Se sabe que existe un enlace importante entre la demencia y una serie de enfermedades comórbidas, sobre todo: enfermedades inflamatorias, diabetes (Peila et al 2002; Ott et al., 1999.) Y obesidad (Whitmer et al (Akitama et al 2000). 2005). Posiblemente la más clara evidencia de este enlace proviene de estudios epidemiológicos (Wang et al 2015;. Biessels et al 2006;. Barret-Connor 2007), que muestran consistentemente que la historia previa de las enfermedades mencionadas (o los medicamentos prescritos en cada caso) cambiar significativamente el riesgo de desarrollar demencia más adelante en la vida. Sin embargo, en la actualidad el campo carece de investigaciones epidemiológicas sistemáticas que pueden separar los efectos debidos a cada una de estas enfermedades y medicamentos. EMIF está proporcionando la primera plataforma con suficiente número de registros como para poner en práctica un amplio estudio sistemático sobre las principales comorbilidades asociadas con la demencia de (es decir, enfermedades inflamatorias, diabetes y obesidad).
Nos proponemos analizar cómo las exposiciones más comunes (2 condiciones y 2 fármacos relacionados) se asocian con las características más evidentes de la demencia (riesgo y la edad de aparición). El objetivo de esta investigación es doble: en primer lugar la propia (ningún estudio previo se ha ocupado de la mayoría de estos fármacos y enfermedades) pregunta científica; y en segundo lugar cómo pilotar preguntas epidemiología deben encaminarse a través EMIF.

El proyecto europeo Marco de Información Médica (EMIF) tiene el objetivo principal de la construcción de una infraestructura para la reutilización eficiente de los datos de salud existentes para la investigación epidemiológica. Dentro del proyecto, la Plataforma EMIF
representa una federación de fuentes heterogéneas de datos de salud (por ejemplo administrativa, bases de datos hospitalarias o de atención primaria, los registros de enfermedades, biobancos). Uno de los principales retos para el proyecto EMIF es para hacer frente a las diferentes características de las fuentes de datos de participantes con el fin de facilitar la ejecución de los grandes, de múltiples datos multinacional
fuente estudios de observación y generan pruebas de alta calidad. Para este propósito, una plantilla de procedimiento de derivación de datos fue desarrollada específicamente. En este estudio de prueba de concepto, el procedimiento estándar será aplicado para la identificación de los pacientes con infarto agudo de miocardio (IAM) en un conjunto de fuentes heterogéneas de datos de salud de observación.
Índices de validez (sensibilidad, PPV) de los algoritmos de detección de casos de origen a la medida de datos se estimaron a partir de pruebas disponibles, y la prevalencia ajustada y la incidencia de IAM se estimaron a partir de las fuentes de datos que participan.

Rationale and Background: The overall ADVANCE proof-of-concept (POC) question is to test the system for benefit-risk monitoring of vaccines in Europe. This will first be done by using test cases. For this POC, the following research question is used: ?Has the initial benefit-risk profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines??
This protocol will test the system related to the estimation of coverage data as they are required for the performance and interpretation of the benefit-risk analysis.
Research Question and Objective: To assess the system capability to estimate aP and wP vaccine coverage.
Study Design: The main study design is a retrospective dynamic cohort study.
Population: Children from birth until 6 years of age (until 6th birthday) during the study period.
Outcome Parameters: Vaccine coverage is the proportion of individuals within the target population
having received the vaccine.
For Objective 1 the following parameters are needed: Number of databases with adequate data for coverage estimates; Number of children vaccinated; Number of children within the target population; Proportion of vaccinated children; Coverage rates overall, wP and aP immunization by database, birth cohort, , age in months and per dose; The variability of vaccine administration over time; Changes of coverage rates over time.
Data Sources: Electronic health care databases (record linkage, surveillance and GP based databases)
currently available in the ADVANCE consortium and eligible are located in Denmark, Spain, Italy, and UK.
Study Size: Total population (0-6 year of age) of all eligible ADVANCE databases.
Data Analysis: Frequencies and distributions are measured by general descriptive statistics. Coverage rates and timeliness of immunization are calculated according to the Kaplan-Meier method. Changes of coverage rates will be assessed by the cumulative sum (CUSUM) method.
Informed Consent and Ethical Approval: This study will be conducted on the basis of secondary use of electronic healthcare records. Each database will apply local governance and privacy rules prior to aggregating and sharing anonymized data.

Rationale and Background: The overall ADVANCE proof-of-concept (POC) objective is to test the system for benefit-risk monitoring of vaccines in Europe. This will first be done by using test cases. For this POC analysis, the following research question is used: ?Has the initial benefit-risk profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines??
This protocol aims to obtain the data on the benefits that will feed into the benefit-risk model.
Research Question and Objectives: 1. To assess the feasibility of healthcare databases to estimate the incidence rates of pertussis following pertussis vaccination; 2. To estimate the incidence rate of diagnosed pertussis in infants and children up to school-entry or age 6 years ? any case at, or between, any dose of primary or booster vaccine, dose-specific; 3. To estimate the risk of non-fatal pertussis-related complications leading to hospitalizations, i.e. seizures and pneumonia in infants and children up to age 6 years; 4. To assess the risk of deaths following pertussis in infants and children up to age 6 years; 5. To calculate calendar month-specific incidence rates which will also allow for time sequential monitoring of effectiveness in the methods development.
Design: The main design is a retrospective dynamic cohort analysis.
The analysis will be conducted utilizing electronic health care data from ADVANCE partners in Denmark,
UK, Netherlands, Spain and Italy.
Population: The source population for this analysis will comprise all children registered in any of the participating databases during the study period and for whom an adequate start and end of follow-up and date of birth can be defined.
Data Sources: Electronic health care databases (record linkage, surveillance and GP-based databases) currently available in the ADVANCE consortium and eligible are located in Denmark, Spain, Italy, The Netherlands and UK. Short descriptions of databases and their full names will be included in this protocol upon final decisions of inclusions.
Data Analysis: Incidence rates of pertussis will be calculated by age in months, sex, country, calendar
time (year and month) and wP/aP type and dose.
The risk of complications and death will be calculated within the 30 days after occurrence of pertussis
disease in all subjects with a recorded diagnosis of pertussis. Risk will be stratified by age in months, sex, country, calendar time and wP/aP type and dose.

Obesity is an important and well known risk factor for cardiovascular diseases (CVD) and all-cause mortality with prevalence across the world continuing to increase (Europe PMC Funders Goup 2014) with the economic cost estimated to be £50 billion by the year 2050 (Morgan & Monica 2010). Currently, the associations with obesity and CVD have not been extensively studied in the electronic health record (EHR) setting. EHRs are an invaluable resource allowing population-level research on large representative scales; they include information captured on patients? medical records such as diagnoses and prescribed treatments that are deemed relevant for patient care. Body mass index (BMI) is recorded on a number of EHR systems; however there are concerns about its completeness and representativeness particularly since BMI may be recorded as a risk based measure.

This study seeks to evaluate the relationship between obesity (as measured by BMI) with cardiovascular disease and all-cause mortality using data from EHR primary care databases in the UK, Spain, Netherlands and Italy through the European Medical Information Framework (EMIF) platform. Characteristics such as demographics, morbidity burden and history of healthcare utilization will be compared between individuals with BMI recorded and those without a BMI recorded on their health records in order to better understand whether any key differences exist between the two groups. In addition, sensitivities about the timing of the recording of BMI on any observed relationships will be explored.

It is anticipated that this study of a well characterized association between obesity (as measured by BMI) and CVD will support future EMIF studies and the development of Platform tools.

Title of Study: Testing new approaches to monitoring benefit/risk with pertussis vaccines as test case: Incidence rates of safety outcomes of whole-cell pertussis and acellular pertussis vaccines in pre-school children.
Study Period: 01 January 1990 ? 31 December 2015
Rationale and Background: The overall ADVANCE proof-of-concept (POC) question is to test the system for benefit-risk monitoring of vaccines in Europe. This will first be done by using test cases. For this POC feasibility study, the following research question is used: ?Has the initial benefit-risk profile in children prior to school-entry booster been maintained after the switch from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines??
This protocol aims to create the safety data for a benefit-risk analysis of aP versus wP vaccines.
Research Question and Objectives:
The objectives of this specific POC feasibility study focusing on the incidence rates of safety outcomes of pertussis vaccines are:
1. To evaluate participating databases on quality criteria for inclusion in the study (i.e. vaccination data on pertussis vaccine available, at least one of the outcomes available, data access and clearance of protocol possible within timelines of POC feasibility study).
2. To provide safety information for a benefit/risk analysis model.
The safety information required for the model is: incidence rates of specific events (i.e. injection site reactions, fever, somnolence, persistent crying, irritability, febrile or afebrile seizure/convulsion, hypotonic-hyporesponsive episode [HHE], extensive limb swelling) in risk and baseline periods. Incidence rates will be estimated within specific risk windows after each dose of wP or aP vaccine in pre-school children and within the periods outside the risk windows (baseline).
3. To provide calendar time specific incidence data as test for methods development in ADVANCE WP4.
Study Design: The main study design is a retrospective dynamic cohort study.
The study will be conducted utilizing electronic health care data from ADVANCE partners in different countries (i.e., Short descriptions of databases in respective coutries and their full names will be included in this protocol upon final decisions of inclusions).
In databases that cover the period in which wP was still provided, the incidence rate (IR) ratio for wP versus baseline risk will be calculated using a self-controlled case series (SCCS) design. This IR ratio will be applied to baseline rates for the aP period in databases that do not capture the wP period, to estimate the rate of events during wP in each specific database.
Population: The study population will comprise all children registered in any of the participating databases during the study period and for whom an adequate start and end of follow-up and date of birth can be defined.
Children will be followed from start of the study period, one month after date of birth (i.e. to allow for pre-vaccination time for the SCCS design and to avoid pre-term related or birth-induced increase in incidence rates), or date of valid data in the database (whichever is the latest) until the end of study period (31-12-2015, the school-entry pertussis booster, transferring out of the database, death, reaching age 6 years: whichever is the earliest).
Variables:
Exposure of interest
Any wP vaccines and aP pertussis-containing vaccines and their doses in the vaccine schedule (D1, D2, D3, D4, D5)
Outcomes
? Injection site reactions: erythema, edema, induration/nodule/sterile abscess, pain/tenderness
? Fever
? Somnolence
? Persistent crying, irritability
? Generalized convulsive seizures
? HHE
? Extensive limb swelling
Data Sources:
? Electronic health care databases (record linkage, surveillance and GP-based databases) currently available in the ADVANCE consortium and eligible are located in Denmark, Spain, Italy, The Netherlands and UK. Short descriptions of databases and their full names will be included in this protocol upon final decisions of inclusions.
Study Size: Total population (0-6 year of age) of all eligible ADVANCE databases
Data Analysis: The purpose of this study is to provide incidence rates (i.e. baseline and risk-window specific) of known adverse reactions following vaccination with pertussis-containing vaccines for use in a multi-criteria decision analysis (MCDA) model of benefits and risks of wP versus aP pertussis vaccines (models are described in a separate benefit-risk study protocol). In some more recent databases, wP information will not be captured. To generate risk-window specific incidence rates for the wP period in these databases, the IR ratio originating from an SCCS analysis of wP versus baseline in other databases will be multiplied by the baseline IR.
Informed Consent and Ethical Approval: This study will be conducted on the basis of secondary use of electronic healthcare records. Each database will apply local governance and privacy rules prior to aggregating and sharing anonymized data.
Milestones:
Draft protocol: July 31 2015
Submission to SC: August 6, 2015
Comments from SC: August 31, 2015
Submission for consortium review: September 2015
Submission to in house clearances/ governance boards: January 2016
Updated protocol after review: April 15, 2016
Final data extraction to CDM: Nov 1, 2016
Running scripts and submission to RRE: Nov 7, 2016
Data analysis: Nov 2016
Data interpretation and reporting: 30 Nov 2016
Final report of study results: January 2017

Non-alcoholic fatty liver disease (NAFLD) is an important clinical syndrome related to ectopic deposition of fat in the liver, known as simple steatosis. Several researchers have encouraged further exploration of the relation of NAFLD and other chronic liver diseases with the development of cognitive impairment and dementia.
We hypothesize that patients with NAFLD are at increased risk of developing cognitive impairment including dementia. The scientific aim of this study is to evaluate whether risk of dementia differs in patients with versus those without a previous diagnosis of NAFLD.
In this study, we will request access to the THIN, HSD, IPCI and SIDIAP databases that were previously analysed in other EMIF projects called Use Cases (UC) on NAFLD (UC 10) or dementia (UC 6, 11 and 12). We will utilize the standardized processes developed by the EMIF-Platform to conduct protocol-based studies in multiple routine health care data across Europe. This will enable us to access the largest cohort assembled to date of patients with dementia and to investigate heterogeneity across country and primary care systems. A pragmatic objective of this study is to further develop the Platform by streamlining already existing processes and experimenting on new ways of working.

Rationale and Background: POC1.2 aims to test near real-time and visual monitoring of coverage, benefits and risks of acellular pertussis (aP) vaccination. POC1.2 is designed as a continuation of POC1 to leverage previously completed work. POC1.2 will use near real-time visual monitoring of aP vaccines in Europe as a test case, aiming to mimic the introduction of a new vaccine. The interactive dashboard developed as an additional analysis to POC1 will be regularly updated for monitoring.

Research Question and Objectives:
The overall objective of the ADVANCE POC studies is to build and test a system (including data availability) for the benefit-risk monitoring of vaccines in Europe. The objective of POC1.2 is to determine the feasibility of periodic and rapid assessments of vaccine coverage, benefits and risks using electronic healthcare databases, while displaying these data using a dashboard.

Target Population: All children from their start of follow-up in the database until school-entry pertussis booster, 6 years of age or any periodic data lock point within the eligible ADVANCE databases.

Observation Period:
The total observation period consists of two distinct periods. The first period starts from 01 January 2014 until the start of the near real-time monitoring upon approval of the protocol and has as objective to establish a baseline. The second period has the objective of near real-time monitoring and will cover a few months. This period will start upon protocol approval until last periodic data lock point (DLP) (i.e. the time the last periodic database extract is produced) and will cover a few months.

Study design: A dynamic cohort study
Exposure: The exposure of interest is vaccination with any acellular pertussis-containing (aP) vaccine recorded in the study population covered by the ADVANCE databases participating in POC1.2
Outcomes: The risk outcomes are hypotonic hypo-responsive episodes (HHE), febrile convulsions/seizures, fever, somnolence and persistent crying. The benefit outcome is pertussis, confirmed or probable.

Data analyses
The test case is near real-time (weekly or bi-weekly/monthly, depending on the database) visual monitoring of vaccination coverage, benefits and risks of pertussis vaccination. The monitoring will be facilitated through the use of an interactive dashboard developed based on the POC1 data. The dashboard contains three monitoring tabs with visualizations:
-Coverage: number of administered doses per week over calendar time and vaccination coverage within specific age groups by calendar time
-Benefits: observed pertussis incidence in the total population by calendar time
-Risks: incidence rates in event specific risk windows and in control periods (out of risk windows) at vaccination eligible ages, separately for each risk outcome by dose, estimated cumulatively over calendar time.

Data Sources:
The potential data sources were selected from all databases available from ADVANCE partners and associated partners, based on the following eligibility criteria:
-Successful database quality assessment based on database fingerprinting and benchmarking for the events and vaccine of interest
-Theoretical ability to generate periodic data, with a target of weekly refresh of data, as recovered based on a detailed survey
Based on these two criteria the following six data sources remained: ASLCR, ARS, PEDIANET, RCGP, SIDIAP and SSI/AUH.

Sample size: Entire eligible study population from the six eligible databases.

Dosing errors are one of the most common types of medication issues and contribute to the mortality and morbidity within the paediatric population. Paediatric patients are at a higher risk than adults of experiencing such problems because of the need for a dose calculation based on the patient?s age, weight (mg/kg), body surface area (mg/m2), and clinical condition.
Antibiotics are the medications most widely prescribed in the paediatric population and one of the drug classes most commonly reported to be involved in paediatric dosing errors.
Despite a number of studies conducted about antibiotics usage in different European countries, the appropriateness of antibiotic dosing (prescribed by doctors in primary or secondary care, dispensed by community or hospital pharmacies, or administered in hospital settings) according to the child?s age, weight and height (and other related parameters, as Body Mass Index – BMI, Body Surface Area – BSA) has not yet been investigated.
In this study, we would like to assess in European Medical Information Framework (EMIF) Electronic Healthcare Records (EHR) databases (DBs) the relationship between dosing of antibiotics prescribed, administered or dispensed (either for outpatients or inpatient settings) to children (age 0-18 yr), and their weight, age and height.