1%) unforeseen readmissions for a previously known affection within 1 year. Fifty-nine readmissions (1.7%) were judged avoidable, most of them occurring within 1 month, which was the interval used to define potentially avoidable readmissions ( n = 174, 5.0%). The intra-sample sensitivity and specificity of the screening algorithm both reached approximately 96%. Higher risk for potentially avoidable readmission was associated with previous hospitalizations, high comorbidity index, and long length of stay; lower risk was associated with surgery and delivery. The model offers satisfactory predictive performance and a good medical plausibility. The proposed measure could be used as an indicator of inpatient care outcome. However, the instrument should be validated using other sets of data from various hospitals.