Beneficios del preoperatorio con recuperación acelerada en pacientes operados de colon por cirugía electiva / Preoperative Benefits with Accelerated Recovery on Patients Operated on for Colon Cancer by Elective Surgery

Introducción: Con la introducción del programa de recuperación acelerada en el servicio de Cirugía General del Hospital Militar de Ejército "Dr. Mario Muñoz Monroy" han ocurrido cambios en la atención perioperatoria del paciente con cirugía electiva para el cáncer de colon. Es de vital importancia conocer sus beneficios en relación al procedimiento tradicional desde que se decide la intervención quirúrgica. Objetivo: Evaluar los beneficios de la recuperación acelerada en pacientes operados de colon por cirugía electiva. Métodos: Se realizó un estudio analítico de caso y control durante el período de enero de 2015 a diciembre de 2019. El grupo de casos cumplió con 12 acciones perioperatorias definidas por el programa de recuperación acelerada y el de control siguió el procedimiento tradicional. Se realizó análisis bivariable de Chi cuadrado y Odds Ratio con intervalo de confianza del 95 por ciento. Resultados: Con la implementación del programa de recuperación acelerada desde el preoperatorio, los pacientes llegaron a la cirugía con adecuada capacidad funcional y compensación de sus comorbilidades. Esta conducta favoreció la evolución posoperatoria, redujo las complicaciones en un 33 por ciento Odds Ratio de 0,05 y la estadía hospitalaria en 5,67 días con Odds Ratio de 2[10,4-5,1]. Conclusiones: Los pacientes con el procedimiento de recuperación acelerada en su preoperatorio recibieron beneficios en relación a reducir el estrés quirúrgico, mayores reservas fisiológicas y mejor recuperación posoperatoria. La estadía hospitalaria está asociada significativamente a la edad de los pacientes, las comorbilidades y número de estas(AU)

Introduction: With the introduction of the accelerated recovery program in the general surgery service of Dr. Mario Muñoz Monroy Military Hospital of the Army (Matanzas, Cuba), changes have occurred in the perioperative care of the patient with elective surgery for colon cancer. It is of vital importance to know its benefits with respect to the traditional procedure from the moment the surgical intervention is decided. Objective: To assess the benefits of accelerated recovery in patients undergoing elective colon surgery. Methods: An analytical case-control study was carried out during the period from January 2015 to December 2019. The case group completed 12 perioperative actions defined by the accelerated recovery program, while the control group followed the traditional procedure. A bivariate analysis of chi-square and odds ratio (OR) with 95 percent confidence interval was performed. Results: With the implementation of the accelerated recovery program from the preoperative period, patients arrived at surgery with adequate functional capacity and compensation of their comorbidities. This behavior favored postoperative evolution, reduced complications by 33 percent (OR: 0.05) and hospital stay by 5.67 days (OR: 2) [10.4-5.1]. Conclusions: With the accelerated recovery procedure in their preoperative period, patients received benefits associated with reduced surgical stress, greater physiological reserves and better postoperative recovery. Hospital stay is significantly associated with patient age, comorbidities and number of comorbidities(AU)

Implementing the meta-analytic approach for the evaluation of surrogate endpoints in SAS and R: a word of caution.

The meta-analytic approach has become the gold-standard methodology for the evaluation of surrogate endpoints and several implementations are currently available in SAS and R. The methodology is based on hierarchical models that are numerically demanding and, when the amount of data is limited, maximum likelihood algorithms may not converge or may converge to an ill-conditioned maximum such as a boundary solution. This may produce misleading conclusions and have negative implications for the evaluation of new drugs. In the present work, we explore the use of two distinct functions in R (lme and lmer) and the MIXED procedure in SAS to assess the validity of putative surrogate endpoints in the meta-analytic framework, via simulations and the analysis of a real case study. We describe some problems found with the lmer function in R that led to a poorer performance as compared with the lme function and MIXED procedure.

Identifying individual predictive factors for treatment efficacy.

Given the heterogeneous responses to therapy and the high cost of treatments, there is an increasing interest in identifying pretreatment predictors of therapeutic effect. Clearly, the success of such an endeavor will depend on the amount of information that the patient-specific variables convey about the individual causal treatment effect on the response of interest. In the present work, using causal inference and information theory, a strategy is proposed to evaluate individual predictive factors for cancer immunotherapy efficacy. In a first step, the methodology proposes a causal inference model to describe the joint distribution of the pretreatment predictors and the individual causal treatment effect. Further, in a second step, the so-called predictive causal information (PCI), a metric that quantifies the amount of information the pretreatment predictors convey on the individual causal treatment effects, is introduced and its properties are studied. The methodology is applied to identify predictors of therapeutic success for a therapeutic vaccine in advanced lung cancer. A user-friendly R library EffectTreat is provided to carry out the necessary calculations.

Quiste de Gartner de localización uterina / Gartner's cyst of uterine location

RESUMEN Los quistes de los conductos de Gartner, generalmente pequeños, benignos y asintomáticos, son vestigios del canal mesonéfrico de Wolff. Representan el 11 % de los quistes vaginales, esta es su localización más frecuente según la literatura consultada. Se presentó un caso operado en el Hospital Militar de Matanzas "Dr. Mario Muñoz Monroy", de localización en la cara posterior del istmo uterino (AU).

ABSTRAC Gartner's duct cyst, mostly little, benign and asymptomatic, are vestiges of the Wolffian mesonephric duct representing 11 % of the vaginal cysts; this location is the most frequently reported and published one up to date. The authors presented the case of a patient who underwent a surgery in the Military Hospital "Dr. Mario Muñoz Monroy¨ with a cyst in the posterior side of the uterine isthmus (AU).

On the relationship between association and surrogacy when both the surrogate and true endpoint are binary outcomes.

The relationship between association and surrogacy has been the focus of much debate in the surrogate marker literature. Recently, the individual causal association (ICA) has been introduced as a metric of surrogacy in the causal inference framework, when both the surrogate and the true endpoint are normally distributed and when both are binary. Earlier work on the normal case has demonstrated that, although the ICA and the adjusted association are related metrics, their relationship strongly depends on unidentifiable parameters and, consequently, the association between both endpoints conveys little information on the validity of the surrogate. In addition, in the normal setting, the magnitude of the ICA does not depend on the mean of the outcomes. The latter implies that identifiable parameters such as mean responses and treatment effects provide no information on the validity of the surrogate. In the present work it is shown that this is fundamentally different in the binary case. We demonstrate that the observed association between the outcomes as well as the success rates in both treatment groups are quite predictive for the ICA. It is shown that finding a good surrogate will be more likely when the association between the endpoints is large, there are sizeable treatment effects and the success rates for both endpoints are similar in both treatment groups. These results are demonstrated using extensive simulations and illustrated on a case study in multi-drug resistant tuberculosis.

Identifying predictive biomarkers of CIMAvaxEGF success in non-small cell lung cancer patients.

BACKGROUND: Immunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non-Small Cell Lung Cancer Patients. METHODS: Data from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success. RESULTS: The mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders. CONCLUSIONS: Peripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.

A reflection on the causal interpretation of individual-level surrogacy.

At the beginning of the 21st century, a new paradigm was introduced for the evaluation of surrogate endpoints based on meta-analysis. In this paradigm, the putative surrogate is assessed at two different levels, the so-called, trial and individual level. Trial level surrogacy is defined as the association between the expected causal treatment effects across different trials populations, whereas the individual level is defined as the association between the surrogate and true endpoints, after adjusting by trial and treatment. It has been argued that the individual level surrogacy does not have a causal interpretation and, consequently, it is a poor metric of surrogacy. In the present work, an alternative definition of individual level surrogacy is introduced based on individual causal treatment effects. In addition, using the maximum entropy principle, a direct link between the individual level surrogacy, as defined in the meta-analytic approach, and the newly proposed definition is established. This new perspective sets the individual level surrogacy in a more coherent framework with respect to the trial level and bridges the two main schools of thought in this domain, namely, the causal inference and meta-analytic schools.

A reflection on the possibility of finding a good surrogate.

Surrogate endpoints need to be statistically evaluated before they can be used as substitutes of true endpoints in clinical studies. However, even though several evaluation methods have been introduced over the last decades, the identification of good surrogate endpoints remains practically and conceptually challenging. In the present work, the question regarding the existence of a good surrogate is addressed using information-theoretic concepts, within a causal-inference framework. The methodology can help practitioners to assess, given a clinically relevant true endpoint and a treatment of interest, the chances of finding a good surrogate endpoint in the first place. The methodology focuses on binary outcomes and is illustrated using data from the Initial Glaucoma Treatment Study. Furthermore, a newly developed and user friendly R package Surrogate is provided to carry out the necessary calculations.

Assessing the predictive value of a binary surrogate for a binary true endpoint based on the minimum probability of a prediction error.

The individual causal association (ICA) has recently been introduced as a metric of surrogacy in a causal-inference framework. The ICA is defined on the unit interval and quantifies the association between the individual causal effect on the surrogate (ΔS) and true (ΔT) endpoint. In addition, the ICA offers a general assessment of the surrogate predictive value, taking value 1 when there is a deterministic relationship between ΔT and ΔS, and value 0 when both causal effects are independent. However, when one moves away from the previous two extreme scenarios, the interpretation of the ICA becomes challenging. In the present work, a new metric of surrogacy, the minimum probability of a prediction error (PPE), is introduced when both endpoints are binary, ie, the probability of erroneously predicting the value of ΔT using ΔS. Although the PPE has a more straightforward interpretation than the ICA, its magnitude is bounded above by a quantity that depends on the true endpoint. For this reason, the reduction in prediction error (RPE) attributed to the surrogate is defined. The RPE always lies in the unit interval, taking value 1 if prediction is perfect and 0 if ΔS conveys no information on ΔT. The methodology is illustrated using data from two clinical trials and a user-friendly R package Surrogate is provided to carry out the validation exercise.

A maximum entropy approach for the evaluation of surrogate endpoints based on causal inference.

The maximum entropy principle offers a constructive criterion for setting up probability distributions on the basis of partial knowledge. In the present work, the principle is applied to tackle an important problem in the surrogate marker field, namely, the evaluation of a binary outcome as a putative surrogate for a binary true endpoint within a causal inference framework. In the first step, the maximum entropy principle is used to determine the relative frequencies associated with the values of the vector of potential outcomes. Subsequently, in the second step, these relative frequencies are used in combination with two newly proposed metrics of surrogacy, the so-called individual causal association and the surrogate predictive function, to assess the validity of the surrogate. The procedure is conceptually similar to the use of noninformative or reference priors in Bayesian statistics. Additionally, approximate, identifiable bounds are proposed for the estimands of interest, and their performance is studied via simulations. The methods are illustrated using data from a clinical trial involving schizophrenic patients, and a newly developed and user-friendly R package Surrogate is provided to carry out the validation exercise.

Enfermedad relacionada con IgG4 a propósito de dos casos / Disease related to IgG4. Apropos of two cases

RESUMEN La enfermedad relacionada con IgG4 (ER-IgG4), es una enfermedad autoinmune multisistémica caracterizada por lesiones fibroesclerosantes inflamatorias formadoras de masas o pseudotumores, concentraciones elevadas de IgG4 séricas e infiltración tisular extensa por células plasmáticas IgG4 positivas. Incluye numerosas entidades que previamente se consideraban órgano-específicas. Puede afectar prácticamente a cualquier órgano, siendo los más afectados páncreas, glándulas salivales, glándulas lacrimales, ganglios linfáticos, retroperitoneo y riñones. El diagnóstico se realiza mediante una combinación de hallazgos clínicos, serológicos, imagenológicos e histopatológicos. Tiene pronóstico reservado pero con un diagnóstico precoz se logra el control y en ocasiones la regresión de la enfermedad, aunque tiende a presentar recaídas. Es una entidad infradiagnosticada debido en parte, a que fue caracterizada recientemente. Se presentan dos casos que forman parte del espectro que abarca esta entidad, la tiroiditis de Riedel y la fibrosis retroperitoneal, que una vez diagnosticados respondieron inicialmente a la terapéutica con altas dosis de corticoides (AU).

ABSTRACT The disease related to IgG4 (ER-IgG4 in Spanish) is a multi-systemic, autoimmune disease characterized by inflammatory fibro-sclerotizing lesions forming masses or pseudo tumors, high concentrations of serum IgG4 and extensive tissue infiltrations by IgG4-positive plasma cells. It includes several entities previously considered organ-specific ones. It can affect almost any organ, being pancreas, salivary glands, lacrimal glands, lymphatic ganglion, retroperineum and kidneys the most affected ones. The diagnosis is made through combining clinical, serologic, imaging and histopathological findings. It has a reserved prognosis but with an early diagnosis its control is reached, and occasionally also the disease's remission, although it tends to have relapses. It is an underdiagnosed disease, partially due to its recent characterization. We present two cases entering the range covered by this disease, the Riedel's thyroiditis and retroperitoneal fibrosis, both initially answering to therapy with high doses of corticoids after diagnosis (AU).

Enfermedad relacionada con IgG4 a propósito de dos casos / Disease related to IgG4. Apropos of two cases

RESUMEN La enfermedad relacionada con IgG4 (ER-IgG4), es una enfermedad autoinmune multisistémica caracterizada por lesiones fibroesclerosantes inflamatorias formadoras de masas o pseudotumores, concentraciones elevadas de IgG4 séricas e infiltración tisular extensa por células plasmáticas IgG4 positivas. Incluye numerosas entidades que previamente se consideraban órgano-específicas. Puede afectar prácticamente a cualquier órgano, siendo los más afectados páncreas, glándulas salivales, glándulas lacrimales, ganglios linfáticos, retroperitoneo y riñones. El diagnóstico se realiza mediante una combinación de hallazgos clínicos, serológicos, imagenológicos e histopatológicos. Tiene pronóstico reservado pero con un diagnóstico precoz se logra el control y en ocasiones la regresión de la enfermedad, aunque tiende a presentar recaídas. Es una entidad infradiagnosticada debido en parte, a que fue caracterizada recientemente. Se presentan dos casos que forman parte del espectro que abarca esta entidad, la tiroiditis de Riedel y la fibrosis retroperitoneal, que una vez diagnosticados respondieron inicialmente a la terapéutica con altas dosis de corticoides (AU).

ABSTRACT The disease related to IgG4 (ER-IgG4 in Spanish) is a multi-systemic, autoimmune disease characterized by inflammatory fibro-sclerotizing lesions forming masses or pseudo tumors, high concentrations of serum IgG4 and extensive tissue infiltrations by IgG4-positive plasma cells. It includes several entities previously considered organ-specific ones. It can affect almost any organ, being pancreas, salivary glands, lacrimal glands, lymphatic ganglion, retroperineum and kidneys the most affected ones. The diagnosis is made through combining clinical, serologic, imaging and histopathological findings. It has a reserved prognosis but with an early diagnosis its control is reached, and occasionally also the disease’s remission, although it tends to have relapses. It is an underdiagnosed disease, partially due to its recent characterization. We present two cases entering the range covered by this disease, the Riedel’s thyroiditis and retroperitoneal fibrosis, both initially answering to therapy with high doses of corticoids after diagnosis (AU).

Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial.

The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials.gov number, NCT00449644) including 160 patients randomized 1:1 to receive bedaquiline or placebo for 24 weeks when added to an 18-24-month preferred five-drug background regimen. Since randomization in C208 Stage II was preserved until study end, the trial results allow for the investigation of the complex relationship between sustained durable outcome with either Week 8 or Week 24 culture conversion as putative surrogate endpoints. The relationship between Week 120 outcome with Week 8 or Week 24 culture conversion was investigated using a descriptive analysis and with a recently developed statistical methodology for surrogate endpoint evaluation using methods of causal inference. The results demonstrate that sputum culture conversion at 24 weeks is more reliable than sputum culture conversion at 8 weeks when assessing the outcome of adding one new drug to a MDR-TB regimen.

Comportamiento de la hemorragia digestiva alta en el quinquenio 2009 a 2013 / Behavior of the high digestive bleeding in the five-year period 2009-2013

Introducción: la hemorragia digestiva alta constituye un problema frecuente de salud en el mundo; así se comporta en Cuba, en la provincia Matanzas y en el hospital de estudio. Actualmente es considerada como causa mayor de morbimortalidad. Objetivo: determinar el comportamiento de la hemorragia digestiva alta en el Hospital Militar de Matanzas. Materiales y Métodos: se realizó una investigación descriptiva, en un periodo de cinco años que incluyó a todos los pacientes ingresados con ese diagnóstico, y los que durante su ingreso por otra causa presentaron episodios de hemorragia. El índice de Rockall permitió evaluar la necesidad de cirugía, recidiva y mortalidad. Resultados: la mayoría de los pacientes pertenecieron al grupo de riesgo intermedio. Los hombres fueron los más afectados, el grupo de tercera edad presentó mayor incidencia. La gastritis hemorrágica fue la primera causa de sangrado. La hipertensión arterial resultó ser el factor de riesgo relevante y el tabaquismo el hábito tóxico más frecuente. Conclusiones: como beneficio relevante se demostró la importancia de la endoscopia precoz para el diagnóstico de la causa, tratamiento y pronóstico de la hemorragia. Se observó una buena correlación entre el pronóstico del paciente al ingreso y su estado al final del tratamiento (AU).

Introduction: the high digestive hemorrhage is a frequent health problem in the world; it behaves the same in Cuba, in the province of Matanzas and in the hospital where the study was carried out. Currently it is considered a major cause of morbi-mortality. Objective: to determine the behavior of the high digestive bleeding in the Military Hospital of Matanzas. Materials and Methods: a descriptive research was carried out in a five-year period. It included all the patients admitted with that diagnosis and those who presented episodes of hemorrhage even if they were admitted by any other cause. The Rockall index allowed to assess the necessity of surgery, the recidivism and mortality. Results: most of the patients belonged to the intermediate risk group. Male patients were the most affected one; the group of elder people showed higher incidence. Hemorrhagic gastritis was the first cause of bleeding. Arterial hypertension was the relevant risk factor and smoking the most frequent toxic habit. Conclusions: as a relevant benefit it was showed the importance of precocious endoscopy for the diagnosis of the hemorrhage cause, treatment and prognosis. It was observed a good correlation between the patient´s prognosis at the admission and his status at the end of the treatment (AU).

Comportamiento de la hemorragia digestiva alta en el quinquenio 2009 a 2013 / Behavior of the high digestive bleeding in the five-year period 2009-2013

Introducción: la hemorragia digestiva alta constituye un problema frecuente de salud en el mundo; así se comporta en Cuba, en la provincia Matanzas y en el hospital de estudio. Actualmente es considerada como causa mayor de morbimortalidad. Objetivo: determinar el comportamiento de la hemorragia digestiva alta en el Hospital Militar de Matanzas. Materiales y Métodos: se realizó una investigación descriptiva, en un periodo de cinco años que incluyó a todos los pacientes ingresados con ese diagnóstico, y los que durante su ingreso por otra causa presentaron episodios de hemorragia. El índice de Rockall permitió evaluar la necesidad de cirugía, recidiva y mortalidad. Resultados: la mayoría de los pacientes pertenecieron al grupo de riesgo intermedio. Los hombres fueron los más afectados, el grupo de tercera edad presentó mayor incidencia. La gastritis hemorrágica fue la primera causa de sangrado. La hipertensión arterial resultó ser el factor de riesgo relevante y el tabaquismo el hábito tóxico más frecuente. Conclusiones: como beneficio relevante se demostró la importancia de la endoscopia precoz para el diagnóstico de la causa, tratamiento y pronóstico de la hemorragia. Se observó una buena correlación entre el pronóstico del paciente al ingreso y su estado al final del tratamiento (AU).

Introduction: the high digestive hemorrhage is a frequent health problem in the world; it behaves the same in Cuba, in the province of Matanzas and in the hospital where the study was carried out. Currently it is considered a major cause of morbi-mortality. Objective: to determine the behavior of the high digestive bleeding in the Military Hospital of Matanzas. Materials and Methods: a descriptive research was carried out in a five-year period. It included all the patients admitted with that diagnosis and those who presented episodes of hemorrhage even if they were admitted by any other cause. The Rockall index allowed to assess the necessity of surgery, the recidivism and mortality. Results: most of the patients belonged to the intermediate risk group. Male patients were the most affected one; the group of elder people showed higher incidence. Hemorrhagic gastritis was the first cause of bleeding. Arterial hypertension was the relevant risk factor and smoking the most frequent toxic habit. Conclusions: as a relevant benefit it was showed the importance of precocious endoscopy for the diagnosis of the hemorrhage cause, treatment and prognosis. It was observed a good correlation between the patient´s prognosis at the admission and his status at the end of the treatment (AU).

Assessing a surrogate predictive value: a causal inference approach.

Several methods have been developed for the evaluation of surrogate endpoints within the causal-inference and meta-analytic paradigms. In both paradigms, much effort has been made to assess the capacity of the surrogate to predict the causal treatment effect on the true endpoint. In the present work, the so-called surrogate predictive function (SPF) is introduced for that purpose, using potential outcomes. The relationship between the SPF and the individual causal association, a new metric of surrogacy recently proposed in the literature, is studied in detail. It is shown that the SPF, in conjunction with the individual causal association, can offer an appealing quantification of the surrogate predictive value. However, neither the distribution of the potential outcomes nor the SPF are identifiable from the data. These identifiability issues are tackled using a two-step procedure. In the first step, the region of the parametric space of the distribution of the potential outcomes, compatible with the data at hand, is geometrically characterized. Further, in a second step, a Monte Carlo approach is used to study the behavior of the SPF on the previous region. The method is illustrated using data from a clinical trial involving schizophrenic patients and a newly developed and user friendly R package Surrogate is provided to carry out the validation exercise. Copyright © 2016 John Wiley & Sons, Ltd.

Properties of Estimators in Exponential Family Settings with Observation-based Stopping Rules.

Often, sample size is not fixed by design. A key example is a sequential trial with a stopping rule, where stopping is based on what has been observed at an interim look. While such designs are used for time and cost efficiency, and hypothesis testing theory has been well developed, estimation following a sequential trial is a challenging, still controversial problem. Progress has been made in the literature, predominantly for normal outcomes and/or for a deterministic stopping rule. Here, we place these settings in a broader context of outcomes following an exponential family distribution and, with a stochastic stopping rule that includes a deterministic rule and completely random sample size as special cases. It is shown that the estimation problem is usually simpler than often thought. In particular, it is established that the ordinary sample average is a very sensible choice, contrary to commonly encountered statements. We study (1) The so-called incompleteness property of the sufficient statistics, (2) A general class of linear estimators, and (3) Joint and conditional likelihood estimation. Apart from the general exponential family setting, normal and binary outcomes are considered as key examples. While our results hold for a general number of looks, for ease of exposition, we focus on the simple yet generic setting of two possible sample sizes, N=n or N=2n.

Biomarkers in Exhaled Breath Condensate Are Not Predictive for Pulmonary Exacerbations in Children with Cystic Fibrosis: Results of a One-Year Observational Study.

BACKGROUND: Cystic Fibrosis (CF) is characterized by chronically inflamed airways, and inflammation even increases during pulmonary exacerbations. These adverse events have an important influence on the well-being, quality of life, and lung function of patients with CF. Prediction of exacerbations by inflammatory markers in exhaled breath condensate (EBC) combined with early treatment may prevent these pulmonary exacerbations and may improve the prognosis. AIM: To investigate the diagnostic accuracy of a set of inflammatory markers in EBC to predict pulmonary exacerbations in children with CF. METHODS: In this one-year prospective observational study, 49 children with CF were included. During study visits with an interval of 2 months, a symptom questionnaire was completed, EBC was collected, and lung function measurements were performed. The acidity of EBC was measured directly after collection. Inflammatory markers interleukin (IL)-6, IL-8, tumor necrosis factor α (TNF-α), and macrophage migration inhibitory factor (MIF) were measured using high sensitivity bead based flow immunoassays. Pulmonary exacerbations were recorded during the study and were defined in two ways. The predictive power of inflammatory markers and the other covariates was assessed using conditionally specified models and a receiver operating characteristic curve (SAS version 9.2). In addition, k-nearest neighbors (KNN) algorithm was applied (SAS version 9.2). RESULTS: Sixty-five percent of the children had one or more exacerbations during the study. The conditionally specified models showed an overall correct prediction rate of 55%. The area under the curve (AUC) was equal to 0.62. The results obtained with the KNN algorithm were very similar. CONCLUSION: Although there is some evidence indicating that the predictors outperform random guessing, the general diagnostic accuracy of EBC acidity and the EBC inflammatory markers IL-6, IL-8, TNF-α and MIF is low. At present it is not possible to predict pulmonary exacerbations in children with CF with the chosen biomarkers and the method of EBC analysis. The biochemical measurements of EBC markers should be improved and other techniques should be considered.

An information-theoretic approach for the evaluation of surrogate endpoints based on causal inference.

In this work a new metric of surrogacy, the so-called individual causal association (ICA), is introduced using information-theoretic concepts and a causal inference model for a binary surrogate and true endpoint. The ICA has a simple and appealing interpretation in terms of uncertainty reduction and, in some scenarios, it seems to provide a more coherent assessment of the validity of a surrogate than existing measures. The identifiability issues are tackled using a two-step procedure. In the first step, the region of the parametric space of the distribution of the potential outcomes, compatible with the data at hand, is geometrically characterized. Further, in a second step, a Monte Carlo approach is proposed to study the behavior of the ICA on the previous region. The method is illustrated using data from the Collaborative Initial Glaucoma Treatment Study. A newly developed and user-friendly R package Surrogate is provided to carry out the evaluation exercise.

Exploring the relationship between the causal-inference and meta-analytic paradigms for the evaluation of surrogate endpoints.

Nowadays, two main frameworks for the evaluation of surrogate endpoints, based on causal-inference and meta-analysis, dominate the scene. Earlier work showed that the metrics of surrogacy introduced in both paradigms are related, although in a complex way that is difficult to study analytically. In the present work, this relationship is further examined using simulations and the analysis of a case study. The results indicate that the extent to which both paradigms lead to similar conclusions regarding the validity of the surrogate, depends on a complex interplay between multiple factors like the ratio of the between and within trial variability and the unidentifiable correlations between the potential outcomes. All the analyses were carried out using the newly developed R package Surrogate, which is freely available via CRAN.