Daniel R Morales

• BMSc MBChB PhD MRCP MRCGP
• Fellow at University of Dundee

Aims Regulatory risk communications are important to ensure medication safety, but their impact is poorly understood. The aim was to quantify the impact of UK risk communications on medication use and other outcomes. Methods We conducted a systematic review of studies reporting prescribing/health outcome data relevant to UK regulatory risk communi...

Aims Hydrochlorothiazide‐induced photosensitivity may increase squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and lip cancer risk. The aim was to quantify these risks. Methods Nested case–control studies using data from the UK THIN database from 01 January 1999 to 01 May 2016. Adults with incident SCC, BCC, melanoma, lip cancer and oral...

Background: The generalisability of randomized controlled trials (RCTs) can be uncertain because the impact of exclusion criteria is rarely quantified. The aim of this study was to systematically review studies examining the percentage of clinical populations with a physical health condition who would be excluded by RCTs of treatments for that con...

Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increa...

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8...

Background As prescribing of newer antihyperglycemic agents expands, there remains limited comparative safety data for older adults a population particularly vulnerable to adverse drug events and underrepresented in clinical trials. We aimed to evaluate the real world safety of second-line antihyperglycemic agents among older adults with type 2 dia...

Background Atrial fibrillation (AF) prevalence is rising due to population ageing and comorbidity is an increasing problem. The aim of this study was to examine the prevalence and association of coexisting health conditions among adults with AF in the general population. Methods Cross-sectional analysis of Clinical Practice Research Datalink (CPRD...

Background Depression is associated with a range of adverse physical health outcomes. We aimed to quantify the association between depression and the subsequent rate of accrual of long-term physical health conditions in middle and older age. Methods and findings We included 172,556 participants from the UK Biobank (UKB) cohort study, aged 40–71 ye...

Objectives The Observational Medical Outcomes Partnership common data model (OMOP‐CDM) is a useful tool for large‐scale network analysis but currently lacks a structured approach to pregnancy episodes. We aimed to develop and implement a perinatal expansion for the OMOP‐CDM to facilitate perinatal network research. Methods We collaboratively devel...

Background Fluoroquinolones (FQs) are commonly used to treat urinary tract infections (UTIs), but some studies have suggested they may increase the risk of aortic aneurysm or dissection (AA/AD). However, no large-scale international study has thoroughly assessed this risk. Methods A retrospective cohort study was conducted using a large, distribut...

Drug development for children presents unique challenges and is highly regulated. Novel approaches, such as the use of extrapolation to address, for example, the need to avoid unethical studies, whilst supporting robust evidence generation have been developed in support of benefit/risk considerations by regulatory authorities. This is only one step...

Purpose The generation of representative disease phenotypes is important for ensuring the reliability of the findings of observational studies. The aim of this manuscript is to outline a reproducible framework for reliable and traceable phenotype generation based on real world data for use in the Data Analysis and Real‐World Interrogation Network (...

Background Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, withou...

Introduction: Amid the global COVID-19 pandemic, vaccines were conditionally authorised for human use to protect against severe infection. The BRAVE toolkit, a user-friendly R Shiny application, was developed retrospectively together with the European Medicine Agency (EMA) with the aim of fulfilling the need for flexible tools to assess vaccine ben...

Purpose The European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) launched a strategy to examine the public health impact of major regulatory interventions aimed at minimising risks of medicinal products. We conducted a lessons learnt analysis of impact studies completed between 2015 and 2023. Methods We surveyed PRA...

Objectives To quantify prevalence, harms, and NHS costs in England of problematic oral non-steroidal anti-inflammatory drug (NSAID) prescribing in high risk groups. Design Population based cohort and economic modelling study. Setting Economic models estimating patient harm associated with NSAID specific hazardous prescribing events, and cost to t...

Objective: To investigate risks of multiple adverse outcomes associated with use of antipsychotics in people with dementia. Design: Population based matched cohort study. Setting: Linked primary care, hospital and mortality data from Clinical Practice Research Datalink (CPRD), England. Population: Adults (≥50 years) with a diagnosis of demen...

Purpose The generation of representative disease phenotypes is important for ensuring the reliability of the findings of observational studies. The aim of this manuscript is to outline a reproducible framework for reliable and traceable phenotype generation based on real world data for use in the Data Analysis and Real-World Interrogation Network (...

Aims Norway and Sweden had different early pandemic responses that may have impacted mental health management. The aim was to assess the impact of the early COVID‐19 pandemic on mental health‐related care. Methods We used national registries in Norway and Sweden (1 January 2018–31 December 2020) to define 2 cohorts: (i) general adult population; a...

Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic. Methods: We conducted a literature review identifying all studies...

Background SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods Across...

Background Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing t...

Objective To assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin. Design Federated pharmacoepidemiological evaluation in LEGEND-T2DM. Setting 10 US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences a...

Background Direct treatment disutility (DTD) represents an individual’s disutility associated with the inconvenience of taking medicine over a long period of time. Objectives The main aim of this study was to elicit DTD values for taking a statin or a bisphosphonate for primary prevention. A secondary aim was to understand factors which influence...

BACKGROUND Clinical guideline development preferentially relies on evidence from randomised controlled trials (RCTs). RCTs are the gold-standard method to evaluate the efficacy of treatments with the highest internal validity but limited external validity, in the sense that their findings may not always be applicable to, or generalisable to clinica...

Background Clinical guideline development preferentially relies on evidence from randomized controlled trials (RCTs). RCTs are gold-standard methods to evaluate the efficacy of treatments with the highest internal validity but limited external validity, in the sense that their findings may not always be applicable to or generalizable to clinical po...

Background Depression is associated with a range of adverse health outcomes, including reduced life expectancy and increased incidence of physical health conditions. The aim of this study was to quantify the association between depression and the subsequent accrual of 69 long term physical health conditions in middle age. Methods We used data from...

Background Multimorbidity, the co-existence of two or more long-term health conditions, is a public health concern due to its association with adverse health outcomes. Recent research has shown that people with multimorbidity including depression have particularly high service use and premature mortality. However, since existing research is largely...

Background: Measurement of multimorbidity in research is variable, including the choice of the data source used to ascertain conditions. We compared the estimated prevalence of multimorbidity and associations with mortality using different data sources. Methods: A cross-sectional study of SAIL Databank data including 2,340,027 individuals of all...

Background: Concerns have been raised that antipsychotic drug prescribing, which has been associated with increased mortality in people with dementia, might have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of SARS-CoV-2. We used multisource, routinely collected health-care data from Wales, UK to in...

Background: Systemic corticosteroids have been widely used for treating patients with severe acute respiratory distress syndrome. Inhaled corticosteroids may have a protective effect for treating acute COVID-19, however little is known about the potential effect of intranasal corticosteroids (INCS) on COVID-19 outcomes and severity. Objective: T...

Background Prediction of lifetime cardiovascular disease (CVD) risk is recommended in many clinical guidelines, but lifetime risk models are rarely externally validated. The aim of this study was to externally validate the QRiskLifetime incident CVD risk prediction tool. Methods Independent external validation of QRiskLifetime using Clinical Pract...

Background Multimorbidity prevalence rates vary considerably depending on the conditions considered in the morbidity count, but there is no standardised approach to the number or selection of conditions to include. Methods and findings We conducted a cross-sectional study using English primary care data for 1,168,260 participants who were all peop...

Background: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general popula...

Objective To determine whether the withdrawal of the Quality and Outcomes Framework (QOF) scheme in primary care in Scotland in 2016 had an impact on selected recorded quality of care, compared with England where the scheme continued. Design Controlled interrupted time series regression analysis. Setting General practices in Scotland and England....

Objective: To assess the real-world cardiovascular (CV) safety for sulfonylureas (SU), in comparison with dipeptidylpeptidase-4 inhibitors (DPP4i) and thiazolidinediones (TZD), through development of robust methodology for causal inference in a whole nation study. Research design and methods: A cohort study was performed including people with ty...

Background: Multimorbidity prevalence rates vary considerably depending on the conditions considered in the morbidity count, but there is no standardised approach to the number or selection of conditions to include. Methods and Findings: We conducted a cross-sectional study using English primary care data for 1168260 participants who were all peopl...

Background: Antipsychotic drugs have been associated with increased mortality, stroke and myocardial infarction in people with dementia. Concerns have been raised that antipsychotic prescribing may have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of the virus. We used multisource, routinely-collecte...

Background : Characterization studies of COVID-19 patients with chronic obstructive pulmonary disease (COPD) are limited in size and scope. The aim of the study is to provide a large-scale characterization of COVID-19 patients with COPD. Methods : We included thirteen databases contributing data from January-June 2020 from North America (US), Europ...

Background UK guidelines recommend the QFracture tool to predict the risk of major osteoporotic fracture and hip fracture, but QFracture calibration is poor, partly because it does not account for competing mortality risk. The aim of this study was to derive and validate a competing risk model to predict major osteoporotic fracture and hip fracture...

Objectives To assess the uptake of second-line antihyperglycemic agents among patients with type-2 diabetes mellitus (T2DM) receiving metformin. Design Serial cross-sectional study (2011-2021). Setting Ten US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics netwo...

Background Opioids can be effective analgesics, but long-term use may be associated with harms. In 2013, the first national, comprehensive, evidence-based pain management guideline was published, from the Scottish Intercollegiate Guideline Network (SIGN 136: Management of Chronic Pain) with key recommendations on analgesic prescribing. This study a...

Background Although morbidity and mortality from COVID-19 have been widely reported, the indirect effects of the pandemic beyond 2020 on other major diseases and health service activity have not been well described. Methods Analyses used national administrative electronic hospital records in England, Scotland and Wales for 2016–2021. Admissions an...

Objective To externally evaluate the QFracture-2012 risk prediction tool for predicting the risk of major osteoporotic fracture and hip fracture. Design External validation cohort study. Setting UK primary care population. Linked general practice (Clinical Practice Research Datalink (CPRD) Gold), mortality registration (Office of National Statist...

Background Although morbidity and mortality from COVID-19 have been widely reported, the indirect effects of the pandemic beyond 2020 on other major diseases and health service activity have not been well described. Methods Analyses used national administrative electronic hospital records in England, Scotland and Wales for 2016-2021. Admissions an...

Background Multimorbidity poses major challenges to healthcare systems worldwide. Definitions with cut-offs in excess of ≥2 long-term conditions (LTCs) might better capture populations with complexity but are not standardised. Aim To examine variation in prevalence using different definitions of multimorbidity. Design and setting Cross-sectional...

Background The great success of HIV treatments means that, increasingly, people living with HIV (PLHIV) are growing old enough to develop age‐associated comorbid conditions. We investigated the evolution of comorbid conditions and demographics among PLHIV in England. Methods In a cross‐sectional study linking Clinical Practice Research Datalink (C...

Purpose: Alpha-1 blockers, often used to treat benign prostatic hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storm release. The proposed treatment based on this hypothesis currently lacks support from reliable real-world evidence, however. We leverage an international network of large-scale heal...

Background Epidemiological studies use a wide range of depression definitions. The aim of this study was to compare some of the most common definitions of depression in a large prospective cohort study with a wide range of information collected at baseline and during follow-up. Methods We used data from the UK Biobank, a cohort study of approximat...

Background There is huge variation in the measurement of multimorbidity in research, in terms of both the number of conditions and the specific conditions included in multimorbidity definitions. Furthermore, the measurement of specific conditions is inconsistent and poorly reported, while code lists frequently remain unpublished, making reproducibi...

Background Acute kidney injury (AKI) is common and associated with adverse outcomes as well as important healthcare costs. However, evidence examining the epidemiology of acute kidney disease (AKD)—recently defined as AKI persisting between 7 and 90 days—remains limited. The aims of this study were to establish the rates of early AKI recovery, prog...

Background Clinical guidelines commonly recommend preventive treatments for people above a risk-threshold. Therefore, decision-makers must have faith in risk-prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to...

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used...

Introduction: Vaccine-induced thrombotic thrombocytopenia (VITT) has been identified as a rare but serious adverse event associated with coronavirus disease 2019 (COVID-19) vaccines. Objectives: In this study, we explored the pre-pandemic co-occurrence of thrombosis with thrombocytopenia (TWT) using 17 observational health data sources across th...

Background Recommended cardiovascular disease (CVD) prediction tools do not account for competing mortality risk and over-predict incident CVD in older and multimorbid people. The aim of this study was to derive and validate a competing risk model (CRISK) to predict incident CVD and compare its performance to that of QRISK3 in UK primary care. Met...

Background: Life expectancy in adults with human immunodeficiency virus (HIV) has increased and managing other health conditions is increasingly important for patients and healthcare planning. The aim of this study was to examine the prevalence and association between different health conditions and HIV status. Methods: We performed a cross-sect...

Background : Characterization studies of COVID-19 patients with chronic obstructive pulmonary disease (COPD) are limited in size and scope. The aim of the study is to provide a large-scale characterization of COVID-19 patients with COPD. Methods : We included thirteen databases contributing data from January-June 2020 from North America (US), Europ...

Purpose Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) Characterizing Health Associated Risks and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisati...

Background: Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of non-vaccine induced TTS in 6 European countries. Methods: Electronic medical records from France, the Netherlands, Italy, Germany, Spain, and the...

Background We investigated whether we could use influenza data to develop prediction models for COVID-19 to increase the speed at which prediction models can reliably be developed and validated early in a pandemic. We developed COVID-19 Estimated Risk (COVER) scores that quantify a patient’s risk of hospital admission with pneumonia (COVER-H), hosp...

Background : Characterization studies of COVID-19 patients with chronic obstructive pulmonary disease (COPD) are limited in size and scope. The aim of the study is to provide a large-scale characterization of COVID-19 patients with COPD. Methods : We included thirteen databases contributing data from January-June 2020 from North America (US), Europ...

Objective: Large international comparisons describing the clinical characteristics of patients with COVID-19 are limited. The aim of the study was to perform a large-scale descriptive characterization of COVID-19 patients with asthma. Methods: We included nine databases contributing data from January-June 2020 from the US, South Korea (KR), Spain,...

Background A detailed characterization of patients with COVID-19 living with obesity has not yet been undertaken. We aimed to describe and compare the demographics, medical conditions, and outcomes of COVID-19 patients living with obesity (PLWO) to those of patients living without obesity. Methods We conducted a cohort study based on outpatient/in...

Background: We described the demographics, cancer subtypes, comorbidities, and outcomes of patients with a history of cancer and COVID-19. Secondly, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza. Methods: We conducted a cohort study using eight routinely-collected hea...

As the SARS-CoV-2 virus (COVID-19) continues to affect people across the globe, there is limited understanding of the long term implications for infected patients. While some of these patients have documented follow-ups on clinical records, or participate in longitudinal surveys, these datasets are usually designed by clinicians, and not granular e...

Background: Primary prevention of cardiovascular disease (CVD) is guided by risk-prediction tools, but these rarely account for the risk of dying from other conditions (ie, competing mortality risk). In England and Wales, the recommended risk-prediction tool is QRISK2, and a new version (QRISK3) has been derived and internally validated. We aimed...

Objectives: To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children/adolescents diagnosed or hospitalized with COVID-19, and to compare them in secondary analyses with patients diagnosed with previous seasonal influenza in 2017-2018. Methods: International network cohort using real-worl...

Objective To investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents. Design Multinational network cohort study. Setting Hospital electronic health records from the United States, Spain, and China, and nationwide claims data from South Korea. Participants 303 264 patients admit...

Background Angiotensin converting enzyme inhibitor (ACEI) intolerance commonly occurs requiring switching to an angiotensin-II receptor blocker (ARB). ACEI intolerance may be mediated by bradykinin potentially affecting airway hyper-responsiveness. Objective Assess the risk of switching to ARBs in asthma. Methods We conducted a new-user cohort st...

Background: SARS-CoV-2 is straining health care systems globally. The burden on hospitals during the pandemic could be reduced by implementing prediction models that can discriminate patients who require hospitalization from those who do not. The COVID-19 vulnerability (C-19) index, a model that predicts which patients will be admitted to hospital...

Aims Maternal antithyroid drug (ATD) use during pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this risk and how it compares to untreated hyperthyroidism due to methodological limitations of previous studies. Methods Systematic review of MEDLINE and EMBASE identifying observat...

Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and...

Objective: Patients with autoimmune diseases were advised to shield to avoid COVID-19, but information on their prognosis is lacking. We characterised 30-day outcomes and mortality after hospitalisation with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seaso...

Background: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response [1,2]. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) [3] Characterizing Health Associated Risks, and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework fo...

Background: Opioids are used to treat patients with chronic pain, but their long-term use is associated with harms. In December 2013, SIGN 136 was published, providing a comprehensive evidence-based guideline for the assessment and management of chronic pain in Scotland. Aims: This study aimed to examine the impact of SIGN 136 on opioid prescribing...

Objective To estimate the proportion of patients hospitalized with COVID-19 who undergo dialysis, tracheostomy, and extracorporeal membrane oxygenation (ECMO). Design A network cohort study. Setting Seven databases from the United States containing routinely-collected patient data: HealthVerity, Premier, IQVIA Hospital CDM, IQVIA Open Claims, Opt...

Background Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro‐arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. M...

Purpose We aimed to describe the demographics, cancer subtypes, comorbidities and outcomes of patients with a history of cancer with COVID-19 from March to June 2020. Secondly, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza. Methods We conducted a cohort study using eight...