Variation Between Multidisciplinary Tumor Boards in Clinical Staging and Treatment Recommendations for Patients With Locally Advanced Non-small Cell Lung Cancer.

BACKGROUND: Accurate diagnosis and staging are crucial to ensure uniform allocation to the optimal treatment methods for non-small cell lung cancer (NSCLC) patients, but may differ among multidisciplinary tumor boards (MDTs). Discordance between clinical and pathologic TNM stage is particularly important for patients with locally advanced NSCLC (stage IIIA) because it may influence their chance of allocation to curative-intent treatment. We therefore aimed to study agreement on staging and treatment to gain insight into MDT decision-making. RESEARCH QUESTION: What is the level of agreement on clinical staging and treatment recommendations among MDTs in stage IIIA NSCLC patients? STUDY DESIGN AND METHODS: Eleven MDTs each evaluated the same 10 pathologic stage IIIA NSCLC patients in their weekly meeting (n = 110). Patients were selected purposively for their challenging nature. All MDTs received exactly the same clinical information and images per patient. We tested agreement in cT stage, cN stage, cM stage (TNM 8th edition), and treatment proposal among MDTs using Randolph's free-marginal multirater kappa. RESULTS: Considerable variation among the MDTs was seen in T staging (κ, 0.55 [95% CI, 0.34-0.75]), N staging (κ, 0.59 [95% CI, 0.35-0.83]), overall TNM staging (κ, 0.53 [95% CI, 0.35-0.72]), and treatment recommendations (κ, 0.44 [95% CI, 0.32-0.56]). Most variation in T stage was seen in patients with suspicion of invasion of surrounding structures, which influenced such treatment recommendations as induction therapy and type. For N stage, distinction between N1 and N2 disease was an important source of discordance among MDTs. Variation occurred between 2 patients even regarding M stage. A wide range of additional diagnostics was proposed by the MDTs. INTERPRETATION: This study demonstrated high variation in staging and treatment of patients with stage IIIA NSCLC among MDTs in different hospitals. Although some variation may be unavoidable in these challenging patients, we should strive for more uniformity.

An optimised dosing regimen versus a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in neonates and infants aged less than 90 days (NeoVanc): study protocol for a randomised controlled trial.

BACKGROUND: Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin's continued efficacy. METHODS: NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy. DISCUSSION: Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02790996. Registered on 7 April 2016. EudraCT, 2015-000203-89. Entered on 18 July 2016.

Decentralized care with generic direct-acting antivirals in the management of chronic hepatitis C in a public health care setting.

BACKGROUND & AIMS: The prevalence of anti-hepatitis C virus antibody in Punjab, India is 3.6%, with 728,000 people estimated to have viremic chronic hepatitis C (CHC). The Mukh-Mantri Punjab Hepatitis C Relief Fund, launched on 18th June 2016, provides no-cost generic direct-acting antivirals (DAAs) with sofosbuvir + ledipasvir ±â€¯ribavirin or sofosbuvir + daclatasvir ±â€¯ribavirin with the goal of eliminating CHC from Punjab. We assessed the safety and efficacy of decentralized treatment of CHC in a public health care setting. METHODS: Primary care providers from 3 university and 22 district hospitals were trained to provide algorithm-based DAA treatment and supervised by telehealth clinics conducted fortnightly. The diagnosis of cirrhosis was based on clinical and radiological evidence, including aspartate aminotransferase-to-platelet ratio index (APRI ≥2.0) and FIB-4 score (>3.25), or on liver stiffness measurement ≥12.5 kPa on Fibroscan®. RESULTS: We enrolled 48,088 individuals with CHC (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhosis; 69.9% genotype [GT] 3) between 18th June 2016 to 31st July 2018. While 36,250 (75.4%) patients completed treatment, 5,497 (11.4%) had treatment interruptions and 6,341 (13.2%) patients are currently ongoing treatment. Sustained virological response at 12 weeks after treatment completion (SVR12) was achieved in 91.6% of patients per protocol, 67.6% in intention-to-treat (ITT) analysis, where all interruptions were treated as failures, and 91.2% in a modified ITT analysis where all patients with successful SVR12 in the interruptions arm were included as cured. SVR12 rates in patients with and without cirrhosis and GT3 versus non-GT3 were comparable. The SVR12 rate was 84.4% in patients who had treatment interruptions. CONCLUSION: Decentralized care of patients with CHC using generic all-oral DAA regimens is safe and effective regardless of genotype or presence of cirrhosis. ClinicalTrials.gov number: NCT01110447. LAY SUMMARY: We assessed the safety and efficacy of public health care using no-cost all-oral generic direct-acting antiviral drugs against hepatitis C in the state of Punjab, India. The goal is elimination of chronic hepatitis C (CHC) by 2030 and involves primary care providers at 25 sites in the state. We enrolled 48,088 individuals (63.8% male; mean age 42.1 years; 80.5% rural; 14.8% compensated cirrhotic; 69.9% genotype 3) between 18th June 2016 to 31st July 2018. Cure was achieved in 91.6% of patients, demonstrating that decentralized care of CHC with generic all-oral regimens is safe and effective.

Using decision thresholds for ranking treatments in network meta-analysis results in more informative rankings.

OBJECTIVES: To evaluate how the rank probabilities obtained from network meta-analysis (NMA) change with the use of increasingly stringent criteria for the relative effect comparing two treatments which ranks one treatment better than the other. STUDY DESIGN AND SETTING: Systematic survey and reanalysis of published data. We included all systematic reviews (SRs) with NMA from the field of cardiovascular medicine that had trial-level data available, published in Medline up to February 2015. We reran all the NMAs and determined the probabilities of each treatment being the best. For the best treatment, we examined the effect on these probabilities of varying, what we call the decision threshold, the relative effect required to declare two treatments different. RESULTS: We included 14 SRs, having a median of 20 randomized trials and 9 treatments. The best treatments had probabilities of being best that ranged from 38% to 85.3%. The effect of changing the decision thresholds on the probability of a treatment being best varied substantially across reviews, with relatively little decrease (∼20 percentage points) in some settings but a decline to near 0% in others. CONCLUSION: Rank probabilities can be fragile to increases in the decision threshold used to claim that one treatment is more effective than another. Including these thresholds into the calculation of rankings may aid their interpretation and use in clinical practice.

Diagnostic protocols-A consultation tool still to be discovered.

RATIONALE: Experienced primary care physicians handle most illnesses to everyone's satisfaction despite limited resources of time and means. However, cases can be multifaceted in that harmless-presenting symptoms may also be warning signals or an indicator of a health disorder that too infrequently presents in family practice to be diagnosed correctly. On the basis of these observations, RN Braun developed 82 diagnostic protocols for a structured recording of various complaints. METHOD: All consultations during the years 2001 to 2014, in which 1 author (WF) had used diagnostic protocols in her single-handed practice, were analyzed retrospectively regarding reasons for encounter, diagnostic classification, and long-term outcome. RESULTS: During the period, a diagnostic protocol was used 1686 times. It was applied at a rate of approximately 5% of 2500 new complaints annually, most often (1366 times) for febrile conditions. In 320 consultations for other complaints, 43 different diagnostic protocols were applied. Among them, the "tabula diagnostica" for various undifferentiated symptoms was used most frequently (n = 54), followed by diagnostic protocols for headache (n = 45), dizziness (n = 36), precordial pain (n = 20), nonspecific abdominal pain (n = 15), low back pain (n = 14), hypertension (n = 12), diarrhea > 1 week (n = 12), epigastralgia (n = 11), depression (n = 10), polyarthralgia (n = 8), cough, and lower abdominal pain (each n = 7). A final diagnosis was established in less than 20% of cases. CONCLUSIONS: This observational study from routine practice gives an insight how diagnostic protocols helped to manage complex patient presentations. A broader use of diagnostic protocols could investigate the potential of this consultation tool to handle the complexity of primary health care. The use of a standardized diagnostic approach could stimulate research, in particular on managing common complaints/undifferentiated illness and their inherent diagnostic uncertainty.

Knowledge-guided mutation in classification rules for autism treatment efficacy.

Data mining methods in biomedical research might benefit by combining genetic algorithms with domain-specific knowledge. The objective of this research is to show how the evolution of treatment rules for autism might be guided. The semantic distance between two concepts in the taxonomy is measured by the number of relationships separating the concepts in the taxonomy. The hypothesis is that replacing a concept in a treatment rule will change the accuracy of the rule in direct proportion to the semantic distance between the concepts. The method uses a patient database and autism taxonomies. Treatment rules are developed with an algorithm that exploits the taxonomies. The results support the hypothesis. This research should both advance the understanding of autism data mining in particular and of knowledge-guided evolutionary search in biomedicine in general.

Capturing Provenance, Evolution and Modification of Clinical Protocols via a Heterogeneous, Semantic Social Network.

Healthcare delivery is largely based on medical best practices as in clinical protocols. Research so far has addressed the computerized execution of clinical protocols by developing a number of related representation languages, execution engines and integrated platforms to support real time execution. However, much less effort has been put into organizing clinical protocols for use and reuse. In this paper we propose a heterogeneous semantic social network to describe and organize clinical protocols based on their provenance, evolution and modifications. The proposed approach allows semantic tagging and enrichment of clinical protocols so that they can be used and re-used across platforms and also be linked directly to other relevant scientific information, e.g. published works in PubMed or personal health records, and other clinical information systems.

Measurement of fecal elastase improves performance of newborn screening for cystic fibrosis.

BACKGROUND: The aim of newborn screening (NBS) for CF is to detect children with 'classic' CF where early treatment is possible and improves prognosis. Children with inconclusive CF diagnosis (CFSPID) should not be detected, as there is no evidence for improvement through early treatment. No algorithm in current NBS guidelines explains what to do when sweat test (ST) fails. This study compares the performance of three different algorithms for further diagnostic evaluations when first ST is unsuccessful, regarding the numbers of children detected with CF and CFSPID, and the time until a definite diagnosis. METHODS: In Switzerland, CF-NBS was introduced in January 2011 using an IRT-DNA-IRT algorithm followed by a ST. In children, in whom ST was not possible (no or insufficient sweat), 3 different protocols were applied between 2011 and 2014: in 2011, ST was repeated until it was successful (protocol A), in 2012 we proceeded directly to diagnostic DNA testing (protocol B), and 2013-2014, fecal elastase (FE) was measured in the stool, in order to determine a pancreas insufficiency needing immediate treatment (protocol C). RESULTS: The ratio CF:CFSPID was 7:1 (27/4) with protocol A, 2:1 (22/10) with protocol B, and 14:1 (54/4) with protocol C. The mean time to definite diagnosis was significantly shorter with protocol C (33days) compared to protocol A or B (42 and 40days; p=0.014 compared to A, and p=0.036 compared to B). CONCLUSIONS: The algorithm for the diagnostic part of the newborn screening used in the CF centers is important and affects the performance of a CF-NBS program with regard to the ratio CF:CFSPID and the time until definite diagnosis. Our results suggest to include FE after initial sweat test failure in the CF-NBS guidelines to keep the proportion of CFSPID low and the time until definite diagnosis short.

Acute kidney stress--a useful term based on evolution in the understanding of acute kidney injury.

Critical care physicians have debated an appropriate term for the clinical phase preceding acute kidney injury (AKI). The recent development of cell cycle arrest biomarkers that signal the potential development of AKI is part of an evolution in the molecular diagnosis and understanding of AKI. It is proposed that the pre-injury phase that leads to AKI can be described as "acute kidney stress". This term has the potential to expand horizons in regard to the early detection of situations that will lead to AKI and the early implementation of corrective measures.

An evaluation of different steam disinfection protocols for cystic fibrosis nebulizers.

BACKGROUND: Contamination is a key element in cystic fibrosis. For this reason, nebulizer hygiene is an important, but complex and time-consuming task for cystic fibrosis patients. The aim of this study was to compare different steam disinfection and drying protocols. METHODS: One hundred nebulizer parts were inoculated with cystic fibrosis-related bacteria in high concentrations (Burkholderia multivorans 3.9 × 10(10)/ml, Staphylococcus aureus 8.9 × 10(8/)ml and Pseudomonas aeruginosa 2.1 × 10(9)/ml). Tubes with Mycobacterium abscessus complex were additionally tested. Six steam disinfectors were compared. Different methods of drying were examined. RESULTS: All tested bacteria were efficiently killed by the different steam disinfectors tested. The risk of contamination depended on the method of drying. CONCLUSIONS: Steam disinfection is a safe disinfection method. It is better to leave the nebulizers wet after steam disinfection than to manipulate them by active drying, which seems to be a source of recontamination.

The 2013 Model of the Clinical Practice of Emergency Medicine.

In 2001, "The Model of the Clinical Practice of Emergency Medicine" was first published. This document, the first of its kind, was the result of an extensive practice analysis of emergency department (ED) visits and several expert panels, overseen by representatives from six collaborating professional organizations (the American Board of Emergency Medicine, the American College of Emergency Physicians, the Society for Academic Emergency Medicine, the Residency Review Committee for Emergency Medicine, the Council of Emergency Medicine Residency Directors, and the Emergency Medicine Residents' Association). Every 2 years, the document is reviewed by these organizations to identify practice changes, incorporate new evidence, and identify perceived deficiencies. For this revision, a seventh organization was included, the American Academy of Emergency Medicine.

Presença de marcadores de células-tronco em linhagens celulares humanas de câncer de mama: possível valor em diagnóstico, prognóstico e terapía / Analysis of stem cells markers in human breast cancer cell lines

O câncer de mama é a doença maligna que mais acomete as mulheres no mundo. Apesar dos inúmeros tratamentos, o óbito se deve principalmente à doença metastática que pode se desenvolver a partir do tumor primário. Esta progressão tumoral decorre da dificuldade de se estabelecer um prognóstico mais preciso. Atualmente, a teoria de células iniciadoras de tumor vem sendo estudada para tentar explicar a biologia do câncer e descrever novos alvos para prognósticos e terapias. O carcinoma mamário foi o primeiro tumor sólido para o qual foi identificada uma subpopulação celular, definida como CD44+/CD24-, apresentando as características de células iniciadoras tumorais. Embora este fenótipo venha sendo muito utilizado para descrever as células iniciadoras tumorais de mama, muitos trabalhos tem questionado a relevância clínica desses marcadores, enfatizando que outros marcadores devem ser identificados. Assim, o objetivo deste trabalho é analisar e caracterizar marcadores de células-tronco que possam estar relacionados com o grau de malignidade no modelo de câncer de mama. Inicialmente, analisou-se a expressão de 10 marcadores de células-tronco em diferentes linhagens de câncer de mama que apresentam graus crescentes de malignidade. O CD90 foi selecionado devido à alta expressão desse marcador na linhagem mais agressiva Hs578T. Para a caracterização deste marcador, realizou-se ensaios funcionais, através do silenciamento do CD90 na linhagem tumorigênica Hs579T e sua superexpressão na linhagem não-tumorigênica MCF10A. As linhagens celulares geradas foram caracterizadas quanto ao crescimento celular, potencial invasivo e metastático. Foi possível observar que houve uma alteração da morfologia nas linhagens transformadas com o CD90 e, também, um maior tempo de dobramento na linhagem Hs578T-CD90- e um menor na MCF10A-CD90+. Além disso, a linhagem MCF10-CD90+ foi capaz de crescer independentemente de EGF. Através da análise da via EGF, foi possível observar que houve um aumento da expressão da forma fosforilada do receptor e dos fatores Erk, c-Jun, e Jnk na linhagem MCF10A-CD90+ e uma diminuição dos mesmos na linhagem Hs578T-CD90-. A análise da atividade do elemento responsivo do fator de transcrição AP1 comprovou que a via de EGF é funcional na linhagem MCF10-CD90+. Também foram analisados os marcadores de transição epitélio-mesenquimal, verificando-se aumento da expressão dos marcadores mesenquimais na linhagem MCF10A-CD90+ e diminuição na linhagem Hs578T-CD90-. Os ensaios in vitro de invasão mostraram que as células MCF10-CD90+ são capazes de migrar e invadir e as células Hs578T-CD90- apresentam diminuição significativa da habilidade de migração e invasão. Além disso, os ensaios de metástase in vitro e in vivo, mostraram que a superexpressão de CD90 levou à malignização das células MCF10A. Por outro lado, a linhagem Hs578T-CD90- apresentou menor potencial metastático in vitro. Portanto, neste trabalho, pela primeira vez, o CD 90 foi caracterizado funcionalmente como um marcador envolvido na transformação maligna do carcinoma mamário, contribuindo, assim, para melhor entendimento da biologia do câncer de mama e para que se possa desenvolver novas ferramentas de diagnóstico/prognóstico e novos protocolos clínicos e terapêuticos

Breast cancer is the malignant disease which affects the highest number of women in the world. In spite of the numerous treatments available, death is primarily due to the metastatic disease that may develop from the primary tumor. This tumor progression occurs because of the difficulty in establishing an accurate diagnosis/prognosis. Currently, the tumor initiating cells theory is being applied in an attempt to explain cancer biology and to unveil new diagnostic and therapeutic targets. Mammary carcinoma was the first solid tumor in which a cellular subpopulation, defined as CD44+/CD24-, was associated with tumor initiating cells. Although this phenotype has been widely used to describe breast tumor initiating cells, several studies have questioned the clinical relevance of these markers, emphasizing that additional markers should be identified. The objective of the present study is to analyze and characterize stem cell markers that may be related to malignancy stages in the breast cancer model. Initially, the expression of 10 stem cell markers was analyzed in different breast cancer cell lines displaying different malignancy grades. CD90 was selected due to its high expression levels in the most aggressive cell line, namely: Hs578T. In order to further characterize this marker, a functional study was performed in which CD90 was silenced in the Hs578T tumorigenic cell line and overexpressed in the non-tumorigenic MCF10A cell line. The resulting cell lines were characterized relative to growth rate and invasive and metastatic potential. A change in morphology readily was observed in the cell lines overexpressing CD90. In addition, the Hs578T-CD90-cell line presented an increased doubling time (DT), while the MCF10A-CD90+ cell line displayed a lower DT.. Furthermore, MC10-CD90+ cells were able to grow in the absence of EGF. Analysis of components of the EGF pathwayrevealed increased expression levels of the phosphorylated form of Erk, c-Jun and Jnk receptors in the MCF10-CD90+ cell line, while Hs578T-CD90- cells presented decreased expression of the same factors and receptors. Analysis of the activity of the AP1 responsive element allowed confirmation that the EGF pathway is functional in the MCF10-CD90+. . Epithelial-mesenquimal transition markers presented increased expression levels in the MCF10A-CD90+ cell line, accompanied by decreased expression levels in Hs578T-CD90- cells. In vitro invasion assays showed that MCF10A-CD90+ cells are capable of migrating and invading, while Hs578T-CD90- cells presented a significant decrease in their ability to migrate and invade. Additionally, in vitro and in vivo metastasis assays showed that malignization ensued upon overexpression of CD90 in MCF10A cells and a lower tendency to form metastasis in vitro was observed for the Hs578T-CD90- cell line. Therefore, the present study presents, for the first time in the literature, the functional characterization of CD90 as a genetic marker involved in the malignant transformation of mammary carcinoma, leading to a better understanding of the breast cancer biology, which may, in turn, lead to the development of new clinical and therapeutic protocols

Protocolo de Manchester na Atenção Primária à Saúde: visão de profissionais, usuários e gestores / Manchester Triage System in Primary Health Care: a view from professionals, users and managers

o presente estudo teve como objetivo compreender a visão de profissionais, usuários e gestores sobre o Protocolo de Manchester na Atenção Primária à Saúde, no município de Sarzedo, localizado na região metropolitana de Belo Horizonte - MG. Constituíram o estudo sete enfermeiros, onze técnicos de enfermagem, quatro médicos e dezessete usuários, perfazendo 39 participantes. Os participantes foram divididos em dois grupos: os primários - enfermeiros; e os secundários - técnicos de enfermagem , médicos e usuários. A pesquisa foi aprovada pelo Comitê de Ética em Pesquisa da UFMG (Parecer: 535.523) e pela secretaria de saúde do município de Sarzedo por meio de carta de anuência. Trata -sede uma pesquisa de natureza qualitativa, na qual a coleta de dados foi realizada no período de março a maio de 2014, sendo utilizada a entrevista com roteiro semiestruturado e observação, após a aquiescência dos sujeitos e assinatura do Termo de Consentimento Livre e Esclarecido (TCLE). Para a análise dos dados, utilizou-se a técnica de análise de conteúdo proposta por Bardin (2009). Os resultados foram organizados em três categorias, a saber: Compreendendo a utilização e implantação do Protocolo de Manchester na Atenção Primária à Saúde; Protocolo de Manchester na Atenção Primária à Saúde e nos Serviços de urgência - "pra urgência, é perfeito, mas na Atenção Básica não rola"; Protocolo de Manchester na Atenção Primária à Saúde na visão do ser cuidado. A análise dos dados permitiu identificar desafios e potencialidades que permeiam a utilização do Protocolo de Manchester na APS. Os participantes salientaram a importância de se instituir critérios para a classificação de risco de usuários que buscam atendimento no primeiro nível de assistência, no entanto, criticaram e consideraram insuficiente utilizar um sistema de triagem desenvolvido para os serviços de urgência e emergência...

The present study is aimed at understanding the point of view from professionals, users and managers of the Manchester Triage System in Primary Health Care in the city of Sarzedo, located in the metropolitan area of Belo Horizonte, Minas Gerais. The study consisted of seven nurses, eleven nursing technicians, four doctors and seventeen users; bringing the total of 39 participants. The participants were divided into two groups: the primary one - nurses; and the secondary one - nursing technicians, doctors and users. This research was approved by the Ethics Committee of UFMG (protocol number: 535.523) and by the Health Secretariat of Sarzedo, made through concession letter. It is a qualitative approach research, in which data collection was carried out within the months of March and May in 2014. Observation and a semi-structured survey questionnaire were used in the interview only afier its participants' consent and their signature on the Informed Consent Fonn ( ICF). In order to do the data analysis, it was used the content analysis technique proposed by Bardin (2009). The results were organized into three categories: Understanding the use and the implantation of the Manchester Triage System in Primary Health Care; Manchester Triage System in Primary Health Care and in Emergency Services- "It works perfectly for the Emergency Care, but in Primary Care it doesn't work at all"; Manchester Triage System in Primary Health Care the view from the one who is being assisted. The data analysis allowed us to identify the challenges and potentialities that permeate the use of the Manchester Triage System in Primary Health Care. The participants stressed the importance of establishing criteria when it comes to the users' risk classification for the ones who look for assistance in a Primary Care level. However, they also criticized the system and regarded it as insufficient, once it was developed to meet the Urgency and Emergency...

A method for discovering and inferring appropriate eligibility criteria in clinical trial protocols without labeled data.

BACKGROUND: We consider the user task of designing clinical trial protocols and propose a method that discovers and outputs the most appropriate eligibility criteria from a potentially huge set of candidates. Each document d in our collection D is a clinical trial protocol which itself contains a set of eligibility criteria. Given a small set of sample documentsD',|D'|≪|D|, a user has initially identified as relevant e.g., via a user query interface, our scoring method automatically suggests eligibility criteria from D, D ⊃ D', by ranking them according to how appropriate they are to the clinical trial protocol currently being designed. The appropriateness is measured by the degree to which they are consistent with the user-supplied sample documents D'. METHOD: We propose a novel three-step method called LDALR which views documents as a mixture of latent topics. First, we infer the latent topics in the sample documents using Latent Dirichlet Allocation (LDA). Next, we use logistic regression models to compute the probability that a given candidate criterion belongs to a particular topic. Lastly, we score each criterion by computing its expected value, the probability-weighted sum of the topic proportions inferred from the set of sample documents. Intuitively, the greater the probability that a candidate criterion belongs to the topics that are dominant in the samples, the higher its expected value or score. RESULTS: Our experiments have shown that LDALR is 8 and 9 times better (resp., for inclusion and exclusion criteria) than randomly choosing from a set of candidates obtained from relevant documents. In user simulation experiments using LDALR, we were able to automatically construct eligibility criteria that are on the average 75% and 70% (resp., for inclusion and exclusion criteria) similar to the correct eligibility criteria. CONCLUSIONS: We have proposed LDALR, a practical method for discovering and inferring appropriate eligibility criteria in clinical trial protocols without labeled data. Results from our experiments suggest that LDALR models can be used to effectively find appropriate eligibility criteria from a large repository of clinical trial protocols.

Understanding protocol performance: impact of criterion and test correlation.

BACKGROUND: A test protocol is created when individual tests are combined. Protocol performance can be calculated prior to clinical use; however, the necessary information is seldom available. Thus, protocols are frequently used with limited information as to performance. The next best strategy is to base protocol design on available information combined with a thorough understanding of the factors that determine protocol performance. Unfortunately, there is limited information as to these factors and how they interact. PURPOSE: The objective of this article and the next article in this issue is to examine in detail the three factors that determine protocol performance: (1) protocol criterion, (2) test correlation, (3) test performance. This article examines protocol criterion and test correlation. The next article examines the impact of individual test performance and summarizes the results of this series. The ultimate goal is to provide guidance on the formulation of a protocol using available information and an understanding of the impact of these three factors on performance. RESEARCH DESIGN: A mathematical model is used to calculate protocol performance for different protocol criteria and test correlations while assuming that all individual tests in the protocol have the same performance. The advantages and disadvantages of the different criteria are evaluated for different test correlations. RESULTS: A loose criterion will produce the highest protocol hit and false alarm rates; however, the false alarm rate may be unacceptably high. A strict criterion will produce the smallest protocol hit and false alarm rates; however, the hit rate may be unacceptably low. Adding tests to a protocol increases the probability that the protocol false alarm rate will be too high with a loose criterion and that the protocol hit rate will be too low with a strict criterion. The intermediate criterion, about which little has been known, provides advantages not available with the other two criteria. This criterion is much more likely to produce acceptable protocol hit and false alarm rates. It also has the potential to simultaneously produce a protocol hit rate higher, and a false alarm rate lower, than the individual tests. The intermediate criteria produce better protocol performance than the loose and strict criteria for protocols with the same number of tests. For all criteria, best protocol performance is obtained when the tests are uncorrelated and decreases as test correlation increases. When there is some test correlation, adding tests to the protocol can decrease protocol performance for a loose or strict criterion. The ability of a protocol to manipulate hit and false alarm rates, or improve performance relative to that of the individual tests, is reduced with increasing test correlation. CONCLUSIONS: The three criteria, loose, strict, and intermediate, have definite advantages and disadvantages over a large range of test correlations. Some of the advantages and disadvantages of the loose and strict criteria are impacted by test correlation. The advantages of the intermediate criteria are relatively independent of test correlation. When three or more tests are used in a protocol, consideration should be given to using an intermediate criterion, particularly if there is some test correlation. Greater test correlation diminishes the advantages of adding tests to a protocol, particularly with a loose or strict criterion. At higher test correlations, fewer tests in the protocol may be appropriate.