KI-MSD ongoing and finalised projects

• KI: Fang Fang, Karin Sundström
• MSD CORE: Carl Baxter, Stina Salomonsson

Project Summary: A diagnosis with cervical or endometrial cancer may have severe implications and these diagnoses are likely to have negative consequences also impacting the women’s family, in terms of both health and economic effects. The magnitude of the impact of these cancer diagnoses are likely to relate to the outcome for the patients. However, impact on a population level in terms of health-related consequences such as burden of mental health-related issues, level of education and family income post diagnosis may be challenging to both capture and interpret. The aims of this study are to describe the incidence and prevalence of endometrial and cervical cancer during the most recent years in Sweden as well as to investigate the association between diagnosis of endometrial and cervical cancer and mental disorders, focusing on the female cancer patient and her first-degree relatives. The study is a non-interventional observational study utilising data from the Swedish population-based registries.

• KI: Irma Fredriksson
• MSD: Demet Sönmez

Project Summary: The definition of triple negative breast cancer (TNBC) disease is different in Sweden compared to international guidelines where the Swedish definition encompasses a somewhat broader patient population due to differences in biological cut-offs used. These differences in definition may lead to differences of disease treatment such as usage of endocrine therapy. For the implementation of new treatment modalities as well as evaluation of current recommended treatments it is of importance to investigate, in-depth, if patients that would be classified as TNBC according to the Swedish (broader) definition but not the international definition respond differently or have inherent different clinical characteristics. The objectives of this study are to describe demographic and clinical characteristics of patients at diagnosis, to describe treatment patterns and surgical outcomes in patients with early triple negative breast cancer, and to describe disease progression of patients diagnosed at an earlier stage and progressing to more advanced stages. The researchers also aim to describe real-world overall survival outcomes in patients diagnosed with different stages of TNBC and to investigate potential differences in patient characteristics and overall survival outcomes in patients defined according to the different criteria for TNBC (international vs Swedish).

• KI: Andreas Pettersson, Johan Askling
• MSD CORE:  Thomas Jemielita, Kai-Li Liaw
• Publication: Manuscript submitted for publication

Project summary: There is considerable interest in using real-world data (RWD) to generate real.-world evidence to support regulatory decisions about the effectiveness of drug products. The overarching aim of this project was to develop and test research strategies for using RWD together with clinical trial data to generate evidence for clinical and regulatory decision making in oncology.

• KI: Karin Sundström
• MSD CORE: Ya-Ting Chen

Project summary: Current data concerning the impact and effectiveness of human papillomavirus (HPV) vaccination is needed to support policy and decision making by public health authorities, clinicians, physicians and scientists. Additionally, understanding data system characteristics and utilisation will support our understanding of vaccines impact and effectiveness with HPV elimination as the goal. The focus of this project is to discuss, understand and describe Gardasil HPV vaccine impact and effectiveness, as well as data systems used for monitoring and evaluating screening and vaccination. Furthermore, the aim is also to understand and identify gaps that need to be addressed in order to support elimination goals and to identify scientific research studies that can conducted to find in gaps related to vaccines impact and effectiveness and data systems.

• KI: Karin Sundström
• MSD CORE: Ya-Ting Chen, Joseph Tota

Project Summary: While the human papillomavirus (HPV) vaccination GARDASIL clinical trial results were favorable, they were derived from randomized, placebo-controlled studies in selected populations. Since the clinical trial setting may be somewhat different from those in which the vaccine is used, it is important to monitor the impact of the vaccine after its launch. This study is meant to provide real-world evidence of the association between GARDASIL vaccination and decreasing trends in cervical neoplasia incidence. The overall aims are to monitor the impact/effectiveness of GARDASIL in the general female population in Sweden utilizing registry data to describe the changing trends of HPV-related disease burden as well as to provide evidence of the association between GARDASIL vaccination and decreasing trends in cervical neoplasia incidence.

• KI: Karin Sundström
• MSD CORE: Susanne Hartwig

Project Summary: Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide. Though most infections resolve, some persist and can lead to low- and high-grade cervical intraepithelial neoplasia (CIN grade 1 and CIN grades 2 and 3, respectively) and adenocarcinoma in situ (AIS). If the CIN lesion does not spontaneously regress, nor is successfully diagnosed and treated, the HPV infection can ultimately lead to invasive cervical cancer (ICC). The study objectives of this study is to assess if a 2-dose schedule with HPV vaccine GARDASIL is non-inferior when compared to a 3-dose vaccination schedule in the prevention of low- and possibly high-grade cervical intraepithelial neoplasia. The study will start in Dec 2021 and end in Dec 2030, with a study report expected in 2031.

• KI: Karin Sundström
• MSD CORE: Joseph Tota

Project Summary: Recurrent Respiratory Papilloma (RRP) is a rare condition marked by recurrent exophytic papillomas of the epithelial mucosa in the respiratory tract. Despite being rare, the health and economic burden associated with RRP is substantial. Nearly 20% of RRP patients experience aggressive disease requiring >40 lifetime procedures, and some patients may undergo >100 surgeries in their lifetime. As there is currently no cure, surgery remains the mainstay of treatment, with effort to maintain voice quality and airway patency. Epidemiologic and clinical data have elucidated the role of HPV in RRP, with HPV types 6 and 11 accounting for over 90% of RRP cases. To date, no study has evaluated the effectiveness of HPV vaccination against RRP. Due to the low incidence of juvenile onset RRP (JoRRP) and adult onset RRP (AoRRP), a randomized controlled trial to evaluate the efficacy of HPV vaccination against incidence of RRP would be prohibitively large and complex. The Scandinavian region has established comprehensive systems of registries nationwide that afford the opportunity to evaluate the effectiveness of GARDASIL in the general female population with minimal biases due to completeness and representativeness of the data. The overall aim of this study is to evaluate the effectiveness of GARDASIL vaccination against incidence of recurrent RRP. Effectiveness will be evaluated separately for JoRRP and adult onset RRP (AoRRP).

• KI: Gustaf Bruze
• MSD CORE: Salini Mohanty

Project Summary: Meningitis is an inflammation of the fluid and membranes (meninges) surrounding the brain and spinal cord. Several types of bacteria cause meningitis (e.g. Streptococcus pneumoniae, Neisseria meningitides, Haemophilus influenzae) which can have very serious outcomes including death. Survivors of bacterial meningitis are at risk from long-term disabling sequelae and impaired quality of life. There are limited data on the severity and distribution of different types of sequelae as well as the financial burden that families and society incur in caring for disabled individuals. In general, most studies have limited patient follow up after their initial infection and do not examine the breadth of sequelae including impaired school performance, behavioral problems, and inability to fulfill professional responsibilities among other sequelae. The aim of this study is to describe post-meningitis sequelae following a bacterial meningitis hospitalization by outcome, type (e.g. cognitive, hearing, vision, behavior, and psychiatric disabilities), severity of sequalae and causative pathogen. The study also aim to estimate the long-term burden of suffering from post-meningitis sequelae following a hospitalization for a bacterial meningitis diagnosis by estimating: disease burden, direct healthcare costs, non-healthcare related burden, direct non-healthcare costs, and indirect costs.

• KI: Joakim Dillner, Karin Sundström
• MSD CORE: Patricia Saddier, Susanne Hartwig
• Publications: Published in Vaccine 2018, Cancer Medicine, 2019, Hum. Vaccines Immunother. 2020 and more.

Project summary: The Gardasil 3-dose Nordic Country Surveillance study was initiated to provide important real-world data on the impact of the the 4-valent human papillomavirus (HPV) vaccine Gardasil after its launch. The study aimed to monitor the impact/effectiveness of Gardasil in the general female population in Sweden, utilizing registry data to describe the changing trends of HPV-related disease burden as well as to provide evidence on the association between Gardasil vaccination and decreasing trends in cervical neoplasia incidence. The results demonstrated that populations with organized HPV vaccination programs saw drops in HPV vaccine types, that significant decline in HPV positivity was seen in the 18–26 age group and that both the low-risk HPV6/11 and the high-risk 16/18 vaccine types had declines.

• KI: Karin Sundström
• MSD CORE: Patricia Saddier, Susanne Hartwig

Project Summary: Prior to initiating a potential 2-dose impact/effectiveness study of Gardasil (HPV vaccine) in Sweden, MSD and KI initiated this study to assess its feasibility, in particular the feasibility of evaluating certain HPV infection outcomes in Sweden. The feasibility results were positive and a Gardasil 2-dose impact/effectiveness study is now ongoing (please see more information under ongoing projects below).

• KI: Davide Vetrano
• MSD CORE: Stina Salomonsson
• Publication: Published in Ageing Res Rev, 2021

Project Summary: Untangling the interdependency of infections, immunity and frailty may help to clarify their roles in the maintenance of health in aging individuals. In this scoping review, the researchers systematically collected evidence on the impact of common infections such as influenza, pneumonia and varicella zoster on frailty development, as well as investigated the role of frailty in the response to immunisation of older adults. Findings were discussed under a unifying framework to identify knowledge gaps and outline their clinical and public health implications to foster a healthier aging. A moderately strong evidence of an association between infections and physical as well as cognitive decline (two essential dimensions of frailty) was provided. Furthermore, the results showed that frailty was associated with an impaired immune response in older ages, likely due to immunosenescence.

• KI: Anders Wimo, Maria Eriksdotter, Bengt Winblad
• MSD CORE: Rezaul Khandker, Baishali Ambegaonkar
• Publication: Published in J Alzheimer’s Dis, 2020

Project summary: A long-term horizon is necessary when the socioeconomic consequences and the potential effects of interventions in Alzheimer's disease (AD) are estimated. The aim of this study was to illustrate the potential societal costs of AD across the disease continuum and to illustrate the potential cost-effectiveness of a hypothetical intervention with disease modifying treatment (DMT). Based on the Swedish dementia registry (SveDem), a Markov model was used to simulate a virtual cohort of 100,000 people with mild cognitive impairment (MCI) due to AD (AD-MCI) in Sweden for 40 years starting at the age of 60. The results demonstrated that lifetime societal costs of AD are substantial and that a future DMT may be potentially cost-effective given assumed treatment effects and costs, but that cost savings are unlikely. At least 25-50% slowing of disease progression would results in favorable epidemiological and health-economic outcomes.

• KI: Barbro Kjellström
• MSD CORE: Tracey Weiss

Project Summary: Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterised by pathologic pulmonary vascular remodeling, resulting in high pulmonary artery pressure and right ventricular dysfunction. The 5-year survival rate for PAH is around 55%. Three non-invasive measures of PAH severity (6-minute walking distance (6MWD), World Health Organisation functional class (WHO FC), and-terminal pro-brain natriuretic peptide (NT-proBNP)) are used to assessed risk status according to the 2022 European Society of Cardiology and European Respiratory Society (ESC/ERS) Pulmonary Hypertension guidelines. The same variables are used in “Achievement of multiple components of clinical improvement (MCI)”, a novel endpoint recently included in the sotatercept clinical program. It is hypothesised that achievement of lower risk status according to the 2022 ESC/ERS guidelines and the MCI has beneficial effects on key clinical outcomes in the PAH population. The project is a retrospective registry study evaluating the feasibility of characterising therapy changes after follow-up by risk status assessment in patients diagnosed with PAH between 2008-2022. Data available from the Swedish PAH & CTEPH registry (SPAHR) and the National Board of Health and Welfare (NBHW) will be used.

• KI: Lars Lund, Gianluigi Savarese
• MSD CORE: Mandy Tan, Dominik Lautsch

Project Summary: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a commonly used biomarker in heart failure (HF) for diagnosis, assessing disease severity, or establishing prognosis. Increases in the concentration of NT-proBNP over time are related to higher risks of hospitalisation and death, and cutoffs of ~5,000 and ~8,000 pg/mL may serve the purpose of risk stratification. However, there is limited real-world evidence on the prevalence of NT-proBNP testing and distribution of NT-proBNP levels in patients with heart failure with reduced ejection fraction (HFrEF) especially those following a worsening heart failure event (WHFE), as well as in patients with heart failure with Mildly Reduced ejection fraction and preserved ejection fraction (HFmrEF/HFpEF). The objectives of this retrospective cohort study are therefore; 1) to describe the prevalence of NT-proBNP in patients with HFrEF, WHFE and NWHFE (patients not following a WHFE); 2) to examine the proportions of patients undergoing NT-proBNP testing at different time points and different settings in the above-defined groups; and 3) to assess the distribution of NT-proBNP levels in the above-defined groups. The study findings will inform the utilisation and distribution of NT-proBNP in clinical practice, which will further have implications for the use of this biomarker in clinical practice.

• KI: Hannes Hagström, Jonas Ludvigsson
• MSD CORE: Gail Fernandes, Tongtong Wang

Project Summary: Prognosis in nonalcoholic fatty liver disease (NAFLD) is difficult to predict. Previous studies have primarily focused on assessing the prognostic performance of fibrosis staging or other clinical risk factors ascertained at the NAFLD diagnosis on incident mortality and liver-related endpoints. The aim of this no-interventional study is to investigate the long-term prognosis in a large cohort of biopsy verified NAFLD patients with a prolonged follow-up time.

• KI: Tomas Jernberg
• MSD CORE: Bob Boggs
• Publication: Published in European Heart Journal - Quality of Care & Clinical Outcomes, 2021

Project summary: Reduction of low-density lipoprotein cholesterol (LDL-C) with statins in patients with myocardial infarction (MI) reduces the risk of recurrent cardiovascular events. The aim of this study was to assess LDL-C treatment target attainment among MI patients according to the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidaemia guidelines from 2011 and 2016. Using the nationwide registers, with data from patients with a recent MI who were followed up to 12–14 months after the event, the results revealed that one out of three patients with a recent MI had not attained the LDL-C target of the 2011 ESC/EAS guidelines and two out of three patients had not attained the LDL-C target of the 2016 guidelines.

• KI: Barbro Kjellström
• MSD CORE: Rogier Klok
• Publication: Published in ESC Heart Failure, 2021

Project summary: Low‐risk status in pulmonary arterial hypertension (PAH) predicts better survival. This study aimed to describe changes in risk status and treatment approaches over multiple clinical assessments in PAH, taking age and comorbidity burden into consideration. Using data from the Swedish PAH registry, the results demonstrated that most patients with PAH did not meet low‐risk criteria during the 3 year follow‐up. In addition, whereas patients at low risk at the first‐year follow‐up tended to continue at low‐risk long term, those who maintained or deteriorated into intermediate or high risk at first‐year follow‐up tended to remain at those risk classes long term. The study also indicated that there was room for treatment escalation in patients that had not reached a low‐risk status at the first‐year follow‐up, which may partly be related to that many patients were treated before implementation of the 2015 ESC/ERS PH guidelines.

• KI: Barbro Kjellström
• MSD CORE: Rogier Klok
• Publication: Published in Pulmonary Circulation, 2020

Project summary: Pulmonary arterial hypertension (PAH) is a rare, chronic disease associated with high mortality, where improvements in treatment strategies over the last decades have led to better symptom control and outcomes. Phosphodiesterase-5 inhibitors are commonly used in pulmonary arterial hypertension but, as suggested by the RESPITE study, phosphodiesterase-5 inhibitor therapy (mono-/combination) does not always have a satisfactory treatment effect. This study aimed to investigate the clinical course of PAH patients not at treatment goal after at least 90 days of treatment with phosphodiesterase-5 inhibitors, alone or in combination with other PAH therapies. The study included patients from the Swedish Pulmonary Arterial Hypertension Registry, and demonstrated that PAH patients treated with phosphodiesterase-5 inhibitors, as single or combination therapy and not achieving the pre-specified treatment goals after 90 days have an unfavorable clinical course.

• KI: Juan Jesus Carrero
• MSD CORE: Swapnil Rajpathak, Rogier Klok
• Publication: A study report describing the two cohorts, documenting the data being compiled and providing examples of possibilities for collaborative research has been finalised.

Project summary: The Stockholm CREAtinine Measurements (SCREAM) project is a region representative healthcare extraction of individuals undergoing at least once creatinine or albuminuria testing. A first extraction, including 1.2 Million individuals, 68% of the complete population census for the region of Stockholm, Sweden has previously been conducted (PMID: 26798472) covering the period 2006-2011. The coverage was virtually complete for patients with cardiovascular disease or diabetes, and included >90% of all elderly. In this project, an expansion of the SCREAM data collection period until December 2019, with a battery of additional laboratory biomarkers and linkages to new data sources was performed. The SCREAM exploitation was focused around four key research methodologies: clinical epidemiology, health services research, pharmacoepidemiology and health economics.

• KI: Jonas Ludvigsson
• MSD CORE: Yanbing Zhou and Larry Liu

Project Summary: Recent healthcare reform has significantly improved the universal healthcare coverage in China. Healthcare systems including hospitals, government agencies, insurance companies and academic centers have accumulated enormous amount of electronic medical records, claims and disease registries in China.  However, the healthcare data infrastructure in China is very fragmented. On the other hand, Sweden has one of the most advanced healthcare data systems in the world. Based on the literature review, case analysis and key informant interview, this study aims to understand the data policy, infrastructure, source, accessibility, quality, management and utilisation of some major healthcare data systems with a focus on cancer in China from individual cohort to national surveillance, from specific disease to regional healthcare archive. Furthermore, to review the healthcare data systems in Sweden and to identify the differences regarding data policy, accessibility and utilisation between the two countries for recommending further development opportunities in China and discuss policy implications.

• KI: Mats Brommels
• MSD CORE: Stina Salomonsson
• Publication: Published J Med Internet Res, 2021

Project summary: Technological advances have radically changed the opportunities for individuals with chronic conditions to practice self-care and to co-produce health care and research. Digital technologies enable patients to perform tasks traditionally carried out by health care professionals in a more convenient way, at lower costs, and without compromising quality. Patients may also share real-world data with other stakeholders to promote individual and population health. However, there is a need for legal frameworks that enable patient privacy and control in such sharing of real-world data. This study aimed to propose a conceptual model that describes how patient-controlled real-world data can be shared effectively in chronic care management, in a way that supports individual and population health, while respecting personal data privacy and control. The context of cystic fibrosis (CF) care in Sweden was chosen where coproduction between patients, their families, and health care professionals is critical in the introduction of new drugs and a qualitative content analysis guided by the knowledge commons framework were conducted.

The model proposes how technical and legal structures that protect the integrity and self-determination of patients can be implemented, which may be applicable in other chronic care settings as well.