Measuring follow-up time in routinely-collected health datasets: Challenges and solutions

A key requirement for longitudinal studies using routinely-collected health data is to be able to measure what individuals are present in the datasets used, and over what time period. Individuals can enter and leave the covered population of administrative datasets for a variety of reasons, including both life events and characteristics of the datasets themselves. An automated, customizable method of determining individuals' presence was developed for the primary care dataset in Swansea University's SAIL Databank. The primary care dataset covers only a portion of Wales, with 76% of practices participating. The start and end date of the data varies by practice. Additionally, individuals can change practices or leave Wales. To address these issues, a two step process was developed. First, the period for which each practice had data available was calculated by measuring changes in the rate of events recorded over time. Second, the registration records for each individual were simplified. Anomalies such as short gaps and overlaps were resolved by applying a set of rules. The result of these two analyses was a cleaned set of records indicating start and end dates of available primary care data for each individual. Analysis of GP records showed that 91.0% of events occurred within periods calculated as having available data by the algorithm. 98.4% of those events were observed at the same practice of registration as that computed by the algorithm. A standardized method for solving this common problem has enabled faster development of studies using this data set. Using a rigorous, tested, standardized method of verifying presence in the study population will also positively influence the quality of research

Presentation to primary care during the prodrome of type 1 diabetes in childhood: A case-control study using record data linkage

Objective To evaluate primary care presentations during the prodrome (12 months prior to onset type‐1 diabetes (T1D), with or without diabetic ketoacidosis [DKA]), to identify opportunities for earlier diagnosis. Methods This was a case‐control study, linking 16 years of data from children (≤15 years) registered at diagnosis of T1D, and routinely collected primary care records in Wales (United Kingdom). Controls (without T1D) were matched on a 3:1 ratio. Conditional logistic regression modeling was used to compare characteristics occurring in cases (children with T1D) and controls; and cases that presented with/without DKA. Results A total of 1345 children with T1D (19% DKA) and 4035 controls were identified. During the 12 months prior to diagnosis, cases were 6.5 times more likely to have at least one primary care contact (P < 0.001). One to 30 days prior to diagnosis, contacts relating to blood tests, fungal conditions, respiratory tract infections (RTIs), urinary conditions, vomiting, and weight were independently associated with T1D, as were contacts relating to blood tests, between 91 and 180 days prior to diagnosis. Children with a contact up to a month prior to diagnosis, relating to RTIs, antibiotic prescriptions, and vomiting, were more likely to present in DKA, as were boys (P = 0.047). Conclusion There are opportunities in primary care for an earlier diagnosis of T1D in childhood. These data could be used to create a predictive diagnostic tool, as a potential aid for primary care health professionals, to prevent presentation in DKA

Risk of congenital anomalies after exposure to asthma medication in the first trimester of pregnancy - a cohort linkage study

OBJECTIVE: To examine the effect of maternal exposure to asthma medications on the risk of congenital anomalies. DESIGN: Meta‐analysis of aggregated data from three cohort studies. SETTING: Linkage between healthcare databases and EUROCAT congenital anomaly registries. POPULATION: 519 242 pregnancies in Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010). METHODS: Exposure defined as having at least one prescription for asthma medications issued (Wales) or dispensed (Norway, Denmark) from 91 days before to 91 days after the pregnancy start date. Odds ratios (ORs) were estimated separately for each register and combined in meta‐analyses. MAIN OUTCOME MEASURES: ORs for all congenital anomalies and specific congenital anomalies. RESULTS: Overall exposure prevalence was 3.76%. For exposure to asthma medication in general, the adjusted OR (adjOR) for a major congenital anomaly was 1.21 (99% CI 1.09–1.34) after adjustment for maternal age and socioeconomic position. The OR of anal atresia was significantly increased in pregnancies exposed to inhaled corticosteroids (3.40; 99% CI 1.15–10.04). For severe congenital heart defects, an increased OR (1.97; 1.12–3.49) was associated with exposure to combination treatment with inhaled corticosteroids and long‐acting beta‐2‐agonists. Associations with renal dysplasia were driven by exposure to short‐acting beta‐2‐agonists (2.37; 1.20–4.67). CONCLUSION: The increased risk of congenital anomalies for women taking asthma medication is small with little confounding by maternal age or socioeconomic status. The study confirmed the association of inhaled corticosteroids with anal atresia found in earlier research and found potential new associations with combination treatment. The potential new associations should be interpreted with caution due to the large number of comparisons undertaken. TWEETABLE ABSTRACT: This cohort study found a small increased risk of congenital anomalies for women taking asthma medication

Desiderata for the development of next-generation electronic health record phenotype libraries

BackgroundHigh-quality phenotype definitions are desirable to enable the extraction of patient cohorts from large electronic health record repositories and are characterized by properties such as portability, reproducibility, and validity. Phenotype libraries, where definitions are stored, have the potential to contribute significantly to the quality of the definitions they host. In this work, we present a set of desiderata for the design of a next-generation phenotype library that is able to ensure the quality of hosted definitions by combining the functionality currently offered by disparate tooling.MethodsA group of researchers examined work to date on phenotype models, implementation, and validation, as well as contemporary phenotype libraries developed as a part of their own phenomics communities. Existing phenotype frameworks were also examined. This work was translated and refined by all the authors into a set of best practices.ResultsWe present 14 library desiderata that promote high-quality phenotype definitions, in the areas of modelling, logging, validation, and sharing and warehousing.ConclusionsThere are a number of choices to be made when constructing phenotype libraries. Our considerations distil the best practices in the field and include pointers towards their further development to support portable, reproducible, and clinically valid phenotype design. The provision of high-quality phenotype definitions enables electronic health record data to be more effectively used in medical domains

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Programmatically encrypting data linkage fields at a project level within the Secure Anonymised Information Linkage (SAIL) databank

ABSTRACT Introduction/Background The ability to link datasets within the Secure Anonymised Information Linkage (SAIL) databank provides researchers with a powerful tool to analyse multiple datasets. The ability to combine several datasets also has the adverse effect of potential identification of an individual. Further encrypting linkage fields at a project level limits the links to datasets specific to the project only. This presentation discusses the opensource web based administration tool that programmatically applies project encryption in a consistent and timely manner, logging administrator actions. Objectives 1). Identify encryption methodology 2). Programme encryption steps and log steps 3). Design and implement web based user administration tool Approach Utilising existing Secure Anonymised Information Linkage (SAIL) databank security, providing researchers with a view of their data, separating data linkage fields into a separate secure lookup table. Using Python programming language to automate the Structured Query Language (SQL) scripts required to accomplish this, as well as Python packages to interact with the databank and web based administration tool. Results Project encrypted views created for several projects and scores of datasets. Encrypted linkage fields unique to each project ensuring views across projects can not be linked either to each other or the original datasets. Conclusion Encryption process is programmable and administered through web tool

Multi-Object Auctions with Resale: Theory and Experiment

Abstract. We study multi-object auctions in the presence of post-auction trade opportunities among bidders who have either single-or multi-object demand. We focus on two formats: Vickrey auctions where package bidding is possible and simultaneous second-price auctions. We show that, under complementarities, the Vickrey format has an equilibrium where the objects are allocated efficiently at the auction stage whether resale markets are present or not. The simultaneous second-price, on the other hand, leads to inefficiency with or without resale possibility. Our experimental findings show that the possibility of resale in second-price auctions decreases the efficiency rate at the auction stage compared to the no resale case. However, after resale, the efficiency rate in second-price is as high as that of Vickrey auction without resale outcomes in the experiment. Preventing resale neither benefits nor hurts auction revenues in a second-price format. (JEL D44, C72, C91