\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,greek,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Phenotypes and Clinical Outcomes of Omalizumab and Mepolizumab treated
Difficult Asthma patients}



\author[1]{Wei Chern Gavin Fong}%
\author[2]{Adnan Azim}%
\author[3]{Deborah Knight}%
\author[1]{Heena Mistry}%
\author[2]{Anna Freeman}%
\author[2]{Mae Felongco}%
\author[2]{Aref Kyyaly}%
\author[2]{Matthew Harvey}%
\author[3]{Patrick Dennison}%
\author[4]{Hongmei Zhang}%
\author[5]{Peter Howarth}%
\author[1]{S Arshad}%
\author[2]{Ramesh Kurukulaaratchy}%
\affil[1]{Isle of Wight NHS Trust}%
\affil[2]{University of Southampton Division of Clinical and Experimental Sciences}%
\affil[3]{University Hospital Southampton NHS Foundation Trust}%
\affil[4]{University of Memphis}%
\affil[5]{University of Southampton}%


\vspace{-1em}



  
  \date{May 04, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Introduction Real-world data on Omalizumab (OMA) and Mepolizumab (MEPO)
can inform their use in severe asthma (SA). We studied patients in the
Wessex AsThma CoHort of difficult asthma (WATCH) to: 1. Phenotypically
compare OMA or MEPO treated patients against a SA, non-biologic group
(SNB). 2. Assess clinical responses to OMA and MEPO. 3. Assess the
spectrum of responses to these biologics. Methods We retrospectively
phenotyped biologic na\selectlanguage{ngerman}ïve patients from WATCH (N=478) commenced on OMA
(N=105) or MEPO (N=62) compared to SNB (N=178). Biologic response was
gauged using standard criteria and response features were identified
using logistic regression. Results OMA and MEPO patients were
phenotypically distinct. Both drugs significantly reduced exacerbations,
acute healthcare encounters (emergency department or hospital
admissions), maintenance oral corticosteroid dose, and improved Asthma
Control Questionnaire 6 (ACQ6) scores. OMA patients with more
exacerbations at baseline (P=0.024), less acute healthcare encounters
(P=0.050), and no anxiety (P=0.008) were more likely to respond to it.
Lower baseline ACQ6 was independently associated with higher odds of
MEPO response (P=0.007). Combined (OMA or MEPO) non-responders had
significantly more psychological co-morbidities and worse baseline
subjective disease markers compared to responder groups. Current
criteria used to measure trial outcomes for MEPO, but not OMA, missed
some modalities of response. Conclusion In a difficult asthma cohort,
OMA and MEPO were used for distinct SA phenotypes, yet both were
multidimensionally efficacious. Among these phenotypes, some clinical
features associated with response were identified which emphasized the
importance of addressing treatable traits when considering biologic
therapy.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\emph{Long title: Phenotypes and Clinical Outcomes of Omalizumab and
Mepolizumab treated Difficult Asthma patients}

\emph{Short title: Real-world Omalizumab and Mepolizumab outcomes}

\textbf{Authors:} Wei Chern Gavin Fong*\textsuperscript{1,2} , Adnan
Azim*\textsuperscript{2,3}, Deborah Knight\textsuperscript{3}, Heena
Mistry\textsuperscript{1,2,3}, Anna Freeman\textsuperscript{2,3}, Mae
Felongco\textsuperscript{2,3}, Aref Kyyaly\textsuperscript{1,2,3},
Matthew Harvey\textsuperscript{2,3}, Patrick
Dennison\textsuperscript{3}, Hongmei Zhang\textsuperscript{4}, Peter
Howarth\textsuperscript{2,3} S Hasan Arshad\textsuperscript{1,2,3} and
Ramesh J Kurukulaaratchy\textsuperscript{1,2,3}

\textbf{Affiliations:} \textsuperscript{1}David Hide Asthma and Allergy
Research Centre, Isle of Wight, UK. \textsuperscript{2}Clinical and
Experimental Sciences, Faculty of Medicine, University of Southampton,
Southampton, UK. \textsuperscript{3} NIHR Southampton Biomedical
Research Centre, University Hospitals Southampton NHS Foundation Trust,
Southampton. \textsuperscript{4}Division of Epidemiology, Biostatistics,
and Environmental Health, School of Public Health, University of
Memphis, Memphis, TN, USA.

*contributed equally

\textbf{Corresponding Author}

Dr. Ramesh J Kurukulaaratchy

David Hide Asthma and Allergy Research Centre, Isle of Wight.

\& School of Clinical and Experimental Sciences, Faculty of Medicine,
University of Southampton \& NIHR Southampton Biomedical Research
Centre, University Hospital Southampton NHS Foundation Trust, UK Level
F, South Academic Block, Southampton General Hospital, Southampton SO16
6YD, United Kingdom. Tel: +442381 208790

Email: R.J.Kurukulaaratchy@soton.ac.uk

\textbf{Conflict of interest:} PD received a non-promotional grant from
Novartis for the WATCH study for data entry clerk funding. PH is an
employee of GlaxoSmithKline.

\textbf{Word count text: Around 3500 Word count abstract: 247}

\textbf{ACKNOWLEDGEMENTS:}

The authors thank the patients who participated in this study and the
WATCH study team who conducted it. They also acknowledge the support of
the National Institute for Health Research (NIHR) Southampton Biomedical
Research Centre and NIHR Clinical Research Facility, which are funded by
NIHR and are a partnership between the University of Southampton and
University Hospital Southampton NHS Foundation Trust. The authors also
acknowledge a non-promotional grant from Novartis (\selectlanguage{ngerman}£35,000) and initial
assistance through a charitable grant (£3,500) for relevant patient
costs (e.g. parking) from the Asthma, Allergy \& Inflammation Research
Charity. The WATCH study itself is not externally funded.

\textbf{ABSTRACT}

\textbf{Introduction}Real-world data on Omalizumab (OMA) and Mepolizumab
(MEPO) can inform their use in severe asthma (SA). We studied patients
in the Wessex AsThma CoHort of difficult asthma (WATCH) to: 1.
Phenotypically compare OMA or MEPO treated patients against a SA,
non-biologic group (SNB). 2. Assess clinical responses to OMA and MEPO.
3. Assess the spectrum of responses to these biologics.

\textbf{Methods}We retrospectively phenotyped biologic naïve patients
from WATCH (N=478) commenced on OMA (N=105) or MEPO (N=62) compared to
SNB (N=178). Biologic response was gauged using standard criteria and
response features were identified using logistic regression.

\textbf{Results}OMA and MEPO patients were phenotypically distinct. Both
drugs significantly reduced exacerbations, acute healthcare encounters
(emergency department or hospital admissions), maintenance oral
corticosteroid dose, and improved Asthma Control Questionnaire 6 (ACQ6)
scores. OMA patients with more exacerbations at baseline (P=0.024), less
acute healthcare encounters (P=0.050), and no anxiety (P=0.008) were
more likely to respond to it. Lower baseline ACQ6 was independently
associated with higher odds of MEPO response (P=0.007). Combined (OMA or
MEPO) non-responders had significantly more psychological co-morbidities
and worse baseline subjective disease markers compared to responder
groups. Current criteria used to measure trial outcomes for MEPO, but
not OMA, missed some modalities of response.

\textbf{Conclusion}

In a difficult asthma cohort, OMA and MEPO were used for distinct SA
phenotypes, yet both were multidimensionally efficacious. Among these
phenotypes, some clinical features associated with response were
identified which emphasized the importance of addressing treatable
traits when considering biologic therapy.

\textbf{Keywords: asthma, asthma treatment, biologics, epidemiology,
personalized medicine}

\emph{Introduction}

Biologic therapies have revolutionised Severe Asthma (SA) management,
heralding a potential era of personalized medicine (1) that better
addresses SA's heterogeneity. In the United Kingdom (UK), four biologics
are currently approved for use in SA (2). The two in longest use are the
anti-immunoglobulin E (IgE) biologic, Omalizumab (OMA) and the
anti-interleukin-5 (IL-5) biologic, Mepolizumab (MEPO). Both agents
proved highly effective in phase-III randomised controlled trials (RCTs)
(3--6) and have been widely adopted into clinical practice. However, RCT
populations are not reflective of real-world patients (7,8). Brown et
al. highlighted that only 9.8\% of their SA cohort met enrolment
criteria of phase-III asthma biologic RCTs (9). Thus, as the portfolio
of biologics continues to expand, real-world data on these drugs is
urgently needed (10) to better understand their place in real-life SA
management. Additionally, an evolving paradox of biologic choice places
greater onus on clinicians to ``get it right first time'', to save costs
and improve patient outcomes. To guide asthma biologic selection, it is
imperative to understand patient phenotypes best suited for individual
drugs, identify features associated with response, and also consider how
best to judge clinical impact of these therapies. Therefore, to help
address these needs, we present parallel real-world clinical data on the
two widely used asthma biologics, OMA and MEPO, from the thoroughly
characterised, longitudinal Wessex AsThma CoHort of difficult asthma
(WATCH) (11).

\emph{Methods}WATCH is a prospective observational study of patients
managed in a tertiary asthma clinic at University Hospital Southampton,
UK with ``high dose therapies'' and/or ``continuous or frequent use of
oral corticosteroids (OCS)'' as per the British Thoracic Society Adult
Asthma Management Guidelines 2016 (12) . Detailed study methodology is
described elsewhere (11). The study had ethical approval (REC reference:
14/WM/1226) and written informed consent was obtained for all
participants.

We conducted a retrospective study of biologic naïve patients from WATCH
who were started on OMA or MEPO between June 2006 and May 2019. Biologic
eligibility was based on National Institute for Health \& Care
Excellence (NICE) guidance (13,14) {[}supplementary table E1{]}. Our
aims were three-fold. First, to define phenotypic characteristics of
patients commencing OMA or MEPO against SA patients who remained
biologic naive. Second, to assess clinical responses to both agents from
biologic trial data and identify features associated with response.
Finally, to assess the spectrum of responses to these biologics.

Biologic trial data were collected at baseline (first biologic visit)
and at subsequent treatment visits: 2-4 weekly for OMA and 4-weekly for
MEPO. This included Asthma Control Questionnaire-6 (ACQ6), incidence of
exacerbations (exacerbations requiring an acute oral corticosteroid
{[}OCS{]} course / increase in maintenance OCS {[}mOCS{]}), incidence of
emergency department or hospital admissions (Acute Healthcare Encounters
{[}AHE{]}), current mOCS dose and Clinic percent predicted
FEV\textsubscript{1} (FEV\textsubscript{1}\%). Hospital anxiety and
depression scale (HADS) and Asthma Quality of Life Questionnaire (AQLQ)
were collected at baseline and final visits for MEPO. Fractional Exhaled
Nitric Oxide (FENO) was collected at all MEPO visits, but only at the
baseline OMA visit. Co-morbidity, anthropometric and demographic data
were extracted from the WATCH database. Maximum peripheral blood
eosinophil count (PBE), total IgE, baseline exacerbations and AHE were
from the 12 months prior to biologic approval. Exacerbations and AHE
were annualised for comparisons.

To describe the biologic-naïve characteristics of the biologic treated
groups, a common comparator `severe asthma, non-biologic' (SNB) group
was extracted from WATCH. SNB subjects (n= 178) were participants who
either had \selectlanguage{english}[?]4 exacerbations or \selectlanguage{english}[?]1 AHE or were on mOCS in the past year
but did not commence biologic therapy during the study period.
Comparisons were made using baseline biologic data for the biologic
treated groups and WATCH enrolment data for the SNB group. Additionally,
biologic treated groups were mapped onto four age-of-onset/sex clinical
clusters {[}male/early-onset (\textless{}18 years), female/early-onset,
male/adult-onset (\selectlanguage{english}[?]18 years), female/adult-onset{]} that we recently
described (15), to further characterise their phenotypic features.

Biologic response was determined by the clinical MDT (Multi-Disciplinary
Team), based on NICE guidance (13,14). For OMA, response was assessed
using the Global Evaluation of Treatment Effectiveness (GETE) (16--18).
For MEPO, response was defined as a \selectlanguage{english}[?]50\% reduction in exacerbations or
in mOCS dose without loss of asthma control. In borderline OCS
responders, factors such as change in AHE, symptom control or
quality-of-life would additionally guide MEPO continuation. Treatment
trials typically ended at 16 weeks for OMA and 12 months for MEPO.
However, equivocal trials were extended up to 32 weeks for OMA and 18
months for MEPO. We defined `super-response' separately for both
biologics. OMA super-responders were defined as 16-week responders who
either had the top quartile of percentage reduction in mOCS dose while
being exacerbation and AHE free; or if not on mOCS, were exacerbation
and AHE free. For MEPO, super-responders were defined as 12-month
responders who either had the top quartile of percentage reduction in
mOCS dose, while having a synchronous reduction in exacerbations; or if
not on mOCS, had the top quartile of percentage reduction in
exacerbations. Statistical analysis was performed with SPSS 26 (IBM
Corp, NY, USA), GraphPad Prism 9 (GraphPad Software, California, USA)
and R (R Foundation, Vienna, Austria). Continuous variables were
presented as Mean (Standard deviation{[}SD{]}) or Median (Interquartile
range{[}IQR{]}). Categorical data were presented as
percentage(frequency). Data were analysed using paired and unpaired
t-tests, Mann-Whitney U test, Wilcoxon-Signed Rank test, Chi-square
test, McNemar test or Fisher's exact test as appropriate. Multiple
logistic regression (backward variable selection) was performed using
variables trending towards significance (P\textless{}0.2). Statistical
significance was set at P-value \textless{} 0.05.

\emph{}

\emph{}

\emph{Results} Among the WATCH cohort, 37.7\% (182/478) completed trials
with either OMA or MEPO. Nearly two-thirds were with OMA (63.7\%;
116/182) and the rest were with MEPO (36.3\%; 66/182). Eleven from OMA
analysis and four from MEPO analysis were excluded due to missing
outcome data.

\emph{Baseline characteristics of Biologic Treated Groups vs SNB
(comparator) group}

Compared to SNB subjects, neither biologic groups had significantly
different baseline exacerbations or AHE (Table 1). However, they both
showed other baseline severity markers, with significantly higher FENO,
worse lung function and more mOCS dependency.

Compared to SNB subjects, OMA subjects had significantly younger age of
asthma onset (Table 1). They were also more ethnically diverse and were
all atopic. They also had a significantly greater prevalence of
rhinitis, allergic bronchopulmonary aspergillosis (ABPA), and nasal
(polyps/sinus) surgery.

Conversely, compared to SNB subjects, MEPO subjects had a significantly
higher maximum PBE (Table 1), were older, diagnosed with asthma later in
life, and predominantly male. Additionally, they had a significantly
higher prevalence of nasal polyps and nasal (polyps/sinus) surgery but
less dysfunctional breathing.

\emph{Omalizumab response}Overall, 99.0\%,(104/105) patients completed
OMA trials. One person withdrew due to side-effects. OMA (Figure 1)
significantly reduced exacerbations {[}Median(IQR), baseline: 5(3) to
0(3) at end-of-trial, P\textless{}0.001{]}, mOCS dose {[}Median(IQR),
baseline: 10(10-20) to 10(5-15) at end-of-trial, P=0.002{]}, AHE
{[}Median(IQR), baseline: 1(2) to 0(0) at end-of-trial, P=0.003{]} and
the proportion of patients with multiple (\textgreater{}1) AHE
{[}Baseline: 36.5\%,(38/104); end-of-trial: 15.4\%,(16/104), P=0.007{]}.
OMA (Figure 1) also significantly improved asthma control {[}Mean (SD)
ACQ6, baseline: 2.96(1.26) to 1.64(1.12) at end-of-trial, P
\textless{}0.001{]}, Clinic FEV\textsubscript{1}\% {[}Mean(SD),
baseline: 67.34(25.93) to 75.40(21.79) at end-of-trial,
P\textless{}0.001{]} and reduced PBE (cells/\selectlanguage{greek}μ\selectlanguage{english}L) {[}Median(IQR) baseline:
200(400) to 200(200) at end-of-trial, P=0.002{]}. However, it did not
significantly reduce mOCS dependency {[}Baseline: 48.1\%, (50/104),
end-of-trial: 41.6\% (42/101), P=NS{]}.

\emph{Omalizumab responders vs non-responders}OMA response, as assessed
by GETE, was achieved in 88.5\%, (92/104) of subjects completing trials.
OMA responders (supplementary table E2) were significantly older
{[}Mean(SD) Age, Responder: 53(15) vs non-responder: 44(12), P=0.025{]}
and had lower prevalence of anxiety {[}Responder: 26.6\%,(21/79) vs
non-responder: 63.6\%,(7/11), P=0.031{]}. In multivariate analysis
(Table 2), anxiety and more AHE at baseline were independently
associated with treatment failure, while more exacerbations at baseline
was independently associated with treatment response.

\emph{Omalizumab super-responders}

Based on our definition, 33.7\%, (35/104) of OMA subjects who completed
trials were super-responders. That constituted 38.0\%, (35/92) of OMA
responders. OMA Super-responders (supplementary Table E3) had
significantly more exacerbations at baseline {[}Median(IQR),
super-responder: 6(2) vs non-super-responder: 4(4), P=0.029{]}, were
less mOCS dependent {[}super-responder: 14.3\%,(5/35) vs
non-super-responder: 65.2\%,(45/69), P\textless{}0.001{]} and had a
lower prevalence of anxiety {[}super-responder: 16.7\%(5/30) vs
non-super-responder: 38.3\%,(23/60), P=0.036{]} and depression
{[}super-responder: 17.2\%,(5/29) vs non-super-responder:
39.3\%,(24/61), P=0.036{]}. Absence of depression and not being on mOCS
were independently associated with OMA super-response (Table 2).

\emph{Mepolizumab response}

MEPO trials were completed by 93.6\%, (58/62) patients, while 4.8\%,
(3/62) withdrew due to adverse effects and 1.6\%, (1/62) withdrew due to
logistical reasons. MEPO (Figure 1) significantly improved symptom
control {[}Mean(SD), ACQ6 baseline: 2.71(1.26) vs 1.95(1.64) at
end-of-trial, P\textless{}0.001{]}, AQLQ {[}Mean(SD), baseline:
4.33(1.27) to 5.41(1.35) at the end-of-trial, P\textless{}0.001{]} and
total HADS {[}Median(IQR), baseline: 9.5(10) to 6(9.5) at end-of-trial,
P=0.012{]}. Furthermore, MEPO (Figure 1) significantly reduced
exacerbations {[}Median(IQR), baseline: 4(3) vs 2(3) at the
end-of-trial, P\textless{}0.001{]}, AHE {[}Median(IQR), baseline: 0(1)
to 0(0) at the end-of-trial, P=0.006{]}, PBE (cells/\selectlanguage{greek}μ\selectlanguage{english}L) {[}Median(IQR),
baseline: 500(350) to 100(100) at end-of-trial, P\textless{}0.001), mOCS
dose {[}Median(IQR), baseline: 10(10) to 5(7) at end-of-trial,
P\textless{}0.001{]}, and mOCS dependency {[}Baseline: 70.7\%,(41/58);
end-of-trial: 56.1\% ,(32/57), P=0.008{]}. However, it did not
significantly improve Clinic FEV\textsubscript{1}\%, FENO nor the
proportion of patients with multiple AHE.

\emph{Mepolizumab responders and non-responders}

Among MEPO subjects who completed their trials, 74.1\%, (43/58) subjects
were responders based on NICE criteria. At baseline, MEPO responders
were on a significantly lower mOCS dose (supplementary Table E4)
{[}Median(IQR), responder: 10(6) vs non-responder: 17(25), P=0.030{]},
had better ACQ6 {[}Mean(SD), responder: 2.33(1.27) vs non-responder:
4(0.94), P \textless{}0.001{]} , better AQLQ {[}Mean(SD), responder:
4.53(1.19) vs non-responder 3.57(1.19), P=0.021{]} , and significantly
less AHE {[}Median(IQR), responder: 0(1) vs non-responder : 1(4),
P=0.030{]}. A smaller proportion of responders had multiple AHE
{[}responder: 9.8\%,(4/41) vs non-responder: 42.9\%,(6/14), P=0.012{]}
and depression {[}responder: 19.1\%,(8/42) vs non-responder:
46.7\%,(7/15), P=0.037{]}. In multivariate analysis (Table 2), only
better ACQ6 at baseline was independently associated with MEPO response.

\emph{Mepolizumab super-responders}

According to our definition, 19\%, (11/58) of MEPO subjects who
completed trials were super-responders, which constituted 25.6\%,
(11/43) of MEPO responders. At baseline, MEPO super-responders
(supplementary Table E5) had significantly lower ACQ6 {[}Mean(SD),
super-responder: 1.93(1.33) vs non-super-responder: 3.03(1.24),
P=0.016{]}, higher AQLQ {[}Mean(SD), super-responder: 5.16(1.40) vs
non-super-responder: 4.09(1.13), P=0.018{]}, more exacerbations
{[}Median(IQR), super-responder: 7(5) vs non-super-responder: 4(5),
P=0.010{]} and better Clinic FEV\textsubscript{1}\% {[}Mean(SD),
super-responder: 79.73(19.97) vs non-super-responder: 63.07(19.84),
P=0.016{]}. Additionally, super-responders also had a significantly
lower BMI {[}Median (IQR), super-responder: 25.1(5) vs
non-super-responder: 29.9(12.3), P=0.009{]} and a lower prevalence of
obesity (BMI[?]30 kgm\textsuperscript{-2}) {[}super-responders:
9.1\%,(1/11) vs non-super-responder: 48.9\%,(23/47), P= 0.019{]}.
Multivariate analysis (Table 2) found that more exacerbations and better
ACQ6 at baseline were independently associated with MEPO super-response.

\emph{Overall biologic non-response}

All biologic non-responders, N=27 (OMA {[}44.4\%,12/27{]}, MEPO
{[}55.6\%,15/27{]}), were combined and compared with the SNB group and
responder groups. Compared to SNB subjects, at baseline, combined
non-responders (CNRs) (Table 3) had significantly more AHE, worse ACQ6
and worse lung function. Furthermore, they were significantly more mOCS
dependent, more atopic and had a larger proportion of multiple AHE.

Compared to both biologic responders, CNRs had significantly worse
baseline ACQ6 and greater prevalence of anxiety. In comparison with MEPO
responders, a significantly larger proportion of CNRs were female, had
depression, dysfunctional breathing and multiple AHE. Furthermore, CNRs
had significantly more AHE at baseline and had younger asthma onset.
Compared to OMA responders, there were no notable differences apart from
those conferred by qualifying criteria (more Atopy/ lower Maximum PBE).

\emph{Stratification of biologic use and outcomes within
Age-of-onset/sex clusters}

Within our biologic (OMA+ MEPO) cohort, the female/early-onset cluster
was most prevalent, while the male/early-onset group was the least.
Although biologic use across these phenotypes (Table 4) was
significantly different, there was no statistically significant
difference in response for either biologic across these phenotypes.

\emph{Alternative assessments of biologic outcomes}

The GETE used in OMA (Figure 2a) captured all modalities of response. It
captured all (100\%, 32/32) patients who had an improvement of AHE
status ([?]1 AHE to 0 AHE), all (100\%, 75/75) patients who had an
OCS/Exacerbation response ([?]50\% reduction in mOCS dose or
exacerbations) and 97.8\%, (48/49) of patients who had an ACQ response
([?]the minimally important difference {[}MID{]} of 0.5).

In comparison, in MEPO, 16.7\%, (6/36) patients who had an ACQ response
and 18.2\%, (4/22) patients who had an AQLQ response ([?]MID of 0.5) were
not deemed responders based on NICE criteria (Figure 2b). Similarly,
30\%, (3/10) subjects who had an improvement of AHE status were not
deemed responders using conventional criteria. Additionally, NICE
criteria did not capture three patients who responded in two separate
domains (ACQ \& AQLQ: 2, AHE \& ACQ:1). Conversely, some MEPO responders
did not show ACQ (21.0\%, 8/38) nor AQLQ (30.8\%, 8/26) responses.

\emph{}

\emph{Discussion}

This is the first real-world study to compare the parallel biologic
na\selectlanguage{ngerman}ïve characteristics of OMA and MEPO treated subjects against a common
comparator that remained biologic naïve (SNB) within the same cohort. A
key finding was that despite potentially overlapping clinical
indications for these drugs, OMA and MEPO treated patients showed
distinctive asthma phenotypes. Regardless of that, both biologic
response rates were comparable to RCTs and other reports (19--26). In
addition, for OMA, even though 43.3\% (45/104) patients were potentially
dual-eligible for MEPO, the OMA response rate was 88.5\%, reiterating
that OMA was efficacious in the phenotype that received it. Indeed, both
OMA and MEPO conferred substantial multidimensional clinical benefit to
the real-world populations which received them. This testifies to the
success of both biologics in targeting treatable traits in difficult
asthma patients. Nevertheless, non-responders emerged to both drugs,
typically characterised by worse baseline disease and psychological
comorbidity.

Of those with highest disease burden in our cohort (OMA, MEPO, SNB),
51.6\% did not receive biologics. Both biologic receiving groups had
hallmarks of greater disease severity with significantly worse lung
function (Clinic FEV\textsubscript{1}\%), worse airway inflammation
(FENO) and greater mOCS dependence compared to SNB. The SNB group are
noteworthy as their characterisation derives from the timepoint of WATCH
enrolment, when 42.3\% of them were new clinic referrals, and thus at an
early phase of conventional treatment optimisation. Their lack of
subsequent biologic need infers a responsiveness to that conventional
optimisation. Conversely, biologics treated subjects had already
undergone substantial treatment optimisation, without sufficient
response, prior to their characterisation in this study.

Although our three high burden groups were similar with regards to ACQ6,
exacerbations and AHE, they were phenotypically distinct. OMA patients
had a younger, early-onset, atopic phenotype, with high proportions of
co-morbid ABPA and rhinitis. Conversely, MEPO patients had an older,
male, late-onset, eosinophilic but less atopic phenotype, associated
with higher prevalence of nasal polyposis but less dysfunctional
breathing. This adds further insight to preliminary suggestions of
typical patient features for these biologics outlined by GINA (27).
Additionally, stratification of biologic use by our recently described
age-of-onset/sex phenotypes (15) further corroborate these findings, as
we found significantly different biologic use across the four
phenotypes. Notably, the female/early-onset phenotype showed highest
prevalence of OMA and lowest prevalence of MEPO use, while the
male/adult-onset phenotype showed highest prevalence of MEPO use. This
may part explain a disparity in biologic effect, whereby OMA but not
MEPO, significantly improved Clinic FEV\textsubscript{1}\%, mirroring
findings of another real-world UK study (26). This observed difference
could be partly explained by the higher representation of MEPO patients
among the male/adult-onset phenotype which had poorest baseline lung
function (15) in our cohort. Other reports have also confirmed that such
patients have more severe, persistent airflow limitation (28),
potentially explaining their limited lung function improvement. Another
disparity was in steroid-sparing effect, whereby MEPO but not OMA,
significantly reduced mOCS dependency. This may reflect different trial
durations. Indeed, other studies which evaluated OMA beyond 16-weeks,
found that it reduced the proportion of patients on mOCS
(16,21,22,29,30). This may also reflect clinical practice during the
single biologic phase, whereby a more conservative mOCS weaning approach
may have been adopted, given the lack of alternatives.

Overall, there is limited knowledge on clinical predictors of OMA and
MEPO response. A pooled analysis of seven clinical trials found that
baseline characteristics were unable to reliably predict OMA benefit
(23). For MEPO, post-hoc analyses of RCT data suggested that baseline
PBE could be a useful predictor of response (31), but this was not
consistently observed in real-world studies (24,26), including ours.
Instead, our data suggests that patients with the most severe and poorly
controlled baseline disease were poorest responders. Thus, for MEPO,
better baseline asthma control was independently associated with
response and super-response. This mirrored the findings of Kavanagh et
al. (26), where in their cohort, poor disease control at baseline was
independently associated with MEPO non-response. Similarly, in OMA, more
`severe' exacerbations, AHE, at baseline were associated with
non-response, while being on mOCS, was associated with
non-super-response. However, while AHE may represent more `severe'
asthma exacerbations, they may also reflect impact of multiple
influences beyond just airways disease. Indeed, Burke et al. identified
that those with repeated AHE were a subgroup of difficult asthma
patients with multiple aggravating comorbidities including obesity,
Gastrointestinal reflux disease, dysfunctional breathing and
psychological morbidity(32). Such complex multifactorial health events
may be less responsive to a simple biologic approach. It is notable that
by adopting a holistic, asthma MDT approach, they reduced AHE
significantly(32). Collectively these findings emphasise the importance
of comprehensive, up-front characterisation of difficult asthma
patients, focused on addressing all treatable traits to maximise
biologic outcome.

Reinforcing this, our data uniquely showed that psychological
co-morbidities may be associated with biologic non-response, an
unexplored aspect by other real-world biologic studies. Anxiety was
independently associated with OMA non-response while depression was
independently associated with OMA non-super-response and was associated
with MEPO non-response. Psychopathologies have been associated with
biologic non-response in other diseases. Analysis of the British Society
for Rheumatology Biologics registry showed that depression reduced the
odds of biologic response (33). The impact of psychopathology on
biologic outcome could be secondary to the well documented interplay
between psychological disease and SA (34). Psychopathologies have been
associated with worse asthma control, more exacerbations and more AHE
(35--37). Furthermore, studies have shown that proinflammatory cytokines
associated with asthma are raised in depression and anxiety (38,39),
which may dampen biologic effect. Brown et al showed in a RCT that
12-week continuous escitalopram therapy for SA patients with co-morbid
major depression significantly reduced OCS use and asthma control (40).
As such, our findings encourage proactive management of psychological
comorbidity alongside consideration of asthma biologics.

Analysis of our pooled biologic data allowed us to describe an overall
biologic unresponsive group. They had early-onset asthma, were
predominantly female yet had comparable exacerbations, mOCS dependence,
FENO, lung function and asthma ICU admissions to responders. However,
they were characterised by more AHE, a larger proportion of multiple
AHE, significantly worse baseline asthma control, alongside greater
proportions of anxiety and depression. We postulate their biologic
unresponsiveness may have been augmented by their high burden of
psychopathologies as although their objective disease markers and
clinical co-morbidities were equivalent, their subjective markers of
disease were not. Our recent work has shown that this group of
early-onset, female patients have the highest prevalence of
psychological co-morbidities, yet also have the highest frequency of
biologic use (15). This reiterates the importance of holistically
addressing treatable traits, through addressing psychopathologies before
biologic therapy.

Head-to-head comparisons between OMA and MEPO response rates were not
appropriate in our data, given their different phenotypic traits, and
the different response tools employed. However, notably,10/15 MEPO
`non-responders' displayed responses in domains outside NICE criteria.
Particularly noteworthy were those who sustained an improvement in AHE
status, including one who had both ACQ and AHE status response. However,
despite improvements in disease control and healthcare utilisation,
important markers of economic and patient-centred efficacy, these MEPO
patients were not classified as responders according to NICE
criteria(14). A post-hoc analysis of two MEPO RCTs found that ACQ was
unreliable in predicting MEPO response (41). Though important, their
findings were based on RCT data which may have limited transferability
to real-world patients (7--9). Additionally, ACQ is used to gauge MEPO
response in the Australian Mepolizumab Registry, and shown to correlate
with improvements in objective measures(25). Conversely, few MEPO
responders did not sustain an ACQ or AQLQ response. This could be
because improvement in NICE defined domains may not equate to the
patient's perception of better asthma control, or quality-of-life. Thus,
in those who are borderline responders, consideration might be made to
measure MEPO response more holistically, perhaps by taking into account
a wider range of measures. However, the economic implications of any
such move need careful deliberation.

Our study had limitations. Inherent to real-world observational studies,
we had some missing data. However, real-world data capture is
representative of clinical populations receiving these treatments. Our
report is also limited by the small numbers in the MEPO group, which
prevented us from uncovering whether the different age-of-onset/sex
phenotypes had differing response predictors. Therefore, future studies
are needed to clarify these findings and further explore
age-of-onset/sex related signals. Our study had several strengths. We
are the first to report detailed real-world clinical outcomes on both
OMA and MEPO in parallel, against a non-biologic comparator in a
difficult asthma cohort. Additionally, our cohort represents an
extensively characterised difficult asthma population from a wide
geographical catchment, enhancing generalisability of findings. This
allowed mapping of previously described clinical clusters onto our data,
consolidating our observations. We also undertook pooled analysis of the
non-responder group and explored other definitions of response in MEPO,
compared to OMA.

\textbf{CONCLUSION:}

In summary, in this real-world difficult asthma cohort, OMA and MEPO
were used for distinct SA phenotypes in which they were both
multidimensionally effective. Among these phenotypes, we identified some
features independently associated with response, which may assist
clinicians. In turn, those findings reiterated the importance of
detailed characterisation and addressing treatable traits alongside
consideration of biologics use in more severe asthma. To further enhance
the personalised and optimal use of biologic therapies, future research
should develop a deeper endotypic understanding of asthma biologic need
and responsiveness.

\emph{References}

1. Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic
medications in asthma and allergic disease: The next steps toward
personalized care. Vol. 135, Journal of Allergy and Clinical Immunology.
Mosby Inc.; 2015. p. 299--310.

2. BTS/SIGN. British guideline for the management of asthma, SIGN 158,
July 2019. Available from:
https://www.brit-thoracic.org.uk/quality-improvement/guidelines/asthma/.
Accessed November 1, 2020.

3. Holgate ST, Chuchalin AG, Hébert J, Lötvall J, Persson GB, Chung KF,
et al. Efficacy and safety of a recombinant anti-immunoglobulin E
antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy.
2004;34(4):632--8.

4. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et
al. Oral Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic
Asthma. N Engl J Med. 2014 Sep 25;371(13):1189--97.

5. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A,
et al. Mepolizumab Treatment in Patients with Severe Eosinophilic
Asthma. N Engl J Med. 2014 Sep 25;371(13):1198--207.

6. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al.
Mepolizumab for severe eosinophilic asthma (DREAM): A multicentre,
double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651--9.

7. Travers J, Marsh S, Williams M, Weatherall M, Caldwell B, Shirtcliffe
P, et al. External validity of randomised controlled trials in asthma:
To whom do the results of the trials apply? Thorax. 2007
Mar;62(3):219--33.

8. Richards LB, JMH van Bragt J, Aarab R, Longo C, Neerincx AH, Sont JK,
et al. Treatment Eligibility of Real-Life Mepolizumab-Treated Severe
Asthma Patients. J Allergy Clin Immunol Pract. 2020;8:2999-3008.e1.

9. Brown T, Jones T, Gove K, Barber C, Elliott S, Chauhan A, et al.
Randomised controlled trials in severe asthma: Selection by phenotype or
stereotype. Eur Respir J. 2018;52(6).

10. Papadopoulos NG, Barnes P, Canonica GW, Gaga M, Heaney L,
Menzies-Gow A, et al. The evolving algorithm of biological selection in
severe asthma. Allergy Eur J Allergy Clin Immunol. 2020;75(7):1555--63.

11. Azim A, Mistry H, Freeman A, Barber C, Newell C, Gove K, et al.
Protocol for the Wessex AsThma CoHort of difficult asthma (WATCH): A
pragmatic real-life longitudinal study of difficult asthma in the
clinic. BMC Pulm Med. 2019;19(1).

12. BTS/SIGN. British guideline for the management of asthma, SIGN 153,
September 2016. Available from:
https://www.brit-thoracic.org.uk/quality-improvement/guidelines/asthma/.
Accessed November 1, 2020.

13. Excellence NIoC. Omalizumab for treating severe persistent allergic
asthma. Technology appraisal guidance. NICE; 2013.
https://www.nice.org.uk/guidance/ta278. Accessed November 1, 2020.

14. Excellence NIoC. Mepolizumab for treating severe refractory
eosinophilic asthma. Technology appraisal guidance. NICE; 2017.
https://www.nice.org.uk/guidance/ta431. Accessed November 1,2020.

15. Azim A, Freeman A, Lavenu A, Mistry H, Haitchi HM, Newell C, et al.
New Perspectives on Difficult Asthma; Sex and Age of Asthma-Onset Based
Phenotypes. J Allergy Clin Immunol Pract. 2020 Nov 1;

16. Braunstahl GJ, Chen CW, Maykut R, Georgiou P, Peachey G, Bruce J.
The eXpeRience registry: The `real-world' effectiveness of omalizumab in
allergic asthma. Respir Med. 2013 Aug 1;107(8):1141--51.

17. Brusselle G, Michils A, Louis R, Dupont L, Van de Maele B, Delobbe
A, et al. `Real-life' effectiveness of omalizumab in patients with
severe persistent allergic asthma: The PERSIST study. Respir Med. 2009
Nov 1;103(11):1633--42.

18. Bousquet J, Rao S, Manga V. Global evaluation of treatment
effectiveness (GETE) is an accurate predictor of response to omalizumab
in patients with severe allergic asthma: A pooled analysis. Eur Respir
J. 2014;44(Suppl 58).

19. Agache I, Rocha C, Beltran J, Song Y, Posso M, Solà I, et al.
Efficacy and safety of treatment with biologicals (benralizumab,
dupilumab and omalizumab) for severe allergic asthma: A systematic
review for the EAACI Guidelines - recommendations on the use of
biologicals in severe asthma. Allergy Eur J Allergy Clin Immunol.
2020;75(5):1043--57.

20. Abraham I, Alhossan A, Lee CS, Kutbi H, MacDonald K. `Real-life'
effectiveness studies of omalizumab in adult patients with severe
allergic asthma: systematic review. Allergy. 2016 May 1;71(5):593--610.

21. Schumann C, Kropf C, Wibmer T, Rüdiger S, Stoiber KM, Thielen A, et
al. Omalizumab in patients with severe asthma: The XCLUSIVE study. Clin
Respir J. 2012 Oct;6(4):215--27.

22. Siergiejko Z, \selectlanguage{polish}Ś\selectlanguage{english}wiebocka E, Smith N, Peckitt C, Leo J, Peachey G, et
al. Oral corticosteroid sparing with omalizumab in severe allergic
(IgE-mediated) asthma patients. Curr Med Res Opin. 2011
Nov;27(11):2223--8.

23. Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H, et al.
Predicting and evaluating response to omalizumab in patients with severe
allergic asthma. Respir Med. 2007 Jul 1;101(7):1483--92.

24. Bagnasco D, Caminati M, Menzella F, Milanese M, Rolla G, Lombardi C,
et al. One year of mepolizumab. Efficacy and safety in real-life in
Italy. Pulm Pharmacol Ther. 2019;58(May).

25. Harvey ES, Langton D, Katelaris C, Stevens S, Farah CS, Gillman A,
et al. Mepolizumab effectiveness and identification of super-responders
in severe asthma. Vol. 55, European Respiratory Journal. 2020.

26. Kavanagh JE, d'Ancona G, Elstad M, Green L, Fernandes M, Thomson L,
et al. Real-World Effectiveness and the Characteristics of a
``Super-Responder'' to Mepolizumab in Severe Eosinophilic Asthma. Chest.
2020;158(2):491--500.

27. Darcey J, Qualtrough A. DIFFICULT-TO-TREAT \& SEVERE ASTHMA in
adolescent and adult patients - diagnosis and management. Glob Initiat
Asthma. 2019;214(10):493--509.

28. De Nijs SB, Venekamp LN, Bel EH. Adult-onset asthma: is it really
different?

29. Barnes N, Menzies-Gow A, Mansur AH, Spencer D, Percival F, Radwan A,
et al. Effectiveness of Omalizumab in Severe Allergic Asthma: A
Retrospective UK Real-World Study. J Asthma. 2013 Jun 14;50(5):529--36.

30. MacDonald KM, Kavati A, Ortiz B, Alhossan A, Lee CS, Abraham I.
Short- and long-term real-world effectiveness of omalizumab in severe
allergic asthma: systematic review of 42 studies published 2008-2018.
Vol. 15, Expert Review of Clinical Immunology. Taylor and Francis Ltd;
2019. p. 553--69.

31. Albers FC, Licskai C, Chanez P, Bratton DJ, Bradford ES, Yancey SW,
et al. Baseline blood eosinophil count as a predictor of treatment
response to the licensed dose of mepolizumab in severe eosinophilic
asthma. Respir Med. 2019 Nov 1;159.

32. Burke H, Davis J, Evans S, Flower L, Tan A, Kurukulaaratchy RJ. A
multidisciplinary team case management approach reduces the burden of
frequent asthma admissions. ERJ Open Res. 2016 Jul 7;2(3).

33. Matcham F, Davies R, Hotopf M, Hyrich KL, Norton S, Steer S, et al.
The relationship between depression and biologic treatment response in
rheumatoid arthritis: An analysis of the British Society for
Rheumatology Biologics Register. Rheumatology. 2018;57:835--43.

34. Vargas PA. Spreading the Word: Comorbidity of Asthma and Depression
Is Not Just the Product of a Vulnerable Personality. Vol. 8, Journal of
Allergy and Clinical Immunology: In Practice. American Academy of
Allergy, Asthma and Immunology; 2020. p. 208--9.

35. Gonz\selectlanguage{ngerman}ález-Freire B, Vázquez I, Pértega-Díaz S. The Relationship of
Psychological Factors and Asthma Control to Health-Related Quality of
Life. J Allergy Clin Immunol Pract. 2020 Jan 1;8(1):197--207.

36. Wang G, Zhou T, Wang L, Wang L, Fu JJ, Zhang HP, et al. Relationship
between current psychological symptoms and future risk of asthma
outcomes: A 12-month prospective cohort study. J Asthma. 2011
Dec;48(10):1041--50.

37. Ahmedani BK, Peterson EL, Wells KE, Williams LK. Examining the
relationship between depression and asthma exacerbations in a
prospective follow-up study. Psychosom Med. 2013;75(3):305--10.

38. Jiang M, Qin P, Yang X. Comorbidity between depression and asthma
via immune-inflammatory pathways: A meta-analysis. Vol. 166, Journal of
Affective Disorders. Elsevier; 2014. p. 22--9.

39. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al.
A Meta-Analysis of Cytokines in Major Depression. Biol Psychiatry. 2010
Mar 1;67(5):446--57.

40. Brown ES, Sayed N, Van Enkevort E, Kulikova A, Nakamura A, Khan DA,
et al. A Randomized, Double-Blind, Placebo-Controlled Trial of
Escitalopram in Patients with Asthma and Major Depressive Disorder. J
Allergy Clin Immunol Pract. 2018 Sep 1;6(5):1604--12.

41. Gunsoy NB, Cockle SM, Yancey SW, Keene ON, Bradford ES, Albers FC,
et al. Evaluation of Potential Continuation Rules for Mepolizumab
Treatment of Severe Eosinophilic Asthma. J Allergy Clin Immunol Pract.
2018 May 1;6(3):874-882.e4.

\emph{}

\emph{Table 1. Baseline characteristics of the Biologic cohorts vs
severe asthma, non-biologics cohort}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\par\null\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Omalizumab group,} \textbf{N= 105 (A)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Omalizumab group,} \textbf{N= 105 (A)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Mepolizumab group,} \textbf{N= 62 (B)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Mepolizumab group,} \textbf{N= 62 (B)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Severe asthma, non-biologic group, N=178 (C)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Severe asthma, non-biologic group, N=178 (C)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{P-values}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{P-values}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Mean (SD) / Median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Missing\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Mean (SD) / Median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Missing\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Mean (SD) / Median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Missing\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{A vs C}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{B vs C}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Annualised rate of exacerbations, median (IQR)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5 (3) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4 (5) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5 (3) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.391\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.744\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Annualised rate of AHE, median (IQR)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1 (2) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0 (1) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0 (1) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.238\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.184\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\selectlanguage{greek}\textbf{Maximum Eos count in the past year, median (IQR) -
cells/µL}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
250 (400) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
500(400) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
200 (300) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
49\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.052\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{ACQ6, median (IQR)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (1.79) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
25\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2.67 (1.67) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (1.8) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.594\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.795\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{FENO, median (IQR) - ppb}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
30 (38) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
36 (52) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
16.85 (24.65) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.007}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Clinic FEV\textsubscript{1} \%, mean (SD)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
66.59 (20.77) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
67.1 (20.77) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
76.78 (23.37) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.007}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Maintenance OCS dose, median (IQR) - mg} \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{BMI, median (IQR) -- kgm\textsuperscript{-2}} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
30.60 (9.75)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
28.95 (28.95)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
30.8 (10.8)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.502\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.214\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Age of asthma diagnosis, median (IQR) - y}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10 (25)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
28 (38.5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
20 (35)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.007}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.039}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Age, median (IQR) - y}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
52 (18.5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
61 (19)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
54.5 (25)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.643\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.015}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Percentage (N)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Missing\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Percentage (N)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Missing\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Percentage (N)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Missing\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{P-value}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{P-value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Multiple AHE (\textgreater{}1), Yes}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
31.3\% (30) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
16.9\% (10) +\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
24.3\% (43) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.215\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.242\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{On Maintenance OCS, Yes}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
47.6\% (50) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
72.6\% (45) \selectlanguage{ngerman}§\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
30.6\% (53) ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Adult-onset asthma, Yes}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
37.6\% (38)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
60.7\% (37)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
52.7\% (89)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.017}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.282\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Sex, Male}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
33.3\% (35)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
53.2\% (33)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
29.8\% (53)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.532\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Ethnicity, White}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
87.6\% (92)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
91.9\% (57)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
94.9\% (169)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.026}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.362\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Rhinitis, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
73.6\% (64)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
72.9\% (43)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
60.1\% (95)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.035}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.082\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{GORD, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
64.4\% (67)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
67.2\% (41)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
65.3\% (111)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.883\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.875\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Smoking, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
43.8\% (46)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
56.5\% (35)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
47.5\% (84)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.552\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.223\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Atopy (SPT / sIgE positive)} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
100\% (105)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
50.0\% (31)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
52.8\% (94)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.703\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Obesity (BMI[?]30kgm\textsuperscript{-2}), Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
52.4\% (55)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
41.9\% (26)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
52.6\% (92)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.975\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.097\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Admitted to ICU for asthma, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
27.9\% (29)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
35.5\% (22)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
32.6\% (58)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.410\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.677\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Intubated for Asthma, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
14.4\% (15)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
14.5\% (9)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
17.4\% (31)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.512\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.598\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Dysfunctional breathing, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
51.5\% (51)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
40.0\% (24)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
55.1\% (92)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.572\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.045}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{ILO, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19.4\% (18)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
13.8\% (8)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
13.2\% 921)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.193\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.911\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Depression, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
31.9\% (29)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
28.3\% (17)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
42.8\% (68)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.089\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.051\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Anxiety, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
30.8\% (28)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
27.1\% (16)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
38.0\% (60)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.252\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.136\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Bronchiectasis, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
15.5\% (16)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19.4\% (12)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
14.2\% (25)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.762\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.336\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Salicylate sensitivity, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
33.0\% (34)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19.4\% (12)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
27.8\% (49)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.416\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.188\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{ABPA, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
12.6\% (13)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
12.9\% (8)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5.2\% (9)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.027}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.081\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Sulphite sensitivity, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8.7\% (9)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9.7 \% (6)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7.4\% (13)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.696\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.590\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{COPD, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5.8\% (6)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9.7 \% (6)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10.8\% (19)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.161\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.805\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Nasal polyps, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
21.4\% (21)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
34.5\% (20)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19\% (31)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.635\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.019}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Nasal (polyps / sinus) surgery, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
31.6\% (30)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
31.7\% (19)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
19.3\% (31)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.025}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.050}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Urticaria or Angioedema, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
12.6\% (13)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8.1\% (5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6.8\% (12)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.101\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.776\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{OSA, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4.9\% (5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6.5\% (4)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
11.5\% (20)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.062\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.259\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{Eczema, Ever} ++\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
31.7\% (33)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
27.4\% (17)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
21.6\% (38)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.060\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.349\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Categorical data are presented as proportions and numbers. Continuous
data are either presented as Median + Interquartile range (IQR) or Mean
+ standard deviation (SD). +: In the preceding 12 months prior to
biologic approval. ++: at WATCH enrolment. \selectlanguage{ngerman}§:at baseline biologic visit.
Exacerbations: incidence of exacerbations requiring OCS / increase in
maintenance OCS in the past 12 months before biologic approval. AHE:
acute healthcare encounters, which include Emergency department/
hospital admissions. EOS: eosinophils. \selectlanguage{greek}µ\selectlanguage{english}L: microlitre. ACQ6: Asthma
Control Questionnaire 6. FENO: fractional exhaled nitric oxide. ppb:
parts per billion. IgE: immunoglobulin E. kU/L: kilounits per litre.
OCS: oral corticosteroids. mg: milligrams. FEV\textsubscript{1}: forced
expiratory volume in one second. Adult-onset: Age of asthma onset [?]18
years. GORD: Gastrointestinal reflux disease. SPT: skin prick test.
sIgE: specific IgE. ICU: intensive care unit. ILO: intermittent
laryngeal obstruction. ABPA: allergic bronchopulmonary aspergillosis.
COPD: chronic obstructive pulmonary disease. OSA: obstructive sleep
apnoea. The severe asthma, non-biologic (SNB) group is a common
comparator group extracted from WATCH. They were participants who either
had [?]4 exacerbations or [?]1 AHE or were on maintenance OCS in the past
year but did not commence biologic therapy during the study period.
Unpaired t-tests, Mann-Whitney U test, Chi-square tests or Fisher's
exact tests were used, where appropriate, to calculate P-values.

\emph{Table 2: Baseline features associated with Biologic Responses}

\textbf{Omalizumab models}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Model name}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Cases included}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Variables included}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Final variables}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{P-value}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{OR; 95 CI}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{AUC of model}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Omalizumab response vs non-response\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
78/104, 75\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Clinic FEV\textsubscript{1}\%, Age, BMI, Sex, Baseline annualised rate
of exacerbations, Multiple AHE, Annualised rate of AHE, Anxiety.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Baseline annualised rate of exacerbations\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.024\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.622 (1.065-2.469)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.856\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lower baseline annualised rate of AHE\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.050\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.297 (1.000-1.681)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
No Anxiety\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.008\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8.772 (1.745-43.478)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Omalizumab super-response vs non-super-response\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
75/104, 72.1\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Baseline annualised rate of exacerbations, Multiple AHE, on mOCS, Adult
onset, Obesity, ICU admission for asthma ever, Anxiety,
Depression.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Not on maintenance OCS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18.182 (4.484-71.429)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.809\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
No Depression\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.009\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4.784 (1.623-29.412)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab models}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab models}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab models}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab models}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab models}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab models}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab models}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Model name}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Cases included}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Variables included}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Final variables}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{P-value}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{OR; 95 CI}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{AUC of model}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Mepolizumab responders vs non-responders\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
42/58, 72.4\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ACQ6, Multiple AHE, Depression, Anxiety, AQLQ baseline, Total HADS
baseline, Baseline annualised rate of AHE, Dysfunctional
Breathing.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lower ACQ6 at baseline\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.007\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4.651 (1.513-14.286)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.859\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mepolizumab super- responders vs non-super-responders\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
47/58, 81\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Baseline annualised rate of exacerbations ACQ6, Clinic
FEV\textsubscript{1}\%, AQLQ baseline, BMI, on mOCS, Adult onset, Atopy,
Smoking ever, Bronchiectasis ever\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Lower ACQ6 at baseline\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.025\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.401 (1.167-9.901)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.811\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Baseline annualised rate of exacerbations\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.023\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1.487 (1.046-2.115)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

FEV\textsubscript{1}: forced expiratory volume in one second. BMI: Body
mass index. Exacerbations: incidence of exacerbations requiring OCS /
increase in maintenance OCS in the past 12 months before biologic
approval. AHE: acute healthcare encounters, which include Emergency
department/ hospital admissions. Multiple AHE: \textgreater{}1 AHE in
the past 12 months before biologic approval. mOCS: maintenance oral
corticosteroids. BMI: Body mass index. Obesity:
BMI[?]30kgm\textsuperscript{-2}. ICU: Intensive care unit. ACQ6: asthma
control questionnaire 6. AQLQ: Asthma Quality of Life Questionnaire.
HADS: hospital anxiety and depression scale. Adult onset: asthma age of
onset [?]18 years. Multiple logistic regression was performed (backward
variable selection) using baseline variables trending towards
significance (P\textless{}0.2). AUC: Area under the Receiver operating
characteristic curve.

\emph{Table 3: Baseline characteristics of combined biologic
non-responders vs SNB and responders}

\textbf{Combined non-responder group, N=27 (A)}

\textbf{Combined non-responder group, N=27 (A)}

\textbf{Omalizumab responder,}

N=92 (B)

\textbf{Omalizumab responder,}

N=92 (B)

\textbf{Mepolizumab responder,}

N=43 (C)

\textbf{Mepolizumab responder,}

N=43 (C)

\textbf{Severe asthma, non-biologic group, N=178 (D)}

\textbf{Severe asthma, non-biologic group, N=178 (D)}

\textbf{P values}

\textbf{P values}

\textbf{P values}

Mean (SD) / Median (IQR)

Missing

Mean (SD) / Median (IQR)

Missing

Mean (SD) / Median (IQR)

Missing

Mean (SD) / Median (IQR)

Missing

\emph{A vs B}

\emph{A vs C}

\emph{A vs D}

\textbf{Annualised rate of exacerbations, median (IQR)}

4 (5) +

2

5 (2) +

1

4 (5) +

1

5 (3) ++

32

0.526

0.864

0.978

\textbf{Annualised rate of AHE, median (IQR)}

1 (3) +

1

0 (2) +

8

0 (1) +

2

0 (1) ++

1

0.095

\textbf{0.002}

\textbf{0.028}

\selectlanguage{greek}\textbf{Maximum Eos count in the past year, median (IQR) - cells/µL}\selectlanguage{english}

400 (400) +

2

200 (400) +

7

500 (500) +

0

200 (300) ++

49

\textbf{0.005}

0.178

\textbf{\textless{}0.001}

\textbf{ACQ6, median (IQR)}

3.67 (1.26) \selectlanguage{ngerman}§

6

3 (1.83) §

20

2.33 (2.27) §

2

3 (1.8) \selectlanguage{english}++

11

\textbf{0.036}

\textbf{\textless{}0.001}

\textbf{0.017}

\textbf{FENO, median (IQR) - ppb}

22 (59.6) SS

4

29.5 (37) SS

24

37 (46.5) SS

2

16.85 (24.65) \selectlanguage{english}++

50

0.514

0.129

0.383

\textbf{Clinic FEV\textsubscript{1} \%, mean (SD)}

61.64 (21.75) SS

1

68.13 (20.49) SS

6

67\% (20.1) SS

1

76.78 (23.37) \selectlanguage{english}++

57

0.483

0.909

\textbf{0.003}

\textbf{BMI, median (IQR) -kgm\textsuperscript{-2}} \selectlanguage{english}++

30.6 (15.9)

0

30.36 (5.99)

0

29.1 (11.5)

0

30.8 (10.8)

3

0.194

0.160

0.469

\textbf{Age at asthma diagnosis, median (IQR) - y} \selectlanguage{english}++

12 (31)

0

11 (25.5)

3

33.5 (40.5)

1

20 (35)

9

0.627

\textbf{0.032}

0.355

\textbf{Age, median (IQR) - y}

54 (28)

0

53 (20.5)

0

61 (19)

0

54.5 (25)

0

0.871

0.110

0.997

\textbf{Percentage (N)}

Missing

\textbf{Percentage (N)}

Missing

\textbf{Percentage (N)}

Missing

\textbf{Percentage (N)}

Missing

\emph{A vs B}

\emph{A vs C}

\emph{A vs D}

\textbf{Multiple (\textgreater{}1) AHE, Yes}

48\% (12) \selectlanguage{english}+

2

27.4\% (23) \selectlanguage{english}+

8

9.8\% (4) \selectlanguage{english}+

2

24.3\% (43) \selectlanguage{english}++

5

0.053

\textbf{0.001}

\textbf{\textless{}0.001}

\textbf{On maintenance OCS, Yes}

66.7\% (18) SS

0

46.7\% (43) SS

0

69.8\% (30) SS

0

30.6\% (53) \selectlanguage{english}++

1

0.069

0.797

\textbf{0.013}

\textbf{Adult-onset asthma}, \textbf{Yes}

38.5\% (10)

0

39.3\% (35)

1

61.9\% (26)

1

52.7\% (89)

9

1.000

0.060

0.178

\textbf{Sex, Male}

33.3\% (9)

0

35.9\% (33)

0

58.1\% (25)

0

29.8\% (53)

0

1.000

\textbf{0.043}

0.822

\textbf{Ethnicity, White}

92.6\% (25)

0

89.1\% (82)

0

90.7\% (39)

0

94.9\% (169)

0

0.732

1.000

0.642

\textbf{Rhinitis, Ever} \selectlanguage{english}++

80.8\% (21)

1

73.0\% (54)

22

68.3\% (28)

2

60.1\% (95)

10

0.430

0.262

\textbf{0.043}

\textbf{GORD, Ever} \selectlanguage{english}++

73.1\% (19)

1

64.1\% (59)

0

61.9\% (26)

1

65.3\% (111)

8

0.485

0.344

0.434

\textbf{Smoking, Ever} \selectlanguage{english}++

51.9\% (14)

0

43.5\% (40)

0

53.5\% (23)

0

47.5\% (84)

1

0.442

0.894

0.670

\textbf{Atopy (SPT /sIgE positive)} \selectlanguage{english}++

74.0\% (20)

0

100\% (92)

0

51.2\% (22)

0

52.8\% (94)

0

\textbf{\textless{}0.001}

0.057

\textbf{0.038}

\selectlanguage{english}\textbf{Obesity (BMI[?]30kgm\textsuperscript{-2}), Ever} \selectlanguage{english}++

55.6\% (15)

0

50.0\% (46)

0

41.9\% (18)

0

52.6\% (92)

3

0.612

0.190

0.772

\textbf{ICU admission for asthma, Ever} \selectlanguage{english}++

33.3\% (9)

0

26.4\% (24)

1

37.2\% (16)

0

32.6\% (58)

0

0.479

0.802

1.000

\textbf{Intubated for Asthma, Ever} \selectlanguage{english}++

18.5\% (5)

0

14.3\% (13)

1

9.3\% (4)

0

17.4\% (31)

0

0.591

0.292

1.000

\textbf{Dysfunctional breathing, Ever} \selectlanguage{english}++

59.3\% (16)

0

48.8\% (42)

6

31.7\% (13)

2

55.1\% (92)

11

0.345

\textbf{0.025}

0.686

\textbf{ILO, Ever} \selectlanguage{english}++

25.9\% (7)

0

17.5\% (14)

12

7.7\% (3)

4

13.2\% (21)

19

0.340

0.077

0.140

\textbf{Depression, Ever} \selectlanguage{english}++

48\% (12)

2

30.4\% (24)

13

19.1\% (8)

1

42.8\% (68)

19

0.107

\textbf{0.012}

0.624

\textbf{Anxiety, Ever} \selectlanguage{english}++

50\% (13)

1

26.6\% (21)

13

20.0\% (8)

3

38.0\% (60)

19

\textbf{0.027}

\textbf{0.011}

0.245

\textbf{Bronchiectasis, Ever} \selectlanguage{english}++

18.5\% (5)

0

14.4\% (13)

2

18.6\% (8)

0

14.2\% (25)

2

0.560

1.000

0.563

\textbf{Salicylate sensitivity, Ever} \selectlanguage{english}++

18.5\% (5)

0

33.3\% (30)

2

18.6\% (8)

0

27.8\% (49)

2

0.140

1.000

0.307

\textbf{ABPA, Ever} \selectlanguage{english}++

14.8\% (4)

0

12.2\% (11)

2

14.0\% (6)

0

5.2\% (9)

4

0.746

1.000

0.079

\textbf{Sulphite sensitivity, Ever} \selectlanguage{english}++

7.4\% (2)

0

7.8\% (7)

2

11.6\% (5)

0

7.4\% (13)

3

1.000

0.699

1.000

\textbf{COPD, Ever} \selectlanguage{english}++

7.4\% (2)

0

6.7\% (6)

2

9.3\% (4)

0

10.8\% (19)

2

1.000

1.000

0.746

\textbf{Nasal polyps, Ever} \selectlanguage{english}++

24\% (6)

2

20.9\% (18)

6

37.5\% (15)

3

19\% (31)

15

0.743

0.258

0.591

\textbf{Nasal (polyps / sinus) surgery, Ever} \selectlanguage{english}++

32\% (8)

2

31.3\% (26)

13

35.7\% (15)

1

19.3\% (31)

17

0.949

0.757

0.145

\textbf{Urticaria or Angioedema, Ever} \selectlanguage{english}++

7.4\% (2)

0

13.3\% (12)

2

7.0\% (3)

0

6.8\% (12)

2

0.517

1.000

1.000

\textbf{OSA, Ever} \selectlanguage{english}++

11.1\% (3)

0

4.4\% (4)

2

4.7\% (2)

0

11.5\% (20)

4

0.350

0.367

1.000

\textbf{Eczema, Ever} \selectlanguage{english}++

25.9\% (7)

0

33.0\% (30)

1

25.6\% (11)

0

21.6\% (38)

2

0.489

1.000

0.614

Categorical data are presented as proportions and numbers. Continuous
data is either presented as Median + Interquartile range (IQR) or Mean +
standard deviation (SD). \selectlanguage{english}+: In the preceding 12 months prior to biologic
approval. \selectlanguage{english}++: at WATCH enrolment. SS: at baseline biologic visit.
Exacerbations: incidence of exacerbations requiring OCS / increase in
maintenance OCS. AHE: acute healthcare encounters, which include
Emergency department/ hospital admissions. EOS: eosinophils. \selectlanguage{greek}µ\selectlanguage{english}L:
microlitre. ACQ6: Asthma Control Questionnaire 6. FENO: fractional
exhaled nitric oxide. ppb: parts per billion. IgE: immunoglobulin E.
kU/L: kilounits per litre. OCS: oral corticosteroids. mg: milligrams.
FEV\textsubscript{1}: forced expiratory volume in one second.
Adult-onset: Age of asthma onset [?]18 years GORD: Gastrointestinal reflux
disease. SPT: skin prick test. sIgE: specific IgE. ICU: intensive care
unit. ILO: intermittent laryngeal obstruction. ABPA: allergic
bronchopulmonary aspergillosis. COPD: chronic obstructive pulmonary
disease. OSA: obstructive sleep apnoea. The severe asthma, non-biologic
(SNB) group is a common comparator group extracted from WATCH. They were
participants who either had [?]4 exacerbations or [?]1 AHE or were on
maintenance OCS in the past year but did not commence biologic therapy
during the study period. Combined non-responders were a combined group
of Omalizumab non-responders (N=12) and Mepolizumab responders (N=15).
Unpaired t-tests, Mann-Whitney U test, Chi-square tests or Fisher's
exact tests were used, where appropriate, to calculate P-values.

\emph{\textbf{Table 4:} \textbf{Stratification of biologic use and
outcomes within Age-of-onset/sex clusters}}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Phenotype and Proportions within overall WATCH cohort}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Phenotype and Proportions within overall WATCH cohort}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Male, early-onset} \textbf{(14.0\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Male, early-onset} \textbf{(14.0\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Female, early-onset (34.7\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Male, adult-onset} \textbf{(20.8\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Female, adult-onset (30.5\%)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Proportions within biologic (Omalizumab or Mepolizumab, N= 167)
cohort}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(\%, n/N)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Proportions within biologic (Omalizumab or Mepolizumab, N= 167)
cohort}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(\%, n/N)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
17.4\% (29/167)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
17.4\% (29/167)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
34.7\% (58/167)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23.4\% (39/167)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24.6\% (41/167)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Distribution within respective biologic group}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(\%, n/N), (A)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Omalizumab, N=105\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15.2\% (16/105)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15.2\% (16/105)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
44.8\% (47/105)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18.1\% (19/105)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21.9\% (23/105)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Mepolizumab, N=62\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21.0\% (13/62)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
21.0\% (13/62)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
17.7\% (11/62)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
32.3\% (20/62)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
29.0\% (18/62)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Biologic response within each phenotype (\%, n/N) +}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Omalizumab responder (B)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100\% (16/16)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100\% (16/16)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80.9\% (38/47)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
94.4\% (17/18)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
91.3\% (21/23)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Mepolizumab responder (C)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
69.2\% (9/13)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
69.2\% (9/13)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
70\% (7/10)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80\% (16/20)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
73.3\% (11/15)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{P-values}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{P-values}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.135\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.135\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.135\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.135\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
C\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.893\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.893\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.893\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.893\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Early-onset is defined as having an age of asthma onset\textless{}18
years. Adult-onset is defined as having an age of asthma onset [?]18
years. + of those who completed biologic trials, i.e.: did not withdraw
due to any reason. A= Chi-squared tests were performed to assess
biologic use across the four age-of-onset/sex clusters. B= Chi-squared
tests were performed to assess biologic response to Omalizumab across
the four age-of-onset/sex clusters. C= Chi-squared tests were performed
to assess biologic response to Mepolizumab across the four
age-of-onset/sex clusters.



\emph{Figure legends}

Figure 1: Biologic outcomes for Omalizumab and Mepolizumab at the
end-of-trial. ACQ6: Asthma Control Questionnaire 6. AHE: acute
healthcare encounters, which include Emergency department/ hospital
admissions. OCS: oral corticosteroids. mg: milligrams.
FEV\textsubscript{1}: forced expiratory volume in one second. AQLQ:
Asthma Quality of Life Questionnaire. HADS: Hospital anxiety and
depression scale.

Figure 2: Alternative assessments of biologic outcomes. Figure 2a:
Side-by-side comparisons of different measures of biologic response.
Figure 2b: Mepolizumab focused measures of biologic response. Numbers
represent patient counts. ACQ: Asthma Control Questionnaire 6. AHE:
acute healthcare encounters, which include Emergency department/
hospital admissions. OCS: Response with regard to exacerbations
(incidence of exacerbations needing an acute OCS course or an increase
in maintenance OCS dose). AQLQ: Asthma Quality of Life Questionnaire.
MDT: multi-disciplinary team decision. Response for ACQ and AQLQ was
defined as a reduction greater than the minimally important difference
of [?]0.5. AHE response was defined as patients who had [?]1 AHE at baseline
but now currently have no AHE. OCS response is defined as a reduction of
maintenance OCS dose or exacerbations by [?]50\%. MDT response is defined
earlier in the methods. The blue outlier in figure 2a and 2b is a
patient who reduced his maintenance OCS from 10-7mg and had no
exacerbations nor AHE in the trial period (from a baseline of 0), and
thereby had a positive trial.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-ALLERGY/Figure-1-ALLERGY}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

