Uso de la estadística en la oncología y la hematología

En este artículo abordamos el uso y la importancia de las herramientas estadísticas que se utilizan principalmente en los estudios médicos del ámbito de la oncología y la hematología, pero aplicables a muchos otros campos tanto médicos como experimentales o industriales. El objetivo del presente trabajo es presentar de una manera clara y precisa la metodología estadística necesaria para analizar los datos obtenidos en los estudios rigurosa y concisamente en cuanto a las hipótesis de trabajo planteadas por los investigadores. La medida de la respuesta al tratamiento elegidas en al tipo de estudio elegido determinarán los métodos estadísticos que se utilizarán durante el análisis de los datos del estudio y también el tamaño de muestra. Mediante la correcta aplicación del análisis estadístico y de una adecuada planificación se puede determinar si la relación encontrada entre la exposición a un tratamiento y un resultado es casual o por el contrario, está sujeto a una relación no aleatoria que podría establecer una relación de causalidad. Hemos estudiado los principales tipos de diseño de los estudios médicos más utilizados, tales como ensayos clínicos y estudios observacionales (cohortes, casos y controles, estudios de prevalencia y estudios ecológicos). También se presenta una sección sobre el cálculo del tamaño muestral de los estudios y cómo calcularlo, ¿Qué prueba estadística debe utilizarse?, los aspectos sobre fuerza del efecto ¿odds ratio¿ (OR) y riesgo relativo (RR), el análisis de supervivencia. Se presentan ejemplos en la mayoría de secciones del artículo y bibliografía más relevante.

Genetic variants of the FADS gene cluster and ELOVL gene family, colostrums LC-PUFA levels, breastfeeding, and child cognition

Introduction: Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs), but controversy persists. Genetic variation in fatty acid desaturase (FADS) and elongase (ELOVL) enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1) to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2) to analyze whether these maternal variants are related to child cognition; and 3) to assess whether children's variants modify breastfeeding effects on cognition. Methods: Data come from two population-based birth cohorts (n = 400 mother-child pairs from INMA-Sabadell; and n = 340 children from INMA-Menorca). LC-PUFAs were measured in 270 colostrum samples from INMA-Sabadell. Tag SNPs were genotyped both in mothers and children (13 in the FADS cluster, 6 in ELOVL2, and 7 in ELOVL5). Child cognition was assessed at 14 mo and 4 y using the Bayley Scales of Infant Development and the McCarthy Scales of Children"s Abilities, respectively. Results: Children of mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis), higher FADS2 activity (regulating DHA synthesis), and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 mo (3.5 to 5.3 points). Not being breastfed conferred an 8- to 9-point disadvantage in cognition among children GG homozygote for rs174468 (low FADS1 activity) but not among those with the A allele. Moreover, not being breastfed resulted in a disadvantage in cognition (5 to 8 points) among children CC homozygote for rs2397142 (low ELOVL5 activity), but not among those carrying the G allele. Conclusion: Genetically determined maternal supplies of LC-PUFAs during pregnancy and lactation appear to be crucial for child cognition. Breastfeeding effects on cognition are modified by child genetic variation in fatty acid desaturase and elongase enzymes.

RTS,S/AS02A malaria vaccine does not induce parasite CSP T cell epitope selection and reduces multiplicity of infection

Objective: The candidate malaria vaccine RTS,S/AS02A is a recombinant protein containing part of the circumsporozoite protein (CSP) sequence of Plasmodium falciparum, linked to the hepatitis B surface antigen and formulated in the proprietary adjuvant system AS02A. In a recent trial conducted in children younger than age five in southern Mozambique, the vaccinedemonstrated significant and sustained efficacy against both infection and clinical disease. In a follow-up study to the main trial, breakthrough infections identified in the trial were examined to determine whether the distribution of csp sequences was affected by the vaccine and to measure the multiplicity of infecting parasite genotypes. Design: P. falciparum DNA from isolates collected during the trial was used for genotype studies. Setting: The main trial was carried out in the Manhiça district, Maputo province, Mozambique, between April 2003 and May 2004. Participants: Children from the two cohorts of the main trial provided parasite isolates as follows: children from Cohort 1 who were admitted to hospital with clinical malaria; children from Cohort 1 who were parasite-positive in a cross-sectional survey at study month 8.5; children from Cohort 2 identified as parasite-positive during follow-up by active detection of infection. Outcome: Divergence of DNA sequence encoding the CSP T cell-epitope region sequence from that of the vaccine sequence was measured in 521 isolates. The number of distinct P. falciparum genotypes was also determined. Results: We found no evidence that parasite genotypes from children in the RTS,S/AS02A arm were more divergent than those receiving control vaccines. For Cohort 1 (survey at studymonth 8.5) and Cohort 2, infections in the vaccine group contained significantly fewer genotypes than those in the control group, (p 1/4 0.035, p 1/4 0.006), respectively, for the two cohorts. This was not the case for children in Cohort 1 who were admitted to hospital (p 1/4 0.478). Conclusions: RTS,S/AS02A did not select for genotypes encoding divergent T cell epitopes in the C-terminal region of CSP in this trial. In both cohorts, there was a modest reduction in the mean number of parasite genotypes harboured by vaccinated children compared with controls, but only among those with asymptomatic infections.

Viabilidad del sistema de pensiones y reformas por el lado de los ingresos: una aproximación intergeneracional

Este artículo, mediante el método de la Contabilidad Generacional, examina la viabilidad a largo plazo y los efectos sobre la redistribución intergeneracional de la renta del sistema de pensiones español. Dado la enorme deuda acumulada, que se traslada a las generaciones futuras, se explora la posibilidad de introducir políticas de reforma por el lado de los ingresos que pretenden mitigar la fuerte dependencia demográfica de las finanzas de la Seguridad Social. El principal resultado obtenido es que la gravedad de la crisis demográfica hace que estos tipos de medidas estudiadas sean claramente insuficientes para restaurar el equilibrio intergeneracional.

La Ley de Estabilidad Presupuestaria en el largo plazo: efecto del ciclo demográfico

La actual situación económica y las perspectivas presupuestarias a largo plazo han suscitado una discusión acerca de la conveniencia de la Ley de Estabilidad Presupuestaria. Este trabajo, empleando contabilidad generacional, evalúa la sostenibilidad de la política fiscal española ampliando el horizonte temporal más allá del ciclo de los negocios, considerando los efectos del ciclo demográfico. Los resultados muestran que, aunque el proceso de consolidación fiscal ha mejorado ostensiblemente la situación financiera de las AA.PP, se sigue trasladando al futuro una deuda implí­cita sustancial

Beyond the Toledo agreement : the intergenerational impact of the spanish pension reform

The paper examines the intergenerational impact of the Spanish public pension system after the 1997 Pension Reform Act. Working within a Generational Accounting framework, we find that maintaining the new legal setting could leave future generations with liabilities as high as 176 percent of base year GDP. As the recent reform measures have been insufficient to achieve the sustainability of the current pension system, we also analyse the impact of alternative reform strategies. Within the current pay-as-you-go setting, a further improvement to tax-benefit linkage in line with the original spirit of the Toledo Agreement is shown to yield and intergenerationally more balanced outcome,than an increase in the retirement age or an expansion of public subsidies financed through indirect taxes. Finally, we examine the generational impact of a move toward a partially funded pension system which might restore theintergenerational balance

Procés de transició del batxillerat a la universitat: factors d’èxit

La problemàtica de la transició batxillerat-universitat és avui un fenomen de preocupació i un tema de debat. La revisió de la recerca posa de manifest que, en l’anàlisi de la transició a la universitat, s’han fet estudis que descriuen resultats acadèmics al final d’un determinat període i seguiments de cohorts específiques en referència a centres específics1 però, no s’ha produït, un plantejament comprensiu i profund que permeti constatar el conjunt de factors psicosocials relacionats amb la qualitat de les transicions acadèmiques. La transició a la universitat és un procés complex que comporta per a l’estudiant canvis personals i vitals significatius, amb conseqüències que afecten també el marc social.

El rendiment i la trajectòria acadèmica en els dos primers anys a la Universitat

La problemàtica de la transició batxillerat-universitat és avui un fenomen de preocupació i un tema de debat. La revisió de la recerca posa de manifest que, en l’anàlisi de la transició a launiversitat, s’han fet estudis que descriuen resultats acadèmics al final d’un determinat període i seguiments de cohorts específiques en referència a centres específics1 però, no s’ha produït, un plantejament comprensiu i profund que permeti constatar el conjunt de factors psicosocials relacionats amb la qualitat de les transicions acadèmiques. La transició a la universitat és unprocés complex que comporta per a l’estudiant canvis personals i vitals significatius, amb conseqüències que afecten també el marc social. El treball desenvolupat s’emmarca en les línies actuals de l’estudi de la transició a la universitat, representades en els treballs de Terenzini (1993) i Pautler (1996) sobre les trajectòries de transició dels estudiants d’EUA o els estudis de Yorke (1998) que analitzen les trajectòries d’abandonament i fracàs universitari a la Gran Bretanya. L’interès d’aquest acull tant la perspectiva de l’impacte de la transició sobre la persona - com el propi procés afecta a la persona -, com la perspectiva del procés, és a dir, quins recursos personals i contextuals permeten reduir l’impacte de la transició i facilitar l’adaptació al canvi de les persones queaccedeixen a la universitat. En aquest sentit l’estudi presenta un model que tracta de captar la interacció dels factors personals i contextuals que expliquen les diferents trajectòries de transicióa la universitat: de continuïtat o d’abandonament, d’èxit en la integració o de fracàs en la superació dels problemes generats per la discontinuïtat d’ambients educatius.

Avaluació programa d’atenció a la treballadora embarassada del Parc de Salut Mar

Objectiu: Descriure i analitzar el programa d’atenció a la dona treballadora durant l’embaràs del Parc de Salut Mar des de que es posà en marxa i proposar millores del programa.Mètodes: Estudi de cohorts retrospectiva de treballadores embarassades del Parc de Salut Mar en el període comprès entre gener de 2008 fins desembre de 2012. Es realitzà una descripció i anàlisi detallada de la cohort, del temps que transcorreguè des de que s’inicià l’embaràs fins que aquest es notificà i del temps des de que es notificà fins que es planificà una acció preventiva. Es calculà la durada mediana i percentils dels dos temps i es valorà l’associació amb les diferents variables, obtenint odds ratios crues (Orc) i ajustades (Ora) i intervals de confiança del 95% (IC 95%).Finalment es realitzà una descripció de les gestants a les que es sol·licità la prestació per risc durant l’embaràs per mitjà de freqüències, durada mediana i percentils del temps que es tardà en ser atorgada i de la setmana de gestació en la qual s’ atorgà.Resultats: S’observà un increment de les notificacions des de l’any 2009. El 50% de les gestants notificaren l’embaràs al voltant de la setmana 15 de gestació (P50=106 dies). No s’aprecià diferència en els temps que es tardà en planificar una acció preventiva quan els riscos foren moderats/important en comparació amb quan foren tolerables o no hi haguessin. El 50% i el 75% d’actuacions preventives es planificaren abans dels 25 i dels 40 dies respectivament. El 50 % dels subsidis foren entregats abans dels 50 dies des de que es realitzà l’informe tècnic i la mediana de la setmana de gestació en la qual s’atorgà la prestació fou de 11 setmanes.Conclusions: Es tracta d’un programa bo i innovador en el qual cal seguir fent millores, sent molt important la unificació de totes les bases de dades en una de sola.

FAM-MDR: a flexible family-based multifactor dimensionality reduction technique to detect epistasis using related individuals

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information.

Systematic review protocol to define classical IgE-associated diseases from birth to adolescence: the MeDALL study

BACKGROUND: Classical disease phenotypes are mainly based on descriptions of symptoms and the hypothesis that a given pattern of symptoms provides a diagnosis. With refined technologies there is growing evidence that disease expression in patients is much more diverse and subtypes need to be defined to allow a better targeted treatment. One of the aims of the Mechanisms of the Development of Allergy Project (MeDALL,FP7) is to re-define the classical phenotypes of IgE-associated allergic diseases from birth to adolescence, by consensus among experts using a systematic review of the literature and identify possible gaps in research for new disease markers. This paper describes the methods to be used for the systematic review of the classical IgE-associated phenotypes applicable in general to other systematic reviews also addressing phenotype definitions based on evidence. METHODS/DESIGN: Eligible papers were identified by PubMed search (complete database through April 2011). This search yielded 12,043 citations. The review includes intervention studies (randomized and clinical controlled trials) and observational studies (cohort studies including birth cohorts, case-control studies) as well as case series. Systematic and non-systematic reviews, guidelines, position papers and editorials are not excluded but dealt with separately. Two independent reviewers in parallel conducted consecutive title and abstract filtering scans. For publications where title and abstract fulfilled the inclusion criteria the full text was assessed. In the final step, two independent reviewers abstracted data using a pre-designed data extraction form with disagreements resolved by discussion among investigators. DISCUSSION: The systematic review protocol described here allows to generate broad,multi-phenotype reviews and consensus phenotype definitions. The in-depth analysis of the existing literature on the classification of IgE-associated allergic diseases through such a systematic review will 1) provide relevant information on the current epidemiologic definitions of allergic diseases, 2) address heterogeneity and interrelationships and 3) identify gaps in knowledge.

Cambio social y homogamia educativa

A partir de una amplia revisión bibliográfica y basándose en los datos de un estudio realizado sobre una muestra representativa de la provincia de Lérida (N=1.219) se analiza en este artículo la persistencia de la homogamia educativa en un contexto de expansión de la escolarización, en especial, de las cohortes femeninas españolas nacidas con posterioridad a 1955. Más allá de la controversia de la homogamia frente a la heterogamia los autores interpretan los resultados como ejemplo de los límites al cambio de modelo de enlace matrimonial.

Breast cancer incidence and overdiagnosis in Catalonia (Spain)

Introduction: Early detection of breast cancer (BC) with mammography may cause overdiagnosis and overtreatment, detecting tumors which would remain undiagnosed during a lifetime. The aims of this study were: first, to model invasive BC incidence trends in Catalonia (Spain) taking into account reproductive and screening data; and second, to quantify the extent of BC overdiagnosis. Methods: We modeled the incidence of invasive BC using a Poisson regression model. Explanatory variables were: age at diagnosis and cohort characteristics (completed fertility rate, percentage of women that use mammography at age 50, and year of birth). This model also was used to estimate the background incidence in the absence of screening. We used a probabilistic model to estimate the expected BC incidence if women in the population used mammography as reported in health surveys. The difference between the observed and expected cumulative incidences provided an estimate of overdiagnosis. Results: Incidence of invasive BC increased, especially in cohorts born from 1940 to 1955. The biggest increase was observed in these cohorts between the ages of 50 to 65 years, where the final BC incidence rates more than doubled the initial ones. Dissemination of mammography was significantly associated with BC incidence and overdiagnosis. Our estimates of overdiagnosis ranged from 0.4% to 46.6%, for women born around 1935 and 1950, respectively. Conclusions: Our results support the existence of overdiagnosis in Catalonia attributed to mammography usage, and the limited malignant potential of some tumors may play an important role. Women should be better informed about this risk. Research should be oriented towards personalized screening and risk assessment tools.

Competing risks to breast cancer mortality in Catalonia

Background: Breast cancer mortality has experienced important changes over the last century. Breast cancer occurs in the presence of other competing risks which can influence breast cancer incidence and mortality trends. The aim of the present work is: 1) to assess the impact of breast cancer deaths among mortality from all causes in Catalonia (Spain), by age and birth cohort and 2) to estimate the risk of death from other causes than breast cancer, one of the inputs needed to model breast cancer mortality reduction due to screening or therapeutic interventions. Methods: The multi-decrement life table methodology was used. First, all-cause mortality probabilities were obtained by age and cohort. Then mortality probability for breast cancer was subtracted from the all-cause mortality probabilities to obtain cohort life tables for causes other than breast cancer. These life tables, on one hand, provide an estimate of the risk of dying from competing risks, and on the other hand, permit to assess the impact of breast cancer deaths on all-cause mortality using the ratio of the probability of death for causes other than breast cancer by the all-cause probability of death. Results: There was an increasing impact of breast cancer on mortality in the first part of the 20th century, with a peak for cohorts born in 1945–54 in the 40–49 age groups (for which approximately 24% of mortality was due to breast cancer). Even though for cohorts born after 1955 there was only information for women under 50, it is also important to note that the impact of breast cancer on all-cause mortality decreased for those cohorts. Conclusion: We have quantified the effect of removing breast cancer mortality in different age groups and birth cohorts. Our results are consistent with US findings. We also have obtained an estimate of the risk of dying from competing-causes mortality, which will be used in the assessment of the effect of mammography screening on breast cancer mortality in Catalonia.

Dissemination of periodic mammography and patterns of use, by birth cohort, in Catalonia (Spain)

Background: In Catalonia (Spain) breast cancer mortality has declined since the beginning of the 1990s. The dissemination of early detection by mammography and the introduction of adjuvant treatments are among the possible causes of this decrease, and both were almost coincident in time. Thus, understanding how these procedures were incorporated into use in the general population and in women diagnosed with breast cancer is very important for assessing their contribution to the reduction in breast cancer mortality. In this work we have modeled the dissemination of periodic mammography and described repeat mammography behavior in Catalonia from 1975 to 2006. Methods: Cross-sectional data from three Catalan Health Surveys for the calendar years 1994, 2002 and 2006 was used. The dissemination of mammography by birth cohort was modeled using a mixed effects model and repeat mammography behavior was described by age and survey year. Results: For women born from 1938 to 1952, mammography clearly had a period effect, meaning that they started to have periodic mammograms at the same calendar years but at different ages. The age at which approximately 50% of the women were receiving periodic mammograms went from 57.8 years of age for women born in 1938–1942 to 37.3 years of age for women born in 1963–1967. Women in all age groups experienced an increase in periodic mammography use over time, although women in the 50–69 age group have experienced the highest increase. Currently, the target population of the Catalan Breast Cancer Screening Program, 50–69 years of age, is the group that self-reports the highest utilization of periodic mammograms, followed by the 40–49 age group. A higher proportion of women of all age groups have annual mammograms rather than biennial or irregular ones. Conclusion: Mammography in Catalonia became more widely implemented during the 1990s. We estimated when cohorts initiated periodic mammograms and how frequently women are receiving them. These two pieces of information will be entered into a cost-effectiveness model of early detection in Catalonia.