Ongoing projects in clinical epidemiology

Our overarching themes are digital health and precision prevention, and we mainly use randomized clinical trials, population-based cohorts, and cohort consortia, to answer our research questions

U-SCREEN-HF

Logo for the U-SCREEN-HF-study.Heart failure is increasingly common in the aging population. Today, circa 250,000 Swedes have a diagnosis of heart failure. Heart failure causes great suffering, and the prognosis is worse than for many cancers, yet it is critically underdiagnosed and undertreated. It is estimated that half of those that have heart failure have not yet been diagnosed or treated.

The aim of the randomized clinical trial "Hembaserad screening för hjärtsvikt (U-SCREEN-HF)" is to investigate whether a stepwise multimodal home-based screening with targeted rapid point-of-care testing of people with symptoms of heart failure leads to an earlier diagnosis of heart failure, and consequently earlier treatment, better quality of life, and a better prognosis.

Because heart failure produces multiple symptoms, the potential for symptom-driven screening for undiagnosed heart failure should be good. Using digital tools to capture symptoms in the general population that may indicate heart failure, persons with high a probability of heart failure will be randomized to either receive or not receive a self-administered finger prick blood-sampling kit by mail. The returned dried blood spots are analyzed for the heart failure marker NTproBNP, and those with elevated levels are invited to the clinic for examinations including an artificial intelligence-driven ultrasound of the heart, whereby a diagnosis of heart failure can be confirmed or ruled out.

All participants will be followed using digital questionnaires about heart failure symptoms and quality of life, and in healthcare databases, to evaluate whether the screening influenced heart failure diagnosis, treatment and prognosis.

Results will inform all stakeholders involved in the care of patients with heart failure (physicians, healthcare systems, clinical guidelines, policy makers, payers, patient organizations), providing the evidence base needed to change clinical practice for a more efficient heart failure diagnostic pathway.

Research theme: Digital Health

This research theme utilizes novel data sources such as patient-reported data, sensor data, and electronic health records, and novel digital tools, to improve clinical treatment decisions and clinical research methods. 

The Anders Wiklöf Institute for Heart Research

The Anders Wiklöf Institute for Heart Research is a focused research initiative striving towards improved prediction and prevention of cardiovascular diseases. The Institute was made possible through a donation by Åland businessman Anders Wiklöf. The Institute brings together experts in cardiovascular diseases, computer science, artificial intelligence (AI), statistics, innovation, and the administration and accessibility of medical data.The Institute is co-localized with with the University’s AI initiative AI4Research. This interdisciplinary initiative now has the opportunity to utilize the outstanding healthcare data that are unique to Sweden in order to improve the healthcare sector’s ability to predict and prevent cardiovascular diseases.

Enhancing emergency department safety, efficacy and cost-effectiveness by artificial intelligence (EmergAI)

Emergency care costs are increasing in developed societies, both in rates of emergency department (ED) visits per person and in costs per visit, and are growing faster than other areas of healthcare spending. Based on limited data in a chaotic environment, emergency medicine doctors need to make quick decisions about patients’ probabilities for a large number of diagnoses and risks, and steer investigations and patient management in the right directions. Both underestimation and overestimation of the likelihood of a dangerous diagnosis can lead to increased costs and patient harm. Numerous sources of unstructured data are available in the ED. These data are today not processed jointly, but are aggregated in the minds of doctors with different experiences and frames of reference, to varying effectiveness. Incomplete history-taking is often the reason for diagnostic errors in the ED. Hence, there is desperate need and immense societal potential for clinical decision-support systems in the ED. In this project, we aim to develop a clinical decision support system for emergency medicine doctors, using sensor data, electronic health records data, registry data, and patient-reported data, validated in a randomized clinical trial, in order to improve the safety, efficacy and cost-effectiveness of emergency care; and investigate the usefulness, effectiveness and safety of the new decision support system in a randomized clinical trial.

Electronic informed consent (eIC)

We have also developed a novel system for electronic informed consent, for use in clinical research. The signing of a consent form for patient participation in research studies is vital in order to comply with regulatory requirements. The method most commonly used today is signature with pen on paper, and with an informed consent procedure that is paper-based w physical participant signature and doctor's counter-signature (in order to comply with Good Clinical Practice, GCP), patients must be physically present at the study site in order to sign the consent form, and a study monitor must travel to each study site to verify each signature. Our novel electronic informed consent application (eIC) has been developed and successfully validated according to GCP-GAMP5, allows for video-based inclusion and web-based monitoring, and is now being used in randomized clinical drug trials.

Future clinical research methods

Digital systematic patient-reported health data have seen significant development in the last decade. Evidence-based patient-reported outcome measure tools (PROMs) have hitherto been used sparsely in healthcare, but currently show promise due to adaptations to digital versions, that are at least as good as PROMs in paper format. Potential benefits include simplified data management, improved completion rate through digital reminders, and increased possibilities to adapt to disabilities. Acces to a digital symptom reporting tool has even suggested to increase survival in cancer patients. Three-dimensional pain drawings are a novelty - the state-of-the art for pain drawings is still to use paper and pencil. A few studies have showed good validity and reliability of digital pain drawings. The usefulness of continuous access to a self-directed self-reported symptom tracking system in research studies is unknown. We have developed such a system for self-directed digital symptom recordings (Symptoms), and now investigate the clinical and research utility of it. We also investigate the potential for home-based collection of capillary blood (self-administered using lancets and filter paper via mail).

A framework for monitoring of new drugs in Sweden

In order to monitor the net public health benefit of new drugs, especially in the light of recent stepwise approval approaches, there is a need to optimize real-time post-marketing evaluation of new drugs using data collected in routine care. We have proposed a framework for continuous monitoring of the effectiveness, safety and cost-effectiveness of new drugs, using prospectively determined protocols designed in collaboration between all relevant stakeholders. The model, called “Sequentially Evaluated Nonrandomised Comparative Effectiveness (SENCE)”, is based on modern causal inference methods, and is designed for electronic health records data, but can use any data source to provide timely observational evidence as soon as data are generated in the healthcare systems. We are developing and researching the method continuously.

Åsa Muntlin, Adjunct senior lecturer at the Department of Medical Sciences

Research theme: Precision Prevention

Signild Åsberg, Associate professor at the Department of Medical Sciences.

This research theme investigates the precision medicine concept in cardiovascular prevention settings. Can prevention be tailored, or does one size really fit all?

Precision prevention

The concept of precision medicine promises maximisation of treatment benefit and minimization of treatment harm by using subtle characteristics (typically involving, but not limited to, gene variants) of patients with the same trait to guide treatment decisions. 

Cardiovascular prevention suffers from poor adherence by patients to the preventive treatments. For instance, only half of those who are prescribed blood pressure-lowering drugs are adherent to the treatment. Hence, any useful application of precision medicine to cardiovascular prevention must address improvement of adherence. The potential public health gains from increasing adherence are vastly larger than e.g. developing a new drug with a slightly more effective blood pressure-lowering effect. 

The main challenge to adherence is patient motivation. We have designed a research program to address patient motivation from two different angles. With the Precision HYpertenSIon Care (PHYSIC)trial, we aim to increase patient motivation and adherence by developing a point-of-care test to minimize side effects of blood pressure-lowering drugs. In the Markers of Imminent Myocardial Infarction (MIMI)study, we aim to increase patient motivation for preventive treatments by developing a point-of-care test to predict a near-term myocardial infarction. In both the PHYSIC and MIMI studies, nearly 1000 proteins, 2000 metabolites, gene methylation, and mRNA will be analysed. 

Decreasing the burden of disease caused by high blood pressure

We have led a series of studies in the Blood Pressure Lowering Treatment Trialists' Collaboration investigating optimal targeting of blood pressure-lowering treatment. This endeavour has involved developing meta-analytic methods in conjunction with randomized clinical trials. Recent contributions to that evidence are investigations of the benefit of selecting people for blood pressure-lowering treatment based on their cardiovascular disease risk rather than their blood pressure. In addition to the randomised trials, we are also utilizing cohort studies to investigate causes of high blood pressure and disturbed diurnal blood pressure patterns using metabolomics and proteomics methods, and to investigate the associations of high blood pressure and disturbed diurnal blood pressure patterns to detrimental outcomes.

Improving stroke management and outcomes

Stroke is the most common clinical manifestation of vascular disease in the brain. We have assembled a cohort study of >200000 stroke patients, registered in Riksstroke (the Swedish Stroke Register) during 2001 through 2009, and a separate cohort study also including TIA-patients for the years 2011 through 2014. Cross-linking with the National Patient Register, the Prescribed Drug Register and Cause of Death Registers has been done to achieve data on previous hospitalizations, drug therapy, death dates, and causes of death. The objectives were to assess co-morbidity, functionality and drug treatment in stroke patients before and after the stroke/TIA. Of particular interest is the use of anti-thrombotic treatment before and after the stroke/TIA. In addition, and in cooperation with Gothenburg University, we have analyzed epilepsy before and after stroke.

Third millennium lifestyle habits

We are investigating risks and benefits of lifestyle habits, mainly tobacco, obesity and physical activity. We have observed clear health risks with use of smokeless tobacco, we have observed an increased risk of atrial fibrillation with very high levels of physical activity (using a cohort of Vasaloppet participants), and we are comparing health effects of significant weight loss obtained through bariatric surgery (using the Swedish bariatric surgery registry, SOReg) versus that obtained through a lifestyle program (Itrim).

Cohort consortia

The Swedish Cohort Consortium (Cohorts.se)

Our role: Johan Sundström PI and initiator, all aspects of project management and funding

Web: Cohorts.se

Marker paper: pubmed.ncbi.nlm.nih.gov/31363756

Sweden is a country with unique opportunities for epidemiological research, thanks to our high quality national socio-demographic and medical registries, covering the whole population since many decades. We have a large number of carefully collected population-based cohorts that have been followed for decades, as well as novel cohorts examined with the latest techniques. But Swedish cohort resources are suboptimally used. We have initiated a Swedish national infrastructure for cohort studies, the Swedish Cohort Consortium (Cohorts.se). In a pilot study of the infrastructure, we have successfully collated individual participant data from more than twenty Swedish cohorts totalling more than one million participants and twenty million person-years at risk. The full consortium will be open for all Swedish cohorts.


The Markers of Imminent Myocardial Infarction (MIMI) study

Our role: Johan Sundström PI and initiator, all aspects of project management and funding

Web: mimistudy.se

We have assembled and are leading a ground-breaking collaborative nested case-cohort study, the Markers of Imminent Myocardial Infarction (MIMI) study, of 2500 initially cardiovascular disease-free persons in eight general population cohorts from all parts of Europe, among which 500 develop a myocardial infarction within the first six months after the baseline examination. In the MIMI study sample, we are measuring a wide array of novel biomarkers in biobanked blood samples, aiming to identify predictors of an imminent myocardial infarction.

Cohorts

The Swedish CArdioPulmonary bioImage Study (SCAPIS)

Our role: Johan Sundström PI for Uppsala site first examination cycle, project management

Web: medsci.uu.se/scapis & scapis.org

Marker paper: pubmed.ncbi.nlm.nih.gov/26096600

The Swedish CArdioPulmonary bioImage Study (SCAPIS)cohort combines the use of new imaging technologies, advances in large-scale omics and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years, invited at random from the community. Participants were examined at six university hospitals using questionnaires, blood and urine biochemistry and biobank storage, anthropometry, electrocardiography, blood pressures including ankle–brachial index, a 7-day accelerometry, lung function tests including dynamic spirometry and gas diffusing capacity, imaging of carotid arteries with ultrasound and MRI in case of large plaques, and a comprehensive CT scan of the heart, lungs and fat depots. The calcium content in each coronary artery was measured and summed to produce a total coronary artery calcification score (CACS), and a contrast CT coronary angiography was performed to assess lumen obstruction and morphology of calcified and noncalcified plaques. Structural changes in lung tissue were imaged over the full lung volume after beta-2 receptor stimulation. Epicardial, subcutaneous, intra‐abdominal, intramuscular and intrahepatic fat deposits were assessed, and the liver tissue was characterized.


The Epidemiology for Health (EpiHealth) study

Our role: Lars Lind PI and initiator, all aspects of project management and funding

Web: epihealth.se/For-scientists & maelstrom-research.org/mica/individual-study/epihealth#

Marker paper: pubmed.ncbi.nlm.nih.gov/23435790

In the EpiHealthstudy, men and women between 45 and 75 years of age were invited at random from the community to study the interplay between genes and life-style factors on the development of common disorders seen in the elderly. Data on lifestyle exposures were collected using a web-based questionnaire and serum/plasma/DNA was biobanked at a visit to a test centre where also physiological measures including blood pressure, lung function, cognitive function, anthropometry and ECG were recorded. Between 2011 and 2015, circa 14,000 participants were included in Uppsala, and circa 11,000 were included in Malmö between 2012 and 2018.


The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study

Our role: Lars Lind PI and initiator, all aspects of project management and funding

Web: medsci.uu.se/pivus

Marker paper: pubmed.ncbi.nlm.nih.gov/16141402

The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS)study is a population-based longitudinal cohort study, started in 2001, of men and women aged 70. A number of cardiovascular characteristics have been collected, e.g. measurements of intima-media thickness, three different tests of endothelial function, MRI of the large arteries, myocardium and adipose tissue, and a large number of biochemical biomarkers, including genomics, proteomics and metabolomics.  A reinvestigation of the cohort at age 75 was performed between March 2006 and Sep 2009, and a reinvestigation at age 80 was performed 5 years later. Apart from analyses of classical risk factors, ultrasound of the carotid arteries and the heart will be performed together with 2 cognitive function tests and MRI of the brain.


The Youth towards year 2000 (Y2K) cohort

Our role: Johan Sundström PI

Web: snd.gu.se/sv/catalogue/study/ext0265

Marker paper: pubmed.ncbi.nlm.nih.gov/8955480

The Youth towards year 2000 (Y2K)cohort includes 411 adolescents (193 boys and 218 girls) born 1978-79 in two socioeconomically contrasting cities, Uppsala, a university city in eastern Sweden, and in Trollhättan, an industrial town in the western part of the country. The participants were invited at random from the community, and were examined on three different occasions, at 15, 17 and 20 years of age, starting in 1993-94. Dietary examinations included a food frequency questionnaire and a combined estimated and weighed 7-day dietary record. Assessments of alcohol and tobacco habits and other lifestyle and psychosocial circumstances were determined using questionnaires. Physical activity was assessed using a questionnaire and a 7-day physical activity diary, validated in a subsample using doubly labelled water and indirect calorimetry examinations. Anthropometry and blood pressure were measured. Bone mineral density and body composition was measured using dual-energy X-ray absorptiometry. Serum and in some cases whole blood from ages 15, 17 and 20 are stored in Uppsala Biobank, in addition to measurement data and questionnaire responses.


The Prospective investigation of Obesity, Energy production and Metabolism (POEM) longitudinal study

Our role: Lars Lind PI and initiator, all aspects of project management and funding

Web: medsci.uu.se/poem

Marker paper: pubmed.ncbi.nlm.nih.gov/23625114

A randomized sample of 500 individuals selected from the inhabitants of the Uppsala County aged 50 have been invited for the baseline examination. The subjects were recruited from 2010 to 2016. The subjects underwent a very detailed examination regarding cardiovascular status and metabolism, including vascular tests, echocardiography, an exercise test with gas exchange, indirect calorimetry, OGTT and sleep apnea recordings.


The Uppsala Longitudinal Study of Adult Men (ULSAM)

Our role: Participation in project management and data collection at multiple examination cycles

Web: pubcare.uu.se/ulsam

Marker paper: pubmed.ncbi.nlm.nih.gov/1216390

The ULSAM study was started in 1970, when 2322 men at the age of 50 participated in a health survey. The men have thereafter been investigated again at ages 60, 70, 77, 82, 88 and 92 years, respectively. The phenotyping focus in the ULSAM cohort has been on gluco- and lipometabolic aspects of cardiovascular disease, but several other research areas have also been explored, such as nutrition, osteoporosis, and dementia. The follow-up time for morbidity and mortality through national registers is now >40 years.

RANDOMIZED Clinical trials

The Precision HYpertenSIon Care (PHYSIC) Study: A Double-Blind, Randomized, Repeated Cross-Over Study

Our role: Johan Sundström PI and initiator, all aspects of project management and funding

Web: clinicaltrials.gov/ct2/show/NCT02774460

Marker paper: pubmed.ncbi.nlm.nih.gov/30265168

High blood pressure is the leading risk factor for premature deaths and a major cost to societies worldwide. Effective blood pressure-lowering drugs are available, but patient adherence to them is low, likely partly due to side effects. To identify patient-specific differences in treatment effects, a repeated cross-over design, where the same treatment contrasts are repeated within each patient, is needed. Such designs have been surprisingly seldom used given the current precision medicine hype. The Precision HYpertenSIon Care (PHYSIC) study aims to investigate if there is a consistent between-person variation in blood pressure response to the common blood pressure-lowering drug classes of a clinically relevant magnitude, given the within-person variation in blood pressure. The study will also investigate the between-person variation in side effects of the drugs. In a double-blind, randomized, repeated cross-over trial, 300 patients with mild hypertension will be treated with four blood pressure-lowering drugs (candesartan, lisinopril, amlodipine, and hydrochlorothiazide) in monotherapy, with two of the drugs repeated for each patient.If the study indicates that there is a potential for precision hypertension care, the most promising predictors of blood pressure and side effect response to the drugs will be explored, as will the potential for development of a biomarker panel to rank the suitability of blood pressure-lowering drug classes for individual patients in terms of anticipated blood pressure effects and side effects, with the ultimate goal to maximise adherence.


TIMING of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation (TIMING)

Our role: Signild Åsberg co-PI, project management

Web: clinicaltrials.gov/ct2/show/NCT02961348

Marker paper: pubmed.ncbi.nlm.nih.gov/29197413

Oral anticoagulation therapy is well established and highly recommended for the prevention of recurrent ischemic stroke in patients with atrial fibrillation, but the optimal time point to start after an acute ischemic stroke is not known. The intervention in the TIMING of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation (TIMING)study will be timing of oral anticoagulation treatment onset. This study will use the Swedish Stroke Register for enrolment, randomization and follow-up, with additional data linkage from other mandatory national registers. Primary outcome will be assessed at 90 days and secondary outcomes (including all-cause mortality and health economic analyses) and will be assessed at 90 days and up to one year after the index ischemic stroke.


SGLT2 inhibitor or metformin as standard treatment of early stage type 2 diabetes (SMARTEST)

Our role: Johan Sundström co-PI and co-initiator, innovation of digital tools, co-funding

Web: clinicaltrials.gov/ct2/show/NCT03982381 and medsci.uu.se/smartest

Marker paper: pubmed.ncbi.nlm.nih.gov/34389234

SGLT2 inhibitors have been shown to reduce cardiovascular and renal complications in type 2 diabetes (T2D) patients at high cardiovascular risk. Metformin is currently widely used as initial monotherapy in T2D but lacks convincing data to show that it reduces risk of complications. We aim to compare the SGLT2 inhibitor dapagliflozin and metformin as first-line T2D medication with regard to development of complications in a registry-based randomised controlled trial. The SMARTEST trial, managed at the Clinical diabetes and metabolism unit, will enrol 4300 subjects at 30-40 study sites in Sweden who will be randomised 1:1 to either metformin or dapagliflozin. Participants must have T2D duration <4 years, no prior cardiovascular disease, and be either drug-naïve or on monotherapy for T2D. The primary endpoint is a composite of all-cause death, major adverse cardiovascular events and occurrence or progression of microvascular complications (retinopathy, nephropathy, diabetic foot lesions). Secondary endpoints include individual components of the primary endpoint, start of insulin therapy, risk factor biomarkers, patient-reported outcome measures, and cost-effectiveness analysis. Outcomes will primarily be assessed using nationwide healthcare registries.

Professor Lars Lind examines a patient with ultrasound.
Last modified: 2023-04-21