Research into the reasons and causes of excess mortality during the coronavirus crisis

During the COVID-19 pandemic, more people died than expected. Research can contribute to preventing or reducing excess mortality during the next pandemic. At the request of the Ministry of Health, Welfare and Sport, ZonMw has therefore set up an in-depth research trajectory into the causes of this excess mortality, which is currently being investigated in several different ways. A research agenda put together by independent experts forms the basis for the research trajectory.

What does the research agenda entail?

Om zo snel als mogelijk onderzoek naar oversterfte te kunnen laten starten, heeft een programmacommissie van onafhankelijke experts een onderzoeksagenda oversterfte opgesteld met kennishiaten die zijn gecategoriseerd in 3 lijnen.

To allow research into excess mortality to start as quickly as possible, a programme committee of independent experts drew up a research agenda (source in Dutch) concerning knowledge gaps, which have been categorised in 3 lines.

  • Line 1 consists of a systematic literature review with international comparisons conducted by Cochrane Netherlands. An overview of the literature is also available.
  • Line 2 consists of research using available research and healthcare data.
  • Within line 3, research will be done with data from the National Institute for Public Health and the Environment (RIVM) and the municipal health services (GGDs).

Within the COVID-19 programme, these 3 lines together form the subprogramme ‘Excess mortality in the Netherlands 2020-2021’. How did this research agenda arise? To set up the research agenda, discussions were first held with researchers from Statistics Netherlands, RIVM and members of the focus group (explanation elsewhere on this page). In the subsequent meeting, the subjects discussed were merged, structured and, if necessary, supplemented with other sources of information. Next, the subjects were prioritised. Members of the focus group have a background in epidemiology, demographics, political science, public health, medical information science, data science, statistics, psychology, medicine, pharmacology, pathology and healthcare research.

What does ZonMw do in the area of COVID-19 and Excess mortality?

On 13 December 2022, ZonMw awarded 11 studies funding within the COVID-19 subprogramme ‘Excess mortality in the Netherlands 2020-2021’. These projects investigate the possible causes of excess mortality in the period 2020-2021. The call for proposals for line 3 has been open since 15 December 2022. This call funds research that makes use of vaccination and positive test data from the RIVM and GGDs.

Current excess mortality projects

In line 3, 9 research proposals have been honourded that will make use of vaccine data of the RIVM and the postive test data of GGDs. More information about this research is available below:

Honourings line 3

Maarten Cuypers
Radboudumc

De COVID-19 pandemie heeft veel impact gehad op de samenleving en gezondheid van burgers, en op mensen met een verstandelijke beperking in het bijzonder. Syndromen die een verstandelijke beperking veroorzaken en het hebben van een algeheel meer kwetsbare gezondheid hebben bijgedragen aan meer ernstige ziekte en sterfte als gevolg van COVID-19. Maar ook sterfte door andere oorzaken zijn tijdens de COVID-19 pandemie sterker toegenomen onder mensen met een verstandelijke beperking dan in de rest van de bevolking. Er zijn al onderzoeken verricht naar de mogelijke verklaringen voor deze verschillen in sterfte, maar tot nu toe konden deze onderzoeken niet beschikken over test- en vaccinatiegegevens. Voor een zo compleet mogelijk beeld is onderzoek met deze basale variabelen essentieel.

Karin Hek
NIVEL

In dit project wordt de rol van COVID-19 vaccinaties bij oversterfte onderzocht. Er wordt rekening gehouden met belangrijke factoren zoals de medische voorgeschiedenis van mensen. Hiervoor worden gegevens uit elektronische patiëntendossiers van huisartsen van ongeveer 8% van de Nederlanders gebruikt. Deze gegevens worden gekoppeld op patiëntniveau aan gegevens over COVID-19 vaccinatie, COVID-19 testen, doodsoorzaken en persoonsgegevens. De geobserveerde sterfte in 2021 onder mensen die wel en mensen die niet gevaccineerd zijn wordt vergeleken met de verwachte sterfte. Hierbij wordt onderscheid gemaakt naar type vaccin, aantal vaccinaties, medische geschiedenis, kwetsbaarheid (bij ouderen) en sociaal demografische kenmerken.

Frits Rosendaal
LUMC

De oversterfte tijdens en na de corona-epidemie kan verscheidene oorzaken hebben: de ziekte zelf, maar mogelijk ook uitgestelde zorg en de maatregelen van de overheid. De oversterfte houdt nog steeds aan, wat komt omdat mensen nog steeds Covid-19 krijgen, maar wat ook kan komen door langdurige gevolgen van de ziekte, of eerder uitgestelde zorg voor andere aandoeningen. Grote landelijke en regionale gegevensbestanden van het CBS, huisartsen en ziekenhuizen zullen worden geanalyseerd door een multidisciplinair team, waarbij gekeken wordt naar sterfte, ziekenhuisopnames, medicatie, doorgemaakte Covid-19, vaccinatie, maar ook naar de invloed van al bestaande aandoeningen, socio-economische factoren en regio, met een focus op hart- en vaatziekten.

Rosan van Zoest 
ahti

Tijdens de COVID-19 pandemie was er sprake van oversterfte. Een pragmatische manier om meer zicht te krijgen op onderliggende mechanismen is door te identificeren welke populatiegroepen harder geraakt worden door de pandemie, zowel t.a.v. ziekte als overlijden. Deze observaties kunnen vervolgens worden afgezet tegen de verwachte sterfte op basis van historische data. Hiermee kan een inschatting worden gemaakt van 'oversterfte' in verschillende groepen binnen de Nederlandse bevolking. In dit project zullen inzichten gegenereerd worden t.a.v. oversterfte en COVID-19 gerelateerde ziekte voor verschillende subgroepen binnen de populatie, op basis van demografische kenmerken (leeftijd, geslacht), sociaal-economische kenmerken (inkomen, achtergrond) en een immuniteitsinschatting voor Corona (als gevolg van eerder doorgemaakte infectie of vaccinatie).

Torsten Kleinow
UvA

De effecten van de COVID-19 pandemie waren gedurende 2020 en 2021 het ernstigst, en leidden tot een substantiële stijging van de waargenomen sterfte in Nederland. In dit project wordt voor verschillende doodsoorzaken het verband onderzocht tussen oversterfte en kenmerken zoals socio-economische variabelen, vaccinatie- en buurtinformatie. Voor iedere te analyseren doodsoorzaak wordt een pre-pandemische sterftekans gedefinieerd die afhankelijk is van sociaal-economische variabelen. Door die te gebruiken als basis voor sterfte tijdens te pandemie, kunnen betrouwbare schattingen gemaakt worden van COVID-gerelateerde oversterfte, en bepaald worden in hoeverre die gerelateerd is aan socio-economische factoren. Vervolgens worden survivalmodellen en andere statistische methoden toegepast om te bepalen welke factoren de grootste impact hebben gehad op de oversterfte.

Annemarie de Boer
UMC Utrecht

De hoger dan verwachte sterftecijfers tijdens de pandemie blijven -althans gedeeltelijk- onverklaard. In deze studie wordt de rol van COVID-19 vaccinatie in de waargenomen oversterfte verder opgehelderd. Eerdere analyses, gebaseerd op Cox-regressie, konden een oorzakelijke rol van COVID-19 vaccinatie niet aantonen, maar konden de mogelijkheid niet uitsluiten dat de resultaten vertekend konden zijn door prognostische verschillen tussen gevaccineerde en niet-gevaccineerde mensen. Dit project past een recent ontwikkelde methode op basis van een 'self-controlled case series' toe. Deze methode is speciaal ontworpen om de sterfte op korte termijn na COVID-19 vaccinatie te kwantificeren. Bovendien is het mogelijk om sterfterisico's op korte termijn tussen subgroepen te vergelijken.

Liesbeth de Wreede 
LUMC

Tijdens de Covid-19-pandemie zijn er meer mensen overleden dan verwacht op grond van historische overlijdensgegevens. Deze oversterfte is voor een groot deel te verklaren door infecties met Covid-19 maar andere oorzaken spelen ook een rol. In dit onderzoek wordt met behulp van een geavanceerd model onderzocht wat die oorzaken waren en welke bevolkingsgroepen het grootste risico liepen. De hele Nederlandse bevolking van 65 jaar en ouder in 2020-2021 wordt meegenomen. Er wordt onderzocht wat het verschil in oversterfte is tussen mensen die wel en niet geïnfecteerd, en wel en niet gevaccineerd waren. Ook wordt onderzocht welke doodsoorzaken vaker of juist minder vaak voorkwamen dan normaal.

Pieter van Baal
Erasmus Universiteit

De Covid-19-pandemie heeft een onevenredige impact gehad op de sterfte van personen met een lage sociaaleconomische status. In hoeverre deze ongelijke impact afhangt van verschillen in vaccinatiegraad en reeds bestaande verschillen in gezondheid is onduidelijk. In dit project zal a) de interactie ingeschat worden tussen reeds bestaande verschillen in gezondheid, vaccinatie en sociaal-economische status met betrekking tot covid-19-mortaliteit b) een simulatiemodel ontwikkeld worden om schattingen te genereren van verloren levensjaren als gevolg van covid-19- sterfte naar sociaal-economische status in diverse scenario's c) de uitkomsten van de scenario's in termen van verloren levensjaren en hun sociaal economische verdeling vergeleken worden.

Eline van den Broek
Amsterdam UMC

Trends in andere landen laten zien dat een groot deel van de oversterfte in 2020 en 2021 werd veroorzaakt door hypertensie en hartaandoeningen. In Nederland heeft de Nederlandse Vereniging voor Cardiologie (NVVZ) een rapport gepubliceerd waarin wordt geconcludeerd dat de pandemie een grote impact heeft gehad op de gehele cardiologische zorgketen, inclusief de acute zorg. De auteurs suggereerden dat dwingende maatregelen van de overheid en zorginstellingen, tekorten aan materiaal en apparatuur, beperktere keuzemogelijkheden in de huisartsenzorg en de angst van patiënten om gebruik te maken van de zorg onder meer de belangrijkste oorzaken waren van aanzienlijk gezondheidsverlies. Het blijft onduidelijk welk deel van de oversterfte kan worden verklaard door uitgestelde diagnose en zorgbehandeling bij patiënten met hypertensie en hartaandoeningen. Deze studie zal de gezondheidsverliezen van uitgestelde zorg inschatten, analyseren in hoeverre gezondheidsverliezen hebben geleid tot sterfte.

De volgende passage heeft ZonMw in de honoreringsbrieven aan de projectleiders toegevoegd:
“Vanwege de zorgen in de Nederlandse samenleving over de mogelijke redenen en oorzaken van oversterfte in Nederland verzoekt ZonMw dat de resultaten zo snel als mogelijk aan het publiek bekend worden gemaakt, zelfs als de publicatie nog niet is geaccepteerd. U kunt, buiten reguliere rapportages om, door het programma secretariaat gevraagd worden om informatie en updates over de voortgang van uw project (mondeling, schriftelijk of als een presentatie) aan te leveren. We verwachten dat u hieraan uw medewerking verleent.”

Programme commission

Voorzitter

prof. dr. L.J. (Louise) Gunning-Schepers

Leden

 prof. dr. M. (Marijn) de Bruin
prof. dr. S. (Saskia) le Cessie
prof. dr. R.H.H. (Rolf) Groenwold
prof. dr. E. (Eelko) Hak
dr. H.J. (Dika) Luijendijk
prof. dr. A.E (Anton) Kunst
dr. A. (Anja) Schreijer

Members of the focus group

The independent focus group encompasses a very broad range of expertise and is made up of 16 members with very diverse affiliations and a background in epidemiology, demography, political science, public health, medical information science, data science, statistics, psychology, medicine, pharmacology, pathology, and healthcare research.

Chair
Prof. dr. R. (Robert) Verheij

Vice chair
Prof. dr. K. (Koos) van der Velden

Members
Prof. dr. A. (Agneta) Fischer
Prof. dr. A. (Arfan) Ikram (tot 1 augustus 2022)
Dr. D. (Dianne) de Korte-de Boer
Prof. dr. E. (Eelco) Hak
Dr. E. (Eline) van den Broek-Altenburg
Prof. dr. F. (Frans) van Poppel
Drs. H. (Hidde) Boonstra
Dr. J. (Jan) von der Thüsen
Prof. dr. K. (Koos) van der Velden
Prof. dr. N. (Niek) Klazinga
Prof. dr. P. (Pieter) van Baal
Prof. dr. R. (Rein) Houben
Prof. dr. R. (Ronald) Meester

Find the questions and answers about the research into excess mortality and COVID-19

ZonMw receives a lot of questions over social media about research into excess mortality and COVID-19, on among others Twitter, LinkedIn and e-mail. If the answer to your question is not listed, contact us at covid19@zonmw.nl.

We have received a lot of questions about research into the ZonMw programme 'Oversterfte in Nederland 2020-2021'. Based on questions and answers, on this page we describe what research is ongoing, what grants are available, and how research proposals are judged.

Frequently asked question and COVID-19

To allow research into excess mortality to start as quickly as possible, a programme committee of independent experts drew up a research agenda concerning knowledge gaps, which have been categorised in 3 lines.

Research agenda Excess mortality in the Netherlands

  • Line 1 consists of a systematic literature review with international comparisons conducted by Cochrane Netherlands.
  • Line 2 consists of research using available research and healthcare data. A list with all 11 studies awarded funding can be found here. This concerns relatively short studies with a duration of six months.
  • Within line 3, research will be done with data, such as vaccination and test data, from the RIVM and GGDs.
  • In the call for proposals 'Excess mortality in the Netherlands in the period 2020-2021_line 2', 13 research proposals were received and 12 of these were declared admissible. This means that 12 proposals were assessed against the predefined criteria of relevance and quality.
  • As a first step in the assessment, two committee members independently assessed each proposal. This assessment was recorded in an assessment report.
  • Subsequently, all proposals and the accompanying assessment reports were discussed in the committee meeting.
  • The committee's assessment was based on the assessment reports and the substantive discussion during the committee meeting. There are two options for each proposal:
    • Award: these applicants received an award letter. The committee could give recommendations to improve the project.
    • Hearing and rebuttal: the applicant received additional questions from the committee and was given the opportunity to respond to these in writing.
  • During the selection meeting on 27 October 2022, the committee advised the immediate awarding of 5 proposals. The remaining 7 applicants were invited to provide a rebuttal and received points of criticism from the committee to respond to. The committee discussed the rebuttals for these proposals during the second selection meeting on 1 December 2022. Each committee member prepared for all of the proposals for this meeting, unless there was a possible personal conflict of interests. During this meeting, the committee members advised awarding another 5 proposals funding. ZonMw accepted this advice and awarded 10 proposals.
  • For the other two proposals, one was rejected due to insufficient quality even though it received the qualification 'very relevant'. The final proposal was awarded funding on 21 December 2022, after an additional meeting with members of the committee. With this last award, the total number of projects awarded funding is 11.

The weighting of relevance and quality was carried out by means of the ranking matrix below. To be eligible for funding, a proposal had to receive the quality assessment 'good' or 'very good', and the relevance assessment 'relevant' or 'very relevant'. Please note: only proposals with an assessment  that falls in the blue spaces were awarded funding is 11.

Afbeelding
Ranking matrix

The proposals were assessed by an independent programme committee consisting of experts from the field. The composition of the committee is given here. The committee members, appointed by the ZonMw board, participated in the committee in their individual capacities as experts from their specific background. When putting the committee together, due consideration was given to the various areas of expertise: democracy, behaviour, statistics, epidemiology, geriatric medicine and health.

Upon their appointment, the committee members stated that they would comply with and respect the ZonMw Code of Conduct on Conflicts of Interests in performing their work. Committee members with possible personal interests regarding a proposal do not assess that proposal and do not take part in the meeting when this proposal is being considered. The interests have been carefully mapped prior to the entire assessment process.

This opportunity was provided. The relevance of this subject was stated, and the possibility for it was created in the research programme. An agenda was set at the beginning of the subprogramme Excess mortality. This agenda describes the various gaps in knowledge about excess mortality. It was drawn up in agreement between the programme committee, researchers from Statistics Netherlands and the RIVM, and members of the focus group. In this research agenda, one of the knowledge gaps described is: 'What are (modifiable) determinants of the (differences in) excess mortality related to vaccination (type of vaccine, vaccination behaviour, progression of vaccination rate, complications associated with vaccinations, vaccination design and booster programme)'.

At this moment, no proposals that examine vaccination and excess mortality have been awarded yet because none of the submitted proposals satisfied the quality requirements. In the period that the call for proposals 'Excess mortality in the Netherlands in the period 2020-2021_line 2' was open, the vaccination data and positive test data from the RIVM and municipal health services (GGDs) were not yet accessible for conducting independent research. In the 11 recently awarded studies, the researchers are making use of the (healthcare) data available and accessible in October/November 2022. The data from the RIVM and GGDs became accessible on 18 November 2022. In the call for proposals 'Excess mortality in the Netherlands in the period 2020-2021_line 3' it is possible to make use of these data to investigate excess mortality.

During the COVID-19 pandemic, more people died than expected. ZonMw has therefore set up an in-depth research trajectory into the causes of this excess mortality at the request of the Ministry of Health, Welfare and Sport. Research results can contribute to preventing or reducing excess mortality during a next pandemic. The programme committee of independent experts has drawn up a research agenda concerning knowledge gaps that have been categorised in 3 lines.

Research agenda excess mortality in the Netherlands

  • Line 1 consists of a systematic literature review with international comparisons that will be conducted Cochrane Netherlands.
  • Line 2 consists of research using available research and healthcare data. A list with all 11 studies awarded funding can be found here. This concerns relatively short studies with a duration of six months.
  • Within line 3, research will be done with data, such as vaccination data and test data, from the RIVM and GGDs.

The research agenda was categorised in 3 lines to allow research into excess mortality to start as quickly as possible. The agenda was set on the basis of research questions that emerged in discussions between the programme committee and experts from the field. These are the researchers from Statistics Netherlands and the RIVM who do research into excess mortality, and the members of the focus group who supervise this research. The experts were asked to provide knowledge questions and research subjects. In addition, the programme committee also itemised which subjects fall under its own remit.

Since 15 December 2022, the call for proposals for line 3 has been open. Within line 3, research is funded that makes use of vaccination data and positive test data from the RIVM and GGDs. This data has recently become accessible for carrying out independent research. Within this call for proposals, the main focus is on the substantiation of the quality of the data, the use of other models, correction for other co-variables, and other timeframes concerning follow-up. These studies are somewhat larger, with a maximum budget of 100,000 euros and a duration of 9 months. Researchers could submit their proposal for the call 'Excess mortality in the Netherlands in the period 2020-2021_line 3' until Tuesday, 31 January 2023.

In the recently published call for proposals, the focus is on line 3 of the research agenda. In this round, independent research is made possible using vaccination data from the RIVM and positive test results from the GGDs. On 18 November 2022, a Parliamentary Letter about COVID-19 explained that this data would be accessible for independent researchers from January 2023 onwards. During the previous funding round (line 2) this data was not yet accessible.

Source: Statistics Netherlands
Researchers must submit an application to Statistics Netherlands to obtain access to the vaccination data. Based on Article 41 of the Statistics Netherlands Act, the director-general of Statistics Netherlands is authorised to grant researchers access to a collection of data for the purpose of statistical or scientific research. In this, Statistics Netherlands has the legal obligation to take measures to prevent the recognition of individual persons, households, businesses or institutions. On the basis of Article 42 of the Statistics Netherlands Act, the director-general only grants a request to access on the basis of Article 41 of the Statistics Netherlands Act if, in the opinion of that director-general, the applicant has taken sufficient measures to prevent that the collection of data will be used for purposes other than statistical or scientific research. Research institutes need to have an authorisation (
Application for access to microdata (cbs.nl)) to obtain access to the remote access environment of Statistics Netherlands.

Activity Start date End date
 Call for proposals line 2 open 11-08-2022 30-09-2022
     • 12 admissible proposals submitted    
 Assessment committee meeting 27-10-2022 27-10-2022
Outcome assessment committee meeting:
• 5 projects awarded funding
• 7 projects rebuttal
   
Applicants' rebuttal 07-11-2022 25-11-2022
Assessment meeting rebuttal 01-12-2022 01-12-2022
 Outcome assessment committee meeting:
• 5 projects awarded funding
• 1 proposal rejected
• 1 proposal additional rebuttal
   
Interview additional rebuttal 21-12-2022 21-12-2022
Call for proposals line 3 open 15-12-2022 31-01-2023

ZonMw has commissioned various studies into COVID-19 vaccination among people with a compromised immune system. These studies supplement the vaccination studies of the RIVM, vaccine manufacturers and international researchers and organisations. At the start of 2021, within the subprogramme Vaccine studies, a network was set up of 8 studies into the optimal use of COVID-19 vaccines in patients with a compromised or weakened immune system (immunodeficiency). The results from these studies have been included in various advisory reports of the Health Council of the Netherlands and have therefore contributed to the Dutch vaccination policy. The results have, amongst other things, revealed that these patients can be safely vaccinated and that a number of patient groups exhibit a good antibody response following vaccination. After two vaccinations, these patients are sufficiently protected against the severe consequences of a COVID-19 infection.

Conversely, there are various patient groups for whom two vaccinations against COVID-19 has an insufficient effect as yet. These patients make insufficient or no antibodies and immune cells and are therefore insufficiently protected against COVID-19. Extra booster vaccinations ensure that a number of these patients acquire a better protection. Follow-up research is ongoing into the effect of repeated boosters and lasting protection by means of vaccination in this vulnerable group of patients. For this, the 8 studies are collaborating with the RIVM and use harmonised protocols to realise the research that renders overarching analyses possible. With this approach, researchers also hope to gain more insight into the correlates of (long-term) protection through vaccination.

On 1 December 2021, Dutch parliamentarian Pieter Omtzigt submitted a motion to request that the government, as soon as possible, commission scientific research into the reasons for the causes of excess mortality in 2020-2021. This is therefore now being investigated in various ways.

Source: Statistics Netherlands
Statistics Netherlands receives monthly vaccination data from CIMS, the COVID Information and Monitoring System of RIVM, in which recent changes are implemented. With these, an up-to-date picture of changes in the database is obtained. As described in the Data Protection Impact Assessment (DPIA), changes are regularly implemented in the database with vaccination data. This happens, for example, when people have received a new vaccine or modified their consent to use their data for research. By comparing the databases with each other each month, insight is obtained into which changes have occurred over the course of time (including the decease of people).

Source: Statistics Netherlands
The variables that the vaccination data contain are described in a 'Data Protection Impact Assessment (DPIA), supply COVID-19 vaccination data by RIVM to Statistics Netherlands', and are identical to the variables that were used in 2022 for the research into excess mortality by the RIVM and Statistics Netherlands. This concerns: citizen service number (BSN), sex, year of birth, vaccine name, vaccination date, vaccine batch, administering organisation, booster code and serial number. The microdata catalogue of Statistics Netherlands contains the specifications of the included data that it has made available (
Catalogue microdata (cbs.nl)). The vaccination history at the level of the individual can be supplemented with other data present at Statistics Netherlands, such as possible use of healthcare, date of death and cause of death. All deceased persons have also been included in the CIMS databases. The DPIA recently drawn up by Statistics Netherlands has been adjusted to clarify the text about this.

Source: Statistics Netherlands
Statistics Netherlands possesses various sources of data necessary for research into excess mortality and, under strict conditions, makes these available for scientific research. However, Statistics Netherlands does not possess all possible relevant data sources researchers might want to use. This can sometimes be due to legal reasons. However, under certain conditions, researchers are allowed to bring their own data into the remote access environment.