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Evaluating medical tests and biomarkersIn primary studies and systematic reviewsWang, J.

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252

Nederlandse samenvatting

Dit proefschrift gaat over de evaluatie van medische tests en biomarkers, zowel

in origineel onderzoek als in systematisch literatuuronderzoek en meta-analyses. Het

beschrijft een aantal studies naar het onderscheidend vermogen van tests en merkers

en methodologische ontwikkelingen om dit type evaluaties verder te versterken.

Deel 1: Vergelijkende meta-analyse van diagnostische accu-ratesse

Bij de evaluatie van medische tests kan het gaan om de beoordeling van één enkele

test, of om een vergelijking van twee of meer tests. In hoofdstuk 2 brengen we verslag

uit van een systematisch literatuuronderzoek voor een vergelijking van diagnostische

tests. We hebben de accuratesse van drie indextests beoordeeld: computertomografie

(CT), beeldvorming op basis van magnetische resonantie (MRI) en botscintigrafie

(BS). Het klinisch probleem was het detecteren van klinische scaphoidfracturen bij

daarvan verdachte patiënten. Het systematische literatuuronderzoek omvatte zowel

studies die slechts één van de genoemde tests hadden geëvalueerd als studies die twee

tests hadden vergeleken in één en dezelfde groep patiënten en tegen één en dezelfde

referentiestandaard. Voor het maken van de uiteindelijke vergelijking werden alle

originele studies geanalyseerd, dus zowel de studies van de afzonderlijk tests als

de vergelijkende studies. We voerden daarna een gevoeligheidsanalyse uit, met

uitsluitend data uit vergelijkende studies, om na te gaan of zo’n meta-analyse met

enkel vergelijkende studies tot een ander antwoord zou leiden dan de hoofdanalyse.

De meta-analyses toonden aan dat BS een iets lagere specificiteit had, maar een veel

hogere sensitiviteit dan CT en MRI. Er werd geen bewijs gevonden voor een verschil

in accuratesse tussen CT en MRI.

In hoofdstuk 3 beschrijven we twee benaderingen voor het uitvoeren van een

vergelijkende meta-analyse van diagnostische tests. Elk van deze benaderingen

houdt rekening met de specifieke kenmerken van drie verschillende soorten studie:

studies van afzonderlijke tests, vergelijkende studies die data rapporteren voor de

255

afzonderlijke tests, en vergelijkende studies die ook nog gegevens verschaffen over

de samenhang tussen de afzonderlijke indextests. De absolute accuratessebenadering

(armgebaseerd) schat eerst de gemiddelde diagnostische accuratesse van elke test

en berekent dan het verschil tussen de tests, terwijl de relatieve verschilbenader-

ing (contrastgebaseerd) eerst het verschil in accuratesse tussen diagnostische tests

berekent, in elke studie afzonderlijk, en vervolgens het gemiddelde verschil tussen

de tests schat. In beide benaderingen hebben we de testuitkomsten rechtstreeks

gemodelleerd met een multinomiale verdeling. Simulaties toonden aan dat beide

benaderingen vergelijkbare resultaten opleveren wanneer alleen data uit vergelijkend

onderzoek worden gebruikt. Het model kan worden uitgebreid met covariaten, en

ook meer dan twee tests analyseren.

Als er zowel evaluatiess van afzonderlijke tests te vinden zijn als vergelijkende

studies, rijst de vraag welke studies in een systematisch literatuuronderzoek moeten

worden betrokken: beide, of enkel de vergelijkende studies? Als we de vergelijking

willen maken op basis van afzonderlijke evaluaties is er sprake van een indirecte

vergelijking. In de studie die in hoofdstuk 4 staat beschreven onderzochten we het

verschil in resultaten tussen een meta-analyse van directe vergelijkingen versus een

meta-analyse van indirecte vergelijkingen. We deden dat met behulp van individuele

patiëntgegevens uit een aantal studies. Er zijn twee belangrijke bronnen van verteken-

ing in indirecte vergelijkingen: heterogeniteit in studieopzet, waarbij studies bij

voorbeeld een andere referentiestandaard kunnen hanteren, of een andere drempel, en

verschillen in patiëntenpopulaties. We hebben twee soorten aanpassingen voorgesteld

om te corrigeren voor de beschreven vertekeningen. Type I-aanpassingen waren

gericht op een drempeleffect en op problemen met de referentiestandaard, terwijl

Type II-aanpassingen aanvullend gericht waren op patiëntkenmerken (bijvoorbeeld

leeftijd). Deze aanpassingen bleken in onze analyse echter niet succesvol bij het

verwijderen van de vertekening uit indirecte vergelijkingen. Er bleef een verschil

bestaan tussen directe en indirecte vergelijkingen, zelfs na toepassing van deze

correcties.

256

Hoofdstuk 5 bestudeert een ander aspect van meta-analyses van studies naar

de diagnostische accuratesse: de keuze van de uitkomstmaat. Bij systematisch

literatuuronderzoek wordt soms de oppervlakte onder de samenvattende ROC-curve

gerapporteerd, als maat voor de accuratesse van een test (area under the summary

ROC curve - AUSROC). Dat gebeurt nadat het bivariate model of het HSROC

model is gebruikt voor de feitelijke meta-analyse. In een simulatiestudie toonden

we aan dat het nagenoeg onmogelijk is om de juiste AUSROC te schatten vanuit een

meta-analyse van 2-bij-2 tabellen. De richting en de mate van vertekening kunnen

afhangen van de manier waarop de drempel werd bepaald in de primaire studies. De

AUSROC moet daarom niet gebruikt worden als een samenvattende maat voor de

diagnostische accuratesse van een test bij systematisch literatuuronderzoek.

Deel 2: De prognostische waarde van biomarkers en klinischevoorspelmodellen

In de studie die in hoofdstuk 6 staat beschreven evalueerden we het onderschei-

dend vermogen van alkalisch fosfatase (ALP), zowel bij de diagnose van primaire

scleroserende cholangitis als een jaar na de diagnose. In plaats van te kijken naar het

testresultaat als risicofactor in een Cox regressiemodel gebruikten we tijdsafhanke-

lijke C-maat om voorspellende waarde van ALP te beoordelen, zowel op de korte

termijn als op de lange termijn. Het onderscheidend vermogen van ALP op T0 en

op T1 en dat van de relatieve verandering werden vergeleken over de duur van de

follow-up. De optimale drempel werd bepaald op basis van de algemene C-grootheid.

We concluderen dat ALP op T1 beter presteert dan ALP op T0, maar er werd

geen formele statistische test uitgevoerd. De tijdafhankelijke C-grootheid leverde

slechts een indicatie van de prognostische waarde over de tijd. Als er geen specifiek

tijdstip van belang is, zou de vergelijking niet gebaseerd moeten worden op deze

tijdafhankelijke C-grootheid.

Ook hoofdstuk 7 gaat over de prognose van primaire scleroserende cholangitis.

257

We ontwikkelden een prognostisch model op basis van meerdere biomarkers en

andere patiëntkenmerken. Er waren een groot aantal ontbrekende waarden voor

de biomarkers op het moment van diagnose, en sommige van de merkers werden

herhaaldelijk gemeten tijdens de follow-up. Het principe van meervoudige im-

putatie werd toegepast en voor verschillende typen variabelen kozen we andere

imputatiemodellen. We hebben alle datasets gecombineerd tot één grote dataset en

gebruikten de Lasso-techniek om de parameter voor sommige variabelen te laten

krimpen tot 0, waardoor ze uit het model werden gestoten. Lasso’s strafparameter

’lambda’ werd bepaald op basis van het onderscheidend vermogen van het model,

uitgedrukt als Harrell’s C-grootheid, met als rationale dat het uiteindelijke model een

klein aantal voorspellers moet bevatten, maar met een C-grootheid die niet meer dan

10% lager is dan die van het optimale model. De interne validatie werd geëntegreerd

in de ontwikkeling van het model, om zo te corrigeren voor het optimisme in de

C-grootheid. Het model werd extern gevalideerd met data die waren verzameld in een

ander cohort, uit Oxford. Een extra recalibratie werd uitgevoerd, om te compenseren

voor een teveel aan krimp. De recalibratie werd uitgevoerd op de prognostische

index, afgeleid van Lasso, maar niet op de geselecteerde variabelen, omdat we het

relatieve belang van alle variabelen wilden bewaren en de risico’s en de gevolgen

van overfitting en van een inflatie van parameters wilden vermijden.

Hoofdstuk 8 beschrijft soortgelijke analyses als die in hoofdstuk 6, maar dan

voor een andere aandoening, nierschade, en voor verscheidene biomarkers. De

prognostische waarde van een aantal merkers bij het voorspellen van chronische

nierschade werd geëvalueerd op basis van de tijdsafhankelijke C-grootheid. Een

nieuwe uitdaging in deze studie was het corrigeren voor de geschatte glomerulaire

filtratiesnelheid (eGFR) op baseline. We gebruikten een Cox-model met baseline

eGFR en met een C-grootheid die was gecorrigeerd voor deze eGFR, maar een

tijdafhankelijke C-grootheid die ook was gecorrigeerd voor deze variabele was niet

beschikbaar; het zou een onderwerp kunnen zijn voor verolgonderzoek. Zonder

deze grootheid is het niet goed mogelijk om de waarden van merkers bij patiënten in

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verschillende fasen, of met een verschillende baseline eGFR, te vergelijken. Een

patiënt in fase 1 kan een grotere kans hebben om te evolueren naar chronische

nierschade dan een patiënt met dezelfde waarde van de merker die zich in fase 2

bevindt. Een patiënt met een eGFR-waarde op baseline die zich bij de grenswaarde

bevindt loopt een groter risico op chronische nierschade.

De evaluatie van medische tests loopt achter op de evaluatie van geneesmiddelen

en die van andere medische interventies. De methoden voor het schatten van de

effectiviteit van biomarkers, van tests en van modellen op basis van meerdere

testresultaten en bevindingen zijn tot nu toe minder ver ontwikkeld; dat geldt zowel

voor origineel onderzoek als voor samenvattend onderzoek op basis van de medische

literatuur. Met het wetenschappelijk onderzoek dat in dit proefschrift staat beschreven

wilden we een bijdrage leveren aan de ontwikkeling van geschikte methoden, en aan

de toepassing ervan in klinisch relevante onderzoek. Daarmee kan de onderbouwing

voor het nemen van beslissingen over tests en teststrategieën worden versterkt, wat

uiteindelijk moet leiden tot betere uitkomsten voor de betrokken patiënten, en tot

een efficiëntere zorg.

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260

List of contributing authors

Fréderike J BemelmanDivision of Internal Medicine, Renal Transplant Unit and Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Ulrich H BeuersDepartment of Gastroenterology and Hepatology, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Kirsten BoonstraDepartment of Gastroenterology and Hepatology, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Patrick MM BossuytDepartment of Clinical Epidemiology, Biostatistics & Bioinformatics, Amsterdam

Public Health research institute, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Frank BroekmansDepartment of Reproductive Medicine

University Medical Center Utrecht, Utrecht, the Netherlands

Simone BroerDepartment of Reproductive Medicine

University Medical Center Utrecht, Utrecht, the Netherlands

Roger W ChapmanTranslational Gastroenterology Unit

John Radcliffe Hospital, Oxford, United Kingdom

Madeleine DollemanDepartment of Reproductive Medicine

University Medical Center Utrecht, Utrecht, the Netherlands

Job N DoornbergDepartment of Orthopaedic Surgery, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

263

Sandrine FlorquinDepartment of Pathology, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Ronald B GeskusDepartment of Clinical Epidemiology, Biostatistics & Bioinformatics, Amsterdam

Public Health research institute, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Afina S GlasDepartment of Urology

Zaans Medical Center, Zaandam, the Netherlands

Jesper KersDepartment of Pathology, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Peter KloenDepartment of Orthopaedic Surgery

Academic Medical Center, Amsterdam, the Netherlands

Mariska MG Leeflang, Department of Clinical Epidemiology, Biostatistics &

Bioinformatics, Amsterdam Public Health research institute, Academic Medical

Center

University of Amsterdam, Amsterdam, the Netherlands

Mario MaasDepartment of Radiology, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Wouter H MalleeDepartment of Orthopaedic Surgery, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Laura MeyerDivision of Internal Medicine, Renal Transplant Unit and Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

264

Ben Willem MolSchool of Paediatrics and Reproductive Health

University of Adelaide, Australia

Hessel Peters-SengersDivision of Internal Medicine, Renal Transplant Unit and Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Cyriel Y PonsioenDepartment of Gastroenterology and Hepatology, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Rudolf W PoolmanDepartment of Orthopaedic Surgery

Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands

Henrica CW de VetDepartment of Epidemiology and Biostatistics, EMGO Institute for Health and Care

Research

VU University Medical Center, Amsterdam, the Netherlands

Elisabeth MG de VriesDepartment of Gastroenterology and Hepatology, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

Rinse K WeersmaDepartment of Gastroenterology and Hepatology

University Medical Center Groningen, Groningen, the Netherlands

Kate D WilliamsonTranslational Gastroenterology Unit

John Radcliffe Hospital, Oxford, United Kingdom

Aeilko H ZwindermanDepartment of Clinical Epidemiology, Biostatistics & Bioinformatics, Amsterdam

Public Health research institute, Academic Medical Center

University of Amsterdam, Amsterdam, the Netherlands

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266

PhD portfolio

Training

Courses in AMC graduate school

Courses YearThe AMC World of Science 2012

Practical Biostatistics 2013

Oral Presentation 2013

Systematic Reviews 2013

Evidence Based Searching 2013

Clinical Epidemiology 2013

Advanced Topics in Clinical Epidemiology 2014

Advanced Topics in Biostatistics 2014

Computing in R 2014

Data analysis in Matlab 2014

Courses in Johns Hopkins Bloomberg School of Public HealthSummer Institutes

Courses YearAnalysis of Longitudinal Data 2015

Multilevel Models 2015

Biostatistical Analysis of Epidemiologic Data III: Semi Parametric Methods 2015

Other courses

Courses YearSystematic Reviews of Diagnostic Test Accuracy for authors, Dutch Cochrane Centre,

Amsterdam, the Netherlands

2012

Missing Data in Clinical Trials, AISECT&EAR-BC, Beijing, China 2013

Evaluation of Accuracy of Medical Devices and Biomarkers, AISECT&EAR-BC, Beijing,

China

2013

Statistical Methods for Diagnostic Test Accuracy Reviews, Systematic Reviews of Diag-

nostic Test Accuracy for authors, MEMTB 2013, Birmingham, UK

2013

Author and Reviewer Workshop, European Journal of Radiology, Amsterdam, the Nether-

lands

2014

Splines, IBS Channel Network Conference 2015, Nijmegen, the Netherlands 2015

Weekly departmental seminars 2012-

2017

269

Presentations

Conferences YearDirect and Indirect Comparisons in Comparative Systematic Reviews of Diagnostic Test

Accuracy Studies, MEMTB 2013, Birmingham, UK (Oral)

2013

Direct versus Indirect Comparisons in Systematic Reviews of Test Accuracy Studies: An

IPD Case Study in Ovarian Reserve Testing, 21st Cochrane Colloquium, Qu¨¦bec City,

Canada (Poster)

2013

Novel prognostic model for primary sclerosing cholangitis: the importance of including

biochemical values, Joint Workshop on "Nonparametric Analyses of complex time to event

data" of the GR-IBS working groups Nonparametric Methodsand Statistics of Stochastic

Processes, Ulm, Germany (Oral)

2014

Individual patient data meta-analysis for diagnostic test accuracy studies: a review of

methods used in practice, IBS channel conference 2015, Nijmegen, the Netherlands (Poster)

2015

Individual patient data meta-analysis for diagnostic test accuracy studies: a review of

methods used in practice, 23st Cochrane Colloquium, Vienna, Austria (Poster)

2015

Searching Chinese biomedical databases: current practice among Cochrane reviewers, 23st

Cochrane Colloquium, Vienna, Austria (Oral)

2015

All estimates of the Area Under the HSROC curve may be biased. A simulation study,

MEMTB 2016, Birmingham, UK (Poster)

2016

Comparative Meta-Analysis of Diagnostic Studies: a Review and Comparison of Currently

Proposed Approaches, ISCB 2017, Vigo, Spain (Poster)

2017

Awards

AMC Young Talent Fund 2015

Other activities

ISCB 2015 conference assistant 2015

Peer reviewer of the Cochrane Library, Diagnostic Test Accuracy Working Group 2013-

2017

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Other publications

Reporting Diagnostic Accuracy Studies: Some Improvements after 10 Yearsof STARDDaniël A Korevaar, Junfeng Wang, W Annefloor van Enst, Mariska M Leeflang,Lotty Hooft, Nynke Smidt, Patrick M M Bossuyt.Radiology 10/2014; 274(3)

The Statue Que and the Development of Systematic Review/Meta-Analysis ofTraditional Chinese Medicine in Past Nineteen YearsJiaying Wang, Junfeng Wang, Shiqi Cheng, Guihua Tian, Yanping Wang, HongcaiShang, Yongyan Wang.Journal of Traditional Chinese Medicine (Chinese Edition), 2017, Vol. 58, No. 11

Spin: The New Challenge of the Reporting of Chinese Medicine’s ClinicalEvidenceJiaying Wang, Junfeng Wang, Hongcai ShangWorld Chinese Medicine (Chinese Edition), June 2017, Vol.12, No. 6

Should we search Chinese biomedical databases when performing systematicreviews?Jérémie F. Cohen, Daniël A. Korevaar, Junfeng Wang, René Spijker and Patrick M.Bossuyt.Systematic Reviews (2015) 4:23

Meta-Epidemiologic Study Showed Frequent Time Trends in SummaryEstimates From Meta-Analyses of Diagnostic Accuracy Studies.Jérémie F. Cohen, Daniël A. Korevaar, Junfeng Wang, Mariska M. Leeflang, PatrickM. Bossuyt.Journal of Clinical Epidemiology 2016 Sep; 77:60-7.

Galactomannan detection for invasive aspergillosis in immunocompromisedpatients.Mariska MG Leeflang, Yvette J Debets-Ossenkopp, Junfeng Wang, Caroline EVisser, Rob JPM Scholten, Lotty Hooft, Henk A Bijlmer, Johannes B Reitsma,Mingming Zhang, Patrick MM Bossuyt, Christina M Vandenbroucke-Grauls.Cochrane Database of Systematic Reviews 2015, Issue 12

271

Diagnostic accuracy of minimally invasive markers for detection of airwayeosinophilia in asthma: a systematic review and meta-analysis.Daniël A Korevaar, Guus A Westerhof, Junfeng Wang, Jérémie F Cohen, RenéSpijker, Peter J Sterk, Elisabeth H Bel, Patrick M M Bossuyt.The Lancet. Respiratory medicine 03/2015; 3(4)

Biomarkers to identify sputum eosinophilia in different adultasthmaphenotypes.Guus A. Westerhof, Daniël A. Korevaar, Marijke Amelink, Selma B. de Nijs,Jantina C. de Groot, Junfeng Wang, Els J. Weersink, Anneke ten Brinke, Patrick M.Bossuyt, Elisabeth H. Bel.Eur Respir J 2015; 46: 688¨C696

Low interobserver agreement among endoscopists in differentiatingdysplastic from non- dysplastic lesions during inflammatory bowel diseasecolitis surveillance.Linda K. Wanders, Erik Mooiweer, Junfeng Wang, Raf Bisschops, G. JohanOfferhaus, Peter D. Siersema, Geert R. D’Haens, Bas Oldenburg, Evelien Dekker.Scandinavian Journal of Gastroenterology. 2015; 50: 1011¨C1017.

Optical diagnosis of malignant colorectal polyps: is it feasible?Manon van der Vlugt, Sascha C van Doorn, Junfeng Wang, Barbara A Bastiaansen,Lodewijk A Brosens, Paul Fockens, Evelien Dekker.Endoscopy International Open, 4(7), E778¨CE783

Development and Validation of the WASP-Classification System for OpticalDiagnosis of Adenomas, Hyperplastic Polyps and Sessile SerratedAdenomas/Polyps.Joep E G IJspeert, Barbara A J Bastiaansen, Monique E van Leerdam, Gerrit AMeijer, Susanne van Eeden, Silvia Sanduleanu, Erik J Schoon, Tanya M Bisseling,Manon Cw Spaander, Niels van Lelyveld, Marloes Bargeman, Junfeng Wang,Evelien Dekker.Gut 03/2015; 81(5).

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Curriculum vitae

Junfeng Wang was born on 4th March 1986

in Harbin, Heilongjiang, China, and grew up

there.

After finishing his secondary education in

Harbin No. 3 High School in 2004, he went to

study Statistics at Renmin University of China,

Beijing. Upon completing his Bachelor degree

in June 2008, he joined Deloitte China as a con-

sultant in Risk Advisory and worked there for

two years. During this period, he was involved

in several projects on credit risk model develop-

ment in leading Chinese banks, and he developed

an interest in predictive modelling.

In 2010, he proceeded to the Netherlands

to pursue a Master degree in Quantitative Fi-

nance and Actuarial Science at Tilburg Universi-

ty. After graduation, he continued his career in

financial risk management in ING Bank, Model

Validation team, in Amsterdam.

In November 2012, he began his PhD study

in Biostatistics, at the department of Clinical

Epidemiology, Biostatistics and Bioinformatics,

Academic Medical Center, University of Ams-

terdam, in the Biomarker and Test Evaluation

(BiTE) group lead by Prof. dr. Patrick Bossuyt.

His research was focused on statistical methods

in evaluating medical tests, biomarkers and pre-

diction models, as presented in this PhD thesis.

In the forth year of his PhD (2016), he got

an opportunity to work one year for Rabobank,

in Utrecht, to keep his knowledge in finance and

risk management up-to-date.

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Acknowledgements

I would like to express my sincere gratitude to:

My supervisors:My promotor, Patrick Bossuyt: For your trust and encouragement. This

accomplishment would not happen without you.

My promotor, Koos Zwinderman: For your insight advice on my research,

especially on the statistical methods.

My co-promotor, Mariska Leeflang: For your consideration and lots of help in

daily supervision.

My co-promotor, Ronald Geskus: For your criticalness and challenges. I really

learnt a lot during our broad discussion.

My PhD committee members: For your time in reading my thesis and the positive

feedbacks.

Dear Corien Meijer: Thank you for helping me with the preparation of my PhD

defence and all the helps during my stay with BiTE.

My paranymphs, Yue Li and Weiluan Chen: For all your advice and kind help

in preparing my PhD defence, reception and the party. Special thanks to Weiluan,

for your intelligence, in designing my thesis cover. I have had the idea for a long

time but never expected the complicated design could come true, until you made it

perfectly reflecting what’s in my mind.

My collaborator, Liesbeth de Vries: For our valuable collaboration. As co-first au-

thor on two of the chapters, you made an important contribution to the development of

this thesis. Also thanks for the memorable "PSC model dinner", I felt really "gezellig".

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Members and former members of BiTE group, Miranda Langendam, JérémieCohen, Daniël Korevaar, Annefloor van Enst, Parvin Tajik, Gowri Gopalakr-ishna, Eleanor Ochodo, Nina Steutel, Erik van Werkhoven, Mona Ghannad,Maria Olsen, and all my dear colleagues in KEBB: It was a great pleasure

working with all of you. I enjoyed the five years in KEBB.

AMC Young Talent Fund and Louise Gunning Public Health Study Fund:Thanks for supporting me to attend the summer school courses in Johns Hopkins

Bloomberg School of Public Health in Baltimore, USA.

My friends in the Netherlands: I have made many friends during my 7 years stay

in the Netherlands. Some of you are still in the Netherlands, and some of you have

left for the next adventure. Thanks you for your company and friendship.

Some very important friends:Xuelai Wang: Thanks for orienting me to the field of public health, and your advice

and help during my application and interview of this PhD position.

Jiaying Wang: Thanks for letting me be grateful for everything happened to me

and our close collaboration.

My dear parents, Hongying Kong and Shengchao Wang: Thanks for your

unconditional support, on every decision I made. This thesis is dedicated to you.

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