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      External validity of phase III trials on vaccines against SARS-CoV-2 to a middle-aged and elderly Western European population

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          Abstract

          Initial results from various phase-III trials on vaccines against SARS-CoV-2 are promising. For proper translation of these results to clinical guidelines, it is essential to determine how well the general population is reflected in the study populations of these trials. This study was conducted among 7162 participants (age-range: 51–106 years; 58% women) from the Rotterdam Study. We quantified the proportion of participants that would be eligible for the nine ongoing phase-III trials. We further quantified the eligibility among participants at high risk to develop severe COVID-19. Since many trials were not explicit in their exclusion criterion with respect to ‘acute’ or ‘unstable preexisting’ diseases, we performed two analyses. First, we included all participants irrespective of this criterion. Second, we excluded persons with acute or ‘unstable preexisting’ diseases. 97% of 7162 participants was eligible for any trial with eligibility for separate trials ranging between 11–97%. For high-risk individuals the corresponding numbers were 96% for any trial with separate trials ranging from 5–96%. Importantly, considering persons ineligible due to ‘acute’ or ‘unstable pre-existing’ disease drastically dropped the eligibilities for all trials below 43% for the total population and below 36% for high-risk individuals. The eligibility for ongoing vaccine trials against SARS-CoV-2 can reduce by half depending on interpretation and application of a single unspecified exclusion criterion. This exclusion criterion in our study would especially affect the elderly and those with pre-existing morbidities. These findings thus indicate the difficulty as well as importance of developing clinical recommendations for vaccination and applying these to the appropriate target populations. This becomes especially paramount considering the fact that many countries worldwide have initiated their vaccination programs by first targeting the elderly and most vulnerable persons.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s10654-021-00729-5.

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          Incidental findings on brain MRI in the general population.

          Meike Vernooij, M Arfan Ikram, Herve L. Tanghe … (2007)
          Magnetic resonance imaging (MRI) of the brain is increasingly used both in research and in clinical medicine, and scanner hardware and MRI sequences are continually being improved. These advances are likely to result in the detection of unexpected, asymptomatic brain abnormalities, such as brain tumors, aneurysms, and subclinical vascular pathologic changes. We conducted a study to determine the prevalence of such incidental brain findings in the general population. The subjects were 2000 persons (mean age, 63.3 years; range, 45.7 to 96.7) from the population-based Rotterdam Study in whom high-resolution, structural brain MRI (1.5 T) was performed according to a standardized protocol. Two trained reviewers recorded all brain abnormalities, including asymptomatic brain infarcts. The volume of white-matter lesions was quantified in milliliters with the use of automated postprocessing techniques. Two experienced neuroradiologists reviewed all incidental findings. All diagnoses were based on MRI findings, and additional histologic confirmation was not obtained. Asymptomatic brain infarcts were present in 145 persons (7.2%). Among findings other than infarcts, cerebral aneurysms (1.8%) and benign primary tumors (1.6%), mainly meningiomas, were the most frequent. The prevalence of asymptomatic brain infarcts and meningiomas increased with age, as did the volume of white-matter lesions, whereas aneurysms showed no age-related increase in prevalence. Incidental brain findings on MRI, including subclinical vascular pathologic changes, are common in the general population. The most frequent are brain infarcts, followed by cerebral aneurysms and benign primary tumors. Information on the natural course of these lesions is needed to inform clinical management. Copyright 2007 Massachusetts Medical Society.
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            The Rotterdam Study: 2018 update on objectives, design and main results

            M Arfan Ikram, Guy Brusselle, Sarwa Darwish Murad … (2017)
            The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1500 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
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              How to assess the external validity of therapeutic trials: a conceptual approach.

              Laura Dekkers, H J Romijn, Jan P. Vandenbroucke … (2010)
              External validity of study results is an important issue from a clinical point of view. From a methodological point of view, however, the concept of external validity is more complex than it seems to be at first glance. Methodological review to address the concept of external validity. External validity refers to the question whether results are generalizable to persons other than the population in the original study. The only formal way to establish the external validity would be to repeat the study for that specific target population. We propose a three-way approach for assessing the external validity for specified target populations. (i) The study population might not be representative for the eligibility criteria that were intended. It should be addressed whether the study population differs from the intended source population with respect to characteristics that influence outcome. (ii) The target population will, by definition, differ from the study population with respect to geographical, temporal and ethnical conditions. Pondering external validity means asking the question whether these differences may influence study results. (iii) It should be assessed whether the study's conclusions can be generalized to target populations that do not meet all the eligibility criteria. Judging the external validity of study results cannot be done by applying given eligibility criteria to a single target population. Rather, it is a complex reflection in which prior knowledge, statistical considerations, biological plausibility and eligibility criteria all have place.
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                Author and article information

                Contributors
                Mohammad Arfan Ikram: m.a.ikram@erasmusmc.nl
                Journal
                Journal ID (nlm-ta): Eur J Epidemiol
                Journal ID (iso-abbrev): Eur J Epidemiol
                Title: European Journal of Epidemiology
                Publisher: Springer Netherlands (Dordrecht )
                ISSN (Print): 0393-2990
                ISSN (Electronic): 1573-7284
                Publication date (Electronic): 26 February 2021
                Publication date PMC-release: 26 February 2021
                Pages: 1-6
                Affiliations
                [1 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Epidemiology, , Erasmus University Medical Center, ; Wytemaweg 80, 3015 CN Rotterdam, the Netherlands
                [2 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Epidemiology, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA
                [3 ]GRID grid.38142.3c, ISNI 000000041936754X, Human Immunomics Initiative, Department of Epidemiology, , Harvard T.H. Chan School of Public Health and Human Vaccines Project, ; Boston, MA USA
                [4 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Immunology and Infectious Diseases, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA
                Article
                Publisher ID: 729
                DOI: 10.1007/s10654-021-00729-5
                PMC ID: 7906827
                PubMed ID: 33634346
                SO-VID: f7f3799e-a580-414b-9833-9f59a6eeb99e
                Copyright © © The Author(s) 2021
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 8 December 2020
                Date accepted : 8 February 2021
                Categories
                Subject: Covid-19

                ScienceOpen disciplines: Public health
                Keywords: sars-cov-2,vaccines,phase iii trials,generalizability,external validity,epidemiology
                Data availability:
                ScienceOpen disciplines: Public health
                Keywords: sars-cov-2, vaccines, phase iii trials, generalizability, external validity, epidemiology

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