University of Groningen

Real-world influenza vaccine effectivenessDarvishian, Maryam

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Chapter 9

Summary

netherlandse samenvatting

Acknowledgement

About the author

other ShARe dissertations

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SuMMARY

Real-world influenza vaccine effectiveness: new designs and methods to adjust for confounding and bias

As recommended by the World Health Organization, seasonal influenza

vaccination of high-risk populations (e.g. elderly and individuals with specific

chronic medical conditions) is the main preventive strategy against influenza and

influenza-related complications. Despite these recommendations, influenza

vaccination coverage rates are still generally low which partly could be due to the

uncertainties about the real-world effectiveness of seasonal influenza vaccine.

Limitations in conducting experimental randomized (placebo-) controlled

trials as well as susceptibility of observational study designs to different sources of

biases contribute to this ongoing uncertainty. In this thesis we therefore estimated

seasonal influenza vaccine effectiveness (IVE) by means of new study designs

and methods to provide more accurate IVE estimates while addressing and/or

adjusting for the potential biases and confounders.

In Chapter 2 a meta-analysis of cohort studies was performed and a novel

bias-adjustment method was applied to investigate the effect of potential biases

and estimate the bias-adjusted IVE estimates. After incorporating the assumed

effect and direction of potential biases, the overall IVE estimates for all outcomes

slightly reduced and the confidence intervals widened reflecting the incorporated

uncertainty about the magnitude of the biases. Additionally, bias-adjusted meta-

analysis showed that even after incorporating the potential influence of biases,

influenza vaccination was still significantly effective against hospitalization from

influenza and/or pneumonia and all-cause mortality.

In Chapter 3 a meta-analysis of 35 test-negative design case-control studies

(TND) among elderly population showed that influenza vaccination was effective

against laboratory-confirmed influenza during epidemic seasons; when the vaccine

matched (IVE: 52%; 95% CI 41 to 61%) and mismatched (IVE: 36%; 95% CI 22 to

48%) the circulating viruses. During non-epidemic seasons, although estimates

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pointed towards some effectiveness, the reduction in laboratory-confirmed

influenza outcome was not statistically significant. In summary, results of our study

showed that seasonal influenza vaccination of elderly people should remain as the

main prevention strategy against influenza and influenza-related complications

among this high-risk population.

In order to provide overall IVE estimates, different meta-analytic statistical

methods could be applied to pool the odds ratios from TND studies. Although

conventional meta-analysis methods such as DerSimonian and Laird (D&L)

random effects model are widely being used in medical sciences, several

simulation studies have shown that in the framework of binary and sparse data,

these methods induce estimation bias. In Chapter 4 a simulation study confirmed

previous studies findings and showed that the performance of D&L with respect to

bias of the effect estimator, probability coverage and type I error, is considerably

lower than a classical binomial-normal approach (2DIM) and three-dimensional

GLMM (3DIM). In addition, although the simulation study showed that the overall

performance of 2DIM is somewhat lower than 3DIM, the difference was not

substantial and 2DIM can be considered as an alternative analysis method.

In Chapter 5 an individual participant data meta-analysis aiming to estimate

the IVE in community-dwelling elderly is presented. In this study IVE estimates

are adjusted for the potential confounders such as presence of high risk medical

conditions, smoking status and interval between symptom onset and swab collection.

Comparing to the aggregated-data meta-analysis presented in Chapter 3,IVE estimates reduced after fully adjustment for the potential confounders but still

showed protective effect against laboratory-confirmed influenza outcome during

epidemic seasons, irrespective of vaccine match status. Moreover, IVE estimates

varies substantially among different subgroups and against different influenza

virus (sub)types.

A test-negative design case-control study estimating IVE in the Netherlands over

a series of 11 influenza seasons (Chapter 6) showed extreme variability in IVE

against different influenza virus (sub)types/lineages and from season to season.

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In summary, the vaccine showed the highest protective effect when the vaccine

strains antigenically matched the circulating viruses and the lowest effect when the

vaccine did not match and/or A(H3N2) was the predominant virus subtype during

the influenza season.

Another test-negative design case-control study presented in Chapter 7 showed

that the IVE estimate varies depending on the type of control group that is included

in the study. In this study, IVE showed the highest protective effect when control

group 2 (individuals negative for influenza viruses but positive for other respiratory

viruses) was included in the analysis. The differences between IVE estimates using

different control groups could partly be explained by potential selection bias or

misclassification bias. Although the decision about including the best control

group is still controversial, in this study control group 2 seems to provide the less

biased estimate because of eliminating false-positive controls and reducing the

lack of non-specific immunity induced by influenza vaccination.

In conclusion, this thesis estimated the influenza vaccine effectiveness while taking

into account the effect of potential confounders and biases. Based on the conducted

studies in this thesis, we recommend future studies to reduce the effect of bias by

conducting high quality individual studies; adjusting for the potential confounders

such as presence of chronic medical conditions; considering epidemiological and

virological factors that contribute to the IVE estimate variations; and taking into

account the limitations of the conventional meta-analytic approaches.

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Nederlandse samenvatting

neDeRlAnDSe SAMenVATTInG

effectiviteit van influenzavaccinatie in de praktijk: nieuwe designs en methoden om te corrigeren voor confounding en bias.

Zoals aanbevolen door de Wereldgezondheidsorganisatie (WHO), is jaarlijkse influenzavaccinatie van groepen met een verhoogd risico op complicaties

ten gevolge van een influenza-infectie zoals ouderen en personen met bepaalde

medische risicofactoren een van de belangrijkste preventieve maatregelen. In

de praktijk is de influenzavaccinatiegraad echter doorgaans laag. Onzekerheid

over de werkelijke effectiviteit van het influenzavaccin kan hiervoor de oorzaak

zijn. Zowel beperkingen bij het opzetten van gerandomiseerd (placebo)

gecontroleerd onderzoek als de gevoeligheid van observationeel onderzoek

voor vertekening door verschillende vormen van bias of confounding,

kunnen bijdragen aan deze onzekerheid. In dit proefschrift zijn nieuwe

onderzoeksopzetten en methoden gebruikt om een meer valide schatting

te maken van de influenzavaccinatie effectiviteit (IVE). Hierbij is rekening

gehouden met potentiële bias en confounding en zijn de IVE schattingen

hiervoor gecorrigeerd.

In hoofdstuk 2 is een meta-analyse gepresenteerd van cohort onderzoeken

waarbij een nieuwe expert-panel methode is toegepast om voor bias te

corrigeren en om de effecten van deze bias op de IVE te kwantificeren.

Wanneer het vermoedelijke effect en de richting van mogelijke bias werden

meegenomen, lieten de gecorrigeerde IVE schattingen een kleine daling zien

voor alle uitkomsten. De meegenomen onzekerheid in de omvang van de bias

werd verder gereflecteerd in bredere betrouwbaarheidsintervallen. De voor

bias gecorrigeerde meta-analyse resultaten geven aan dat influenzavaccinatie

significant effectief is tegen hospitalisatie ten gevolge van influenza en/of

pneumonie als ook de totale sterfte tijdens de epidemie.

In hoofdstuk 3 is een meta-analyse van 35 test-negative design case-control

studies (TND) gepresenteerd. Hierbij bleek influenzavaccinatie effectief tegen

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laboratorium-bevestigde influenza gedurende seizoenen met epidemische

influenza-activiteit; bij een match tussen het vaccin en de circulerende virussen

werd de IVE geschat op 52% (95% BI 41 tot 61%) en bij een mismatch was de IVE

36% (95% BI 22 tot 48%).

Om de totale IVE te kunnen schatten, werden verschillende meta-analytische

statistische methoden toegepast om de odds ratio van TND studies te poolen.

Hoewel gebruikelijke methoden voor meta-analyses zoals het DerSimonian

and Laird (D&L) random effects model veel gebruikt worden in de medische

wetenschappen voor het combineren van odds ratios, hebben verschillende

simulatiestudies in de literatuur aangetoond dat deze methoden een onzuivere

schatting geven. In hoofdstuk 4 zijn de bevindingen van deze eerdere

studies bevestigd voor TND studies met behulp van een simulatiestudie.

De prestatie van D&L met betrekking tot de zuiverheid van de schatter, het

betrouwbaarheidsniveau van de betrouwbaarheidsintervallen, en de fout van

de eerste order (type 1 fout), is beduidend slechter dan die van de klassieke

binomiaal-normaal aanpak (2DIM) en de drie-dimensionale componenten

aanpak (3DIM). Het verschil tussen 2DIM en 3DIM was beperkt, ook al

presteerde 3DIM net iets beter. Dus 2DIM kan worden beschouwd als een

alternatieve analyse methode.

In hoofdstuk 5 zijn resultaten van een meta-analyse met individuele

patiëntendata gepresenteerd waarbij het doel was om de IVE bij ouderen te

bepalen. De schattingen voor IVE zijn in dit onderzoek gecorrigeerd voor

mogelijke confounders, zoals de aanwezigheid van medische risicofactoren,

roken en de periode tussen het begin van symptomen en afname van het neus-

keel monster. Na correctie voor mogelijke confounding, werd de IVE lager

geschat ten opzichte van de meta-analyse op basis van geaggregeerde data

zoals gepresenteerd in hoofdstuk 3. Gedurende seizoenen met epidemische

influenza is er nog steeds een beschermend effect van het influenzavaccin

aantoonbaar, ongeacht de match van het vaccin. Daarbij varieerde de IVE

aanzienlijk tussen verschillende subgroepen en bij verschillende circulerende

influenza virus(sub)types.

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Nederlandse samenvatting

Een test-negative design case-control onderzoek om de IVE in Nederland te

bepalen gedurende een periode van 11 opeenvolgende influenzaseizoenen liet zien

dat de IVE extreem variabel was bij verschillende influenza virus (sub)typen/lijnen

en varieerde tussen de verschillende seizoenen (hoofdstuk 6). Samengevat

beschermde het vaccin het meest wanneer de viruscomponenten in het vaccin

anti-genetisch overeenkwamen met de circulerende virussen. Daartegenover was

de bescherming het minst wanneer het vaccin niet overeenkwam en/of A(H3N2)

het overheersende virus subtype was gedurende het influenzaseizoen.

In hoofdstuk 7 presenteren we een test-negative design case-control onderzoek

waarin we aantonen dat de IVE varieert afhankelijk van het gebruikte type

controle groep in de studie. Dit onderzoek wees aan dat het beschermde effect

van influenzavaccinatie het grootst was wanneer controlegroep 2 (personen

negatief getest voor influenza virussen, maar positief voor ander virussen)

geïncludeerd werd in de analyse. De verschillen in de geschatte IVE tussen de

verschillende controlegroepen kan gedeeltelijk verklaard worden door mogelijke

selectiebias of misclassificatiebias. De beslissing welke controlegroep het beste

geïncludeerd kan worden, is nog steeds controversieel. Door eliminatie van fout-

positieve controles en het verminderen van het gebrek aan aspecifieke immuniteit

geïnduceerd door influenzavaccinatie, leek de uitkomst bij controlegroep 2 in deze

studie het minst biased.

Samenvattend is in dit proefschrift de influenzavaccinatie effectiviteit bepaald met

inachtneming van het effect van potentiële confounders en bias. Gebaseerd op

de onderzoeken uitgevoerd in deze thesis raden wij bij toekomstige onderzoeken

aan het effect van bias te reduceren door individuele studies van hoge kwaliteit

uit te voeren welke; (1) corrigeren voor mogelijke confounders waaronder de

aanwezigheid van chronische medische condities; (2) de epidemiologische en

virologische factoren die bijdragen aan de IVE-variaties meewegen en (3) rekening

houden met de beperkingen van conventionele meta-analytische methoden.

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Acknowledgements

ACKnoWleDGeMenTS

During the past four years of rewarding but also, at times, challenging journey

of my promotion, I was supported by many people, whom I would like to thank

sincerely.

First and foremost, I would like to express my deepest gratitude to my promoters

Prof. Eelko Hak and Prof. Edwin van den Heuvel. Dear Eelko, we first met when I

was trying to find an interesting research topic for my master project. Back then,

you gave me the opportunity to join your research team and freedom to explore and

learn by my own. Thank you for all the support and encouragements. Dear Edwin,

although I did not have a statistical background, you gave me the opportunity to

work under your supervision. I have learnt a lot from you but most importantly,

you taught me to believe in my capabilities and myself. Thank you very much for

standing by my side during ups and downs in my research.

Many thanks also go to my committee members Prof. T.J.M. Verhij, Prof. G.H. de

Bock and Prof. A.L.W. Huckriede for assessing my thesis.

I sincerely thank Prof. James Coyne for all the insightful advises and mentorship.

Thank you for listening, guidance, inspiration and encouragements.

I would like to thank all my project partners and co-authors of my manuscripts

particularly dr. Gieder Gefenaite, dr. Rebbeca Turner, dr. Maarten Bijlsma, dr.

Adam Meijer, dr. Heath Kelly and Frederika Dijkstra. Dear Giedre, you were a

great inspiration for me, I have learnt a lot from you. Thank you very much for your

critical thinking with great remarks and suggestions. Dear Adam, it was a privilege

to work with you and your team especially Ton Marzec, Gabriel Goderski, Mariam

Bagheri, Sharon van den Brink, Lisa Wijsman, and Pieter Overduin. Thanks for all

the great scientific discussions, your valuable comments and your patience. I am

also very thankful to Truus van ittersum for her kind assisting in searching medical

databases and her valuable guidelines.

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I also would like to thank the colleagues of department of Epidemiology and

Unit PharmacoTherapy, -Epidemiology & -Economics (PTEE), in particular their

secretaries, Aukje, Roelian and Jannie. Thanks for all your kind assisting whenever

I needed an emergency appointment with my supervisors or arrangements

for attending international courses and conferences. Dear Anh, Anne, Natalia,

Leanne, Qi, Marloes, Lorreto, Kim, Lilian, Niloofar, Leyla, Noha, Akbar, Ivan,

Yuan, Clarissa and all other members, I really enjoyed our corridor discussions,

knowledge exchanges, outside activities and fun times. Dear Nino and Thembile,

colleagues of the medical statistics unit, you were not only great colleagues but also

good friends. It was really great to have you around during all the happy and sad

moments.

Dear Janet, you were a great officemate. It was really great to have you as an

officemate at the beginning and later as a close friend. It always seemed like there

was no problem that you couldn’t solve J. You’re simply the best. Thank you for

everything.

Dear Marcy and Christiaan, thank you for being my paranymphs. Dear Marcy, I am

really thankful for all the virology/vaccinology-related information that you always

generously shared with me. Dear Christiaan, I was really lucky that when I was

struggling to change my LATEX file to word, you were there to help me out. You

both are excellent colleagues and paranymphs. Thank you for being there for me.

Dear my Iranian friends, Somayeh, Shifteh, Marziyeh, Neda, Zohreh, Fahimeh,

Fareeba, Pariya, and Naghemh, you made life in Groningen more pleasant and

joyful for me and my family. Thank you all for staying by my side through the ups

and downs during all these years. I am also very grateful to dr. Alireza Sadjadi

and his spouse, Masi for all their support when I was hospitalized during my

pregnancy. Your daily visits and supportive words helped me to tolerate all the

difficult moments and worries. I am also thankful to my close friends in Iran,

Fatemeh, Reyhaneh and Mahsa. Dear Fatemeh, you are not just a friend but my

sister. You have been supportive and helpful during all these 14 years of friendship.

I am so lucky to have you in my life.

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Acknowledgements

My very deep gratitude goes to my wonderful family, my lovely parents and my

brothers. First of all, I am grateful to my beloved parents and grandfather, who left

us too early, but their memory stays with me forever. Sincere thanks also to my two

brothers, Saeed and Soroush and their lovely family for their endless love, support

and encouragements.

AND

Last but certainly not least, I am thankful to my wonderful spouse Mahdi. My dear

Mahdi, I cannot imagine how I could finalize this task and bring this journey to the

end without your unlimited love, support, and patience. Thank you my dear; thank

you for all the sacrifices you have made to accompany me on this amazing journey.

My lovely Matin, for about 9 months, I was working on my projects while two

hearts were beating in my body. The true love that was flowing in my veins, was

giving me an incredible strength. Our deep love got even stronger after your birth.

Your smiles shine my daily life and I am grateful for having you my little darling.

Life is a wonderful journey with my little Matin and beloved Mahdi, by my side.

Maryam Darvishian

May 2016, Groningen, The Netherlands

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About the author

AbouT The AuThoR

Maryam Darvishian was born on March 6th 1983 in Tehran, Iran. After completing

high school studies (major biology and natural sciences), she took the Iranian

National University entrance exam in 2003 and she was qualified to enter Iran

University of Medical Sciences and Health Services, one of the most prestigious

Medical Universities in Iran. She did her bachelor studies in Public Health and

graduated in 2007. During her bachelor studies, she worked as the head of student’s

research committee at the department of Health Sciences. After graduation from

Iran University, her intense interest in Epidemiology persuaded her to continue

her education in this course. Therefore, she applied to several universities and

among universities that she got admission (e.g. Erasmus University Medical

Center Rotterdam and Florida International University) she joined to two years

(2010-2012) research master program; clinical and psychosocial epidemiology

at University Medical Center Groningen (UMCG), Netherlands. For her master

thesis, she conducted a bias-adjusted meta-analysis of cohort studies assessing

influenza vaccine effectiveness among community-dwelling elderly in close

collaboration with Medical Research Council (MRC) Biostatistics Unit, Institute

of Public Health, Cambridge. After finishing her master successfully, she wrote

a PhD proposal to continue her research on influenza vaccine effectiveness. This

proposal was awarded with funding from Graduate School of Medical Sciences,

SHARE institute at UMCG. Her PhD project started in September 2012 and was

supervised by Prof. Eelko Hak and Prof. Edwin van den Heuvel. Her PhD thesis

includes six original research chapters, with a publication in the Lancet Infectious

Diseases Journal. The manuscript of this thesis was submitted to the reading

committee in March 21, 2016 and will be defended in June 21, 2016. In November

2015 she worked on a grant proposal entitled “Assessing Hepatitis C Treatment

Effectiveness: The Birtish Columbia Hepatitis Testers Cohort (BC-HTC) ” under

supervision of Dr. Naveed Janujua which later was awarded with funding from

the Canadian Network on Hepatitis C. In July 2016, she will start her new job as

a postdoc researcher at the University of British Columbia and BCCDC, Canada.

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Research institute SHARE

ReSeARCh InSTITuTe ShARe

This thesis is published within the Research Institute ShARe (Science in

Healthy Ageing and healthcaRE) of the University Medical Center Groningen /

University of Groningen.

Further information regarding the institute and its research can be obtained from our

internetsite: http://www.share.umcg.nl/.

More recent theses can be found in the list below.

((co-) supervisors are between brackets)

2016

Göhner, CPlacental particles in pregnancy and preeclampsia(prof SA Scherjon,prof E Schleuβner, dr MM Faas, dr T Plösch)

Vries AJ dePatellar tendinopathy; causes, consequences and the use of orthoses(prof RL Diercks, dr I van den Akker-Scheek, dr J Zwerver, dr H van der Worp)

holland b vanPromotion of sustainable employment; occupational health in the meat processing industry(prof MF Reneman, prof S Brouwer, dr R Soer, dr MR de Boer)13.04.2016 EXPAND

otter TAMonitoring endurance athletes; a multidisciplinary approach(prof KAPM Lemmink, prof RL Diercks, dr MS Brink)

bielderman JhActive ageing and quality of life; community-dwelling older adults in de-prived neighbourhoods(prof CP van der Schans, dr MHG de Greef, dr GH Schout)

bijlsma MJAge-period-cohort methodology; confounding by birth in cardiovascular pharmacoepidemiology(prof E Hak, prof S Vansteelandt, dr F Janssen)

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Chapter 9

Dingemans eAAWorking after retirement; determinants and conzequences of bridge employ-ment(prof CJIM Henkens, dr ir H van Solinge)

Jonge l deData quality and methodology in studies on maternal medication use in rela-tion to congenital anomalies(prof IM van Langen, prof LTW de Jong-van den Berg, dr MK Bakker)

Vries fM deStatin treatment in type 2 diabetes patients(prof E Hak, prof P Denig, prof MJ Postma)

Jager MUnraveling the role of client-professional communcation in adolescent psy-chosocial care(prof SA Reijneveld, prof EJ Knorth, dr AF de Winter, dr J Metselaar)

Mulder bMedication use during pregnancy and atopic diseases in childhood(prof E Hak, prof SS Jick, dr CCM Schuling-Veninga, dr TW de Vries)

Romkema SIntermanual transfer in prosthetic training(prof CK van der Sluis, dr RM Bongers)

Diest M vanDeveloping an exergame for unsupervised home-based balance training in older adults(prof GJ Verkerke, prof K Postema, dr CJC Lamoth, dr J Stegenga)

Waterschoot fPCNice to have or need to have? Unraveling dosage of pain rehabilitation(prof MF Reneman, prof JHB Geertzen, prof PU Dijkstra)

Zijlema Wl(Un)healthy in the city; adverse health effects of traffic-related noise and air pollution(Prof JGM Rosmalen, prof RP Stolk)

Zetstra-van der Woude APData collection on risk factors in pregnancy(prof LTW de Jong-van den Berg, dr H Wang)

Mohammadi SThe intersecting system of patients with chronic pain and their family care-givers; cognitions, behaviors, and well-being(prof M Hagedoorn, prof R Sanderman, dr M Deghani)

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Research institute SHARE

Verbeek TPregnancy and psychopathology(prof MY Berger, prof CLH Bockting, dr H Burger, dr MG van Pampus)

2015

broekhuijsen KTiming of delivery for women with non-severe hypertensive disorders of pregnancy(prof PP van den Berg, prof BWJ Mol, dr MTM Faassen, dr H Groen)

Tuuk K van derWho’s at risk? Prediction in term pregnancies complicated by hypertensive disorders(prof PP van den Berg, prof BWJ Mol, dr MG van Pampus, dr H Groen))

Vitkova MPoor sleep quality and other symptoms affecting quality of life in patients with multiple sclerosis(prof SA Reijneveld, prof Z Gdovinova, dr JP van Dijk, dr J Rosenberger)

Sudzinova ARoma ethnicity and outcomes of coronary artery disease(prof SA Reijneveld, dr JP van Dijk, dr J Rosenberger)

For more 2015 and earlier theses visit our website

INVITATION

You are cordially invited to the publicdefense of the doctoral thesis of

Maryam Darvishianentitled

Real-world influenzavaccine effectiveness

New designs and methods toadjust for confounding and bias

On Tuesday, 21st of June 2016 at 11.00h sharp

in the Aula of the Academy Building, Broerstraat 5, Groningen

Afterwards there will be a receptionin the

Academy Building (Spiegelzaal)

Paranymphs:Franklin Christiaan Karel Dolk

Heng Liu

E-mail:maryamdarvishianpromotion@gmail.com

Real-world influenzavaccine effectiveness

New designs and methods to adjust for confounding and bias

Maryam Darvishian

Maryam

Darvishian

Real-w

orld influenza vaccine eff

ectivenessN

ew designs and m

ethods to adjust for confounding and bias

Maryam Darvishian.indd 1 13/05/16 11:36