| \;speaker |
\;
<
strong>Chris Mela
\n Roche Products Ltd
| \;\n Clinical Overvi
ew of Immunology Diseases | Immunology is viewed as a complex and daunting subject with a
multitude of antibodies\, interleukins\, molecules\, cells and pathways t
hat interact in mysterious ways. This perception can worry anyone stating
research in a new immunological area or disease. The reality is that the i
mmune system spans almost every disease from aging to zoonosis and that ce
rtain concepts are common across all of these. By understanding some of th
ese themes we can demystify immunology and turn the fear into fascination.
\;
|
Dr Bernd Genser 1\,2 \;
1. BGStats Consulting Vienna Austria
\n
2. Mannheim Institute of Public Health\, Social and Preventive Medici
ne\, University of Heidelberg\, Germany | An approach for integrating existing knowledge in
to the statistical analysis of multiple immune markers: \;An applicat
ion to cytokine data collected in a large immuno-epidemiological study aim
ed to investigate risk factors for atopy and asthma | BACKGROUND: Immunologists often measure
several correlated immunological markers\, such as concentrations of diffe
rent cytokines produced by different immune cells and/or measured under di
fferent conditions\, to draw insights from complex immunological mechanism
s. Although there have been recent methodological efforts to improve the s
tatistical analysis of immunological data\, a framework is still needed fo
r the simultaneous analysis of multiple\, often correlated\, immune marker
s. This framework would allow the immunologists&rsquo\; hypotheses about t
he underlying biological mechanisms to be integrated.
\n
METHODS: We present an analytical approach for statistical analysis
of correlated immune markers\, such as those commonly collected in modern
immuno-epidemiological studies.
\n RESULTS: We demo
nstrate i) how to deal with interdependencies among multiple \;
\
n measurements of the same immune marker\, ii) how to analyse a
ssociation patterns among different markers\, iii) how to aggregate differ
ent measures and/or markers to immunological summary scores\, iv) how to m
odel the inter-relationships among these scores\, and v) how to use these
scores in epidemiological association analyses. We illustrate the applicat
ion of our approach to multiple cytokine measurements from 818 children en
rolled in a large immuno-epidemiological study (SCAALA Salvador)\, which a
imed to quantify the major immunological mechanisms underlying atopic dise
ases or asthma. We demonstrate how to aggregate systematically the informa
tion captured in multiple cytokine measurements to immunological summary s
cores aimed at reflecting the presumed underlying immunological mechanisms
(Th1/Th2 balance and immune regulatory network). We show how these aggreg
ated immune scores can be used as predictors in regression models with out
comes of immunological studies (e.g. specific IgE) and compare the results
to those obtained by a traditional multivariate regression approach.
\n CONCLUSION: The proposed analytical approach may be
especially useful to quantify complex immune responses in immuno-epidemiol
ogical studies\, where investigators examine the relationship among epidem
iological patterns\, immune response\, and disease outcomes
&nb
sp\; |
Nicola Scott \;
\n GSK |
Leveraging Data across Multiple Immuno-Inflammation Indications: Early Cli
nical Development of a Novel Compound | \;Recent research has identified that necroptosis
is the major driver of TNF-&alpha\; dependent inflammation and disease. A
clinical development program for a first in class compound is currently a
ssessing a target which blocks solely the TNF-&alpha\; necroptosis pathway
. Following completion of the First Time in Human study\, we will next foc
us in on the human validation of blocking this pathway\, which in turn wil
l result in a greater understanding of the compound and mechanism early in
clinical development. \;This will be achieved through experimental m
edicine (EM) studies in three Immuno Inflammation indications that are tre
ated with anti-TNFs: Psoriasis\, Rheumatoid Arthritis and Ulcerative Colit
is. \;Each study is extremely data rich due to the number of biomarke
rs\, mechanistic and efficacy endpoints that will be collected. \;The
se EM studies will be conducted in parallel\, thus providing a unique oppo
rtunity to leverage data across the three indications in order to benchmar
k against anti-TNFs\, and thus inform the clinical development of this com
pound |
Karine Lheritier PhD
\n
Novartis | Complex study design in patients with Hereditary Periodic Fevers (HPF)\,
an orphan autoimmune disease. | \;Familial Mediterranean fever (FMF)\, Hyperimmunoglobuli
nemia D with periodic fever syndrome (HIDS) and TNF-receptor&ndash\;associ
ated periodic syndrome (TRAPS) are a cluster of autoimmune disease called
HPF syndromes. These are rare and distinct heritable disorders characteriz
ed by short and recurrent attacks of fever and severe localized inflammati
on that occur periodically or irregularly. \;
\n
The planning of a single study within this cluster of autoimmune disease
presents multiple and complex design challenges. Canakinumab is an anti-i
nterleukin-1&beta\; monoclonal antibody being developed for the treatment
of IL-1&beta\; - driven inflammatory diseases and has already been shown t
o be effective in patients with CAPS which is also classified under this s
ingle term of HPF syndromes.
\n Efficacy and safety
of Canakinumab in colchicine resistant FMF\, HIDS and TRAPS patients have
been shown in phase II studies. However\, there are currently no approved
treatments for \;
\n these conditions. Our challenge
was to design a single study on patients suffering from these 3 rare condi
tions. This required inclusion of a randomised\, double-blind\, placebo-co
ntrol and a randomized withdrawal element\, a long-term follow-up part\, i
n addition to clinical constraints such as up-titration of the dose\, chan
ge in the dose frequency\, co-primary efficacy endpoints with different ti
mepoints. Requests from different health authorities such as the Paediatri
c Committee at the European to include patients >\;28 days in this clini
cal trial were also built into the design.
\; |
\n Jen Pulley
\n Roche | \;\n A bioequiv
alence study design which includes the option for sample size re-estimatio
n (SSR) at the Interim Analysis | \;In Immunology we are currently designing a bio-e
quivalence study using a two stage sample size re-estimation adaptive desi
gn. This design will allow the sample size assumptions to be re-evaluated
once approximately half the subjects have completed the study.
\n
Our initial study design used overall power and fixed analysis wit
h no adjustment for type I error. This design was rejected by the health a
uthorities so the team revised the study design. Two revised study designs
using conditional power with a promising zone was proposed to health auth
orities. Each of the two revised designs made the adjustment for the type
I error within the 90% CI calculation using either the t-distribution meth
od or adjusted normal method.
\n This presentation will di
scuss the methods used for the revised SSR study designs and the ongoing i
nteractions with health authorities.
\; |
\;
\n Kie
ran Alden
York Computational Immunology Lab
| E
ngineering simulations to understand and gain inspiration from biological
systems | Simulation
is increasingly providing relevant tools to interrogate human biology\, t
o counter a continued reliance on predictions from animal experiments. Yet
simulations designed to explore complex biological mechanisms capture a r
ange of uncertain factors that impact the relationship between a predictio
n and the real world: factors that together act as a barrier to wider simu
lation use and acceptance in laboratory or clinical studies. Developing ro
bust\, evidence-based engineering approaches to simulation composition\, i
mplementation\, analysis\, and application has been a key feature of resea
rch in the York Computational Immunology Lab for a number of years\, withi
n significant immunological case studies. In this talk I will provide an o
verview of the techniques we have been developing to overcome barriers to
simulation acceptance and increase belief in predictions these simulations
derive\, in the context of a number of ongoing immunological research stu
dies.
|
\;\n
\n Jacquie Christie
GSK | \; | \;Across immunology indications\, a com
mon question is how long should a patient persevere with a treatment if th
ey not initially receive sufficient benefit. \; In this talk statistic
al approaches to address this question will be discussed
|
Brian Tom
\n MRC Biostatisti
cs Unit | RA-MAP Proje
ct - Towards an improved understanding of immune function and response in
RA | \;There i
s compelling evidence to implicate dysregulated immune function in the pat
hogenesis (origin and progression) of rheumatoid arthritis (RA). The RA-MA
P Project is an MRC/ABPI Inflammation and Immunology Initiative that aims
to improve understanding of the human immune system in rheumatoid arthriti
s\, using ex vivo and functional read outs\, through the application of es
tablished and new technologies and through different complementary studies
. We conjecture that discrete\, dynamic immunological profiles are present
in leucocyte subsets\, plasma or serum derived from human blood that are
informative of current and future disease states in RA (or health) and the
reby relevant immune function.
\n In this talk\, I
will describe the plan of investigation adopted\, the data collected and t
he statistical methodology that may be used to investigate immune dysregul
ation in RA by the RA-MAP consortium. |