Missing data in clinical trials

There is a need to plan an appropriate statistical analysis of missing data for researchers working in clinical trials in HIV. Based on it, the main objectives of this thesis are: - Review the different typologies of missing data in clinical trials in HIV. - Explore the most important methods used to handle missing data, describe the advantages and disadvanteges, apply some of these methods to the Lluta Fundacio' study and implement in the R environment one of the new approaches. - Generate some guidelines that should be followed by researchers working in clinical trials (in particular in the Lluita Fundacio') and give some recommendation when it would be better to use a method instead of another according to the estimates and confidence intervals.El projecte que s'ofereix té com a principal motivació desenvolupar un pla per a la correcta anàlisi estadística de dades en presència de valors mancants o missings. S'aplicarà i estudiarà en el contexte dels estudis clínics que es desenvolupen a la Fundació de Lluita contra la SIDA (http://www.flsida.org). Es donen dades mancants per moltes causes i la problemàtica es dona tant en estudis longitudinals com transversals, observacionals o experimentals. L'estudiant haurà d¿abordar els següents aspectes: Determinar quin tipus de dades mancants afecten als estudis de recerca en VIH que es duen a terme a la FLS, tant a les covariants fixes (basals i retrospectives) com a les longitudinals. S¿estudiarà la metodologia més rellevant per fer inferència amb dades mancants. S'aplicaran algunes d'aquestes metodologies a alguns dels estudis de la FLS distingint les anàlisis segons el tipus d¿estudi i el patró per les dades mancants

The economic cost to households of childhood malaria in Papua New Guinea: a focus on intra-country variation

Background We compare direct and indirect household costs associated with malaria treatment for children <3 years in two provinces of Papua New Guinea. In particular, we explore the role of uncertainty around mean household costs and whether assuming a normal distribution for household costs limits the accuracy of any direct cost comparisons. Methods Exit surveys were undertaken at inpatient and outpatient health facilities. In order to handle uncertainty and facilitate comparisons, parametric and non-parametric bootstrap methods were used to estimate direct and indirect costs at the individual data level. The inpatient and outpatient incremental costs from Madang and Maprik health facilities were compared and significant differences between provinces were identified. Results Differences were noted between provinces for both inpatient and outpatient household costs. Total arithmetic mean costs for an outpatient malaria episode were US$7.54 in Madang and US$9.20 in Maprik. Total mean inpatient malaria episode costs were US$25.20 in Madang and US$14.08 in Maprik. As cost distributions were not normal, non-parametric bootstrap techniques were used for cost comparisons. Total household costs per outpatient episode of malaria were lower, although not significantly, in Maprik than in Madang (incremental cost of US$−1.67; 95$11.16; 95% CI 5.47, 25.33). A difference was noted between provinces in the proportion of indirect costs in total household costs for an outpatient visit: 76% in Madang vs 94% in Maprik. The proportion for indirect costs associated with inpatient visits varied less: 63% in Madang vs 68% in Maprik. Conclusions Intra-country differences need to be considered in estimating household costs for both outpatient and inpatient malaria treatment. Our findings suggest that it is important to recognize the impact of both direct and indirect costs on individuals' capacity to afford treatment. Certain indirect costs are difficult to measure accurately, particularly respondents' interpretations of their productive versus non-productive time. Despite this, exploring intra-country cost variation can provide important information to health policy maker

Longitudinal investigation of the parietal lobe anatomy in bipolar disorder and its association with general functioning

The parietal lobe (PL) supports cognitive domains, including attention and memory, which are impaired in bipolar disorder (BD). Although cross-sectional voxel-based morphometry studies found reduced PL grey matter (GM) in BD, none has longitudinally focused on PL anatomy in BD, relating it to patients? functioning. Thirty-eight right-handed BD patients and 42 matched healthy subjects (HS) underwent a Magnetic Resonance Imaging (MRI) scan at baseline. Seventeen BD patients and 16 matched HS underwent a follow-up MRI. PL white matter (WM) and GM volumes were measured. The trajectory of parietal volumes over time and the possible relation with the global functioning were investigated in both BD patients and HS. At baseline, BD patients showed significant reduced PL WM and GM and different WM laterality compared with HS. Furthermore, smaller PL WM volumes predicted lower global functioning in BD, but not in HS. At follow-up, although BD patients reported reduced PL WM compared with HS, no different pattern of volume changes over time was detected between groups. This study suggests the involvement of the PL in the pathophysiology of BD. In particular, PL WM reductions seem to predict an impairment in general functioning in BD and might represent a marker of functional outcome

Increased gyrification in schizophrenia and non affective first episode of psychosis

Prefrontal cortex gyrification has been suggested to be altered in patients with schizophrenia and first episode psychosis. Therefore, it may represent a possible trait marker for these illnesses and an indirect evidence of a disrupted underlying connectivity. The aim of this study was to add further evidence to the existing literature on the role of prefrontal gyrification in psychosis by carrying out a study on a sizeable sample of chronic patients with schizophrenia and non-affective first-episode psychosis (FEP-NA) patients. Methods: Seventy-two patients with schizophrenia, 51 FEP-NA patients (12 who later develop schizophrenia) and 95 healthy controls (HC) underwent magnetic resonance imaging (MRI). Cortical folding was quantified using the automated gyrification index (GI). GI values were compared among groups and related to clinical variables. Results: Both FEP-NA and patients with schizophrenia showed a higher mean prefrontal GI compared to HC (all p. <. 0.05). Interestingly, no differences have been observed between the two patients groups as well as between FEP-NA patients who did and did not develop schizophrenia. Conclusions: Our results suggest the presence of a shared aberrant prefrontal GI in subjects with both schizophrenia and first-episode psychosis. These findings support the hypothesis that altered GI represents a neurodevelopmental trait marker for psychosis, which may be involved in the associated neurocognitive deficits

Activations in gray and white matter are modulated by uni-manual responses during within and inter-hemispheric transfer: effects of response hand and right-handedness

Because the visual cortices are contra-laterally organized, inter-hemispheric transfer tasks have been used to behaviorally probe how information briefly presented to one hemisphere of the visual cortex is integrated with responses resulting from the ipsi- or contra-lateral motor cortex. By forcing rapid information exchange across diverse regions, these tasks robustly activate not only gray matter regions, but also white matter tracts. It is likely that the response hand itself (dominant or non-dominant) modulates gray and white matter activations during within and inter-hemispheric transfer. Yet the role of uni-manual responses and/or right hand dominance in modulating brain activations during such basic tasks is unclear. Here we investigated how uni-manual responses with either hand modulated activations during a basic visuo-motor task (the established Poffenberger paradigm) alternating between inter- and within-hemispheric transfer conditions. In a large sample of strongly right-handed adults (n&nbsp;=&nbsp;49), we used a factorial combination of transfer condition [Inter vs. Within] and response hand [Dominant(Right) vs. Non-Dominant (Left)] to discover fMRI-based activations in gray matter, and in narrowly defined white matter tracts. These tracts were identified using a priori probabilistic white matter atlases. Uni-manual responses with the right hand strongly modulated activations in gray matter, and notably in white matter. Furthermore, when responding with the left hand, activations during inter-hemispheric transfer were strongly predicted by the degree of right-hand dominance, with increased right-handedness predicting decreased fMRI activation. Finally, increasing age within the middle-aged sample was associated with a decrease in activations. These results provide novel evidence of complex relationships between uni-manual responses in right-handed subjects, and activations during within- and inter-hemispheric transfer suggest that the organization of the motor system exerts sophisticated functional effects. Moreover, our evidence of activation in white matter tracts is consistent with prior studies, confirming fMRI-detectable white matter activations which are systematically modulated by experimental condition

Medición e impacto del pago por desempeño en el ámbito de las artroplastias

Qualitat assistencial; Centres; ArtroplàstiesCalidad asistencial; Centros; ArtroplastiasQuality of care; Centers; ArthroplastyEl presente proyecto se planteó como fase de implementación y validación de un grupo de 13 indicadores para monitorizar la calidad asistencial y desempeño de centros que realizan artroplastias de cadera y rodilla. A partir de dicha implementación y mostrar su factibilidad, robustez y validez, se planteó una reflexión sobre sus potenciales utilidades en el marco de la evaluación y monitorización de la calidad asistencial y desempeño, así como su inclusión en sistemas de compra de servicios a proveedores para incentivar dicha calidad. También para su incorporación en futuros estudios para valorar hasta qué punto dichos sistemas de incentivación evidencian un impacto en mejoras asistenciales u organizativas. Algunos de los retos de esta implementación fueron, entre otras cuestiones, la vinculación de diversos sistemas de información sanitarios y registros para el cálculo de los indicadores, la aplicación de modelos de ajuste para una adecuada interpretación de los resultados, así como la desagregación de los indicadores a nivel específico de centro. En la mayoría de iniciativas publicadas hasta el momento sobre la efectividad, seguridad y eficiencia de las artroplastias en nuestro contexto, se venía haciendo a nivel global. Como objetivo nos planteamos valorar la utilidad del grupo de 13 indicadores: a) para monitorizar la calidad asistencial de centros que realizan artroplastias de cadera y rodilla; b) para analizar el desempeño de estos centros comparado con un estándar global de calidad; c) para su inclusión en contratos programa con proveedores para incentivar su calidad asistencial, y d) para futuras evaluaciones del impacto de estos sistemas de contratación en la mejora de la calidad.El present projecte es va plantejar com a fase d'implementació i validació d'un grup de 13 indicadors per monitoritzar la qualitat assistencial i acompliment de centres que realitzen artroplàsties de maluc i genoll. A partir d'aquesta implementació i mostrar la seva factibilitat, robustesa i validesa, es va plantejar una reflexió sobre els seus potencials utilitats en el marc de l'avaluació i monitorització de la qualitat assistencial i acompliment, així com la seva inclusió en sistemes de compra de serveis a proveïdors per incentivar aquesta qualitat. També per la seva incorporació en futurs estudis per valorar fins a quin punt aquests sistemes d'incentivació evidencien un impacte en millores assistencials o organitzatives. Alguns dels reptes d'aquesta implementació van ser, entre altres qüestions, la vinculació de diversos sistemes d'informació sanitaris i registres per al càlcul dels indicadors, l'aplicació de models d'ajust per una adequada interpretació dels resultats, així com la desagregació dels indicadors a nivell específic de centre. En la majoria d'iniciatives publicades fins al moment sobre l'efectivitat, seguretat i eficiència de les artroplàsties en el nostre context, es venia fent a nivell global. Com a objectiu ens plantegem valorar la utilitat del grup de 13 indicadors: a) per monitoritzar la qualitat assistencial de centres que realitzen artroplàsties de maluc i genoll; b) per analitzar l'acompliment d'aquests centres comparat amb un estàndard global de qualitat; c) per a la seva inclusió en contractes programa amb proveïdors per incentivar la seva qualitat assistencial, i d) per a futures avaluacions de l'impacte d'aquests sistemes de contractació en la millora de la qualitat.This project was designed as the implementation and validation phase for a group of 13 indicators to monitor the quality of care and performance of centres which carry out hip and knee arthroplasty. Once this stage was completed, an analysis of the potential benefits in the framework of the evaluation and monitoring of the quality of care and performance was carried out to demonstrate their feasibility, robustness and validity, as well as to determine whether the indicators should be included in procurement systems of services from suppliers in an effort to promote quality of care and to develop future studies to assess the extent to which these incentive systems demonstrate an impact on health care and organizational improvements. There were several challenges involved in this implementation, among which were the question of linking several health information systems and registries for measuring indicators, the application of adjustment models for the correct interpretation of the results, and the breaking down of the indicators into specific centre by centre level, given that the majority of initiatives published to date concerning the effectiveness, safety and efficiency of arthroplasties in our setting, only present results at overall level. Our objectives were to propose an evaluation of the usefulness of the group of 13 indicators: a) to monitor the quality of care for centres performing hip and knee arthroplasty, b) to analyse the performance of these centres compared with a global quality standard; c) to include them in contract programs with suppliers to promote quality of care and d) for future evaluations of the impact of these procurement systems on quality improvement

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis