| \;speaker |
\;
Chris Mela
\n Roche Products Ltd
| \;\n Clinical O
verview of Immunology Diseases | Immunology is viewed as a complex and daunting subject w
ith a multitude of antibodies\, interleukins\, molecules\, cells and pathw
ays that interact in mysterious ways. This perception can worry anyone sta
ting research in a new immunological area or disease. The reality is that
the immune system spans almost every disease from aging to zoonosis and th
at certain concepts are common across all of these. By understanding some
of these themes we can demystify immunology and turn the fear into fascina
tion. \;
|
Dr Bernd Genser 1\,2
\;
1. BGStats Consulting Vienna Austria
\n
2. Mannheim Institute of Public Health\, Social and Preventive M
edicine\, University of Heidelberg\, Germany | An approach for integrating existing knowled
ge into the statistical analysis of multiple immune markers: \;An app
lication to cytokine data collected in a large immuno-epidemiological stud
y aimed to investigate risk factors for atopy and asthma | BACKGROUND: Immunologists often mea
sure several correlated immunological markers\, such as concentrations of
different cytokines produced by different immune cells and/or measured und
er different conditions\, to draw insights from complex immunological mech
anisms. Although there have been recent methodological efforts to improve
the statistical analysis of immunological data\, a framework is still need
ed for the simultaneous analysis of multiple\, often correlated\, immune m
arkers. This framework would allow the immunologists&rsquo\; hypotheses ab
out the underlying biological mechanisms to be integrated.
\n
METHODS: We present an analytical approach for statistical anal
ysis of correlated immune markers\, such as those commonly collected in mo
dern immuno-epidemiological studies.
\n RESULTS: We
demonstrate i) how to deal with interdependencies among multiple \;\n measurements of the same immune marker\, ii) how to anal
yse association patterns among different markers\, iii) how to aggregate d
ifferent measures and/or markers to immunological summary scores\, iv) how
to model the inter-relationships among these scores\, and v) how to use t
hese scores in epidemiological association analyses. We illustrate the app
lication of our approach to multiple cytokine measurements from 818 childr
en enrolled in a large immuno-epidemiological study (SCAALA Salvador)\, wh
ich aimed to quantify the major immunological mechanisms underlying atopic
diseases or asthma. We demonstrate how to aggregate systematically the in
formation captured in multiple cytokine measurements to immunological summ
ary scores aimed at reflecting the presumed underlying immunological mecha
nisms (Th1/Th2 balance and immune regulatory network). We show how these a
ggregated immune scores can be used as predictors in regression models wit
h outcomes of immunological studies (e.g. specific IgE) and compare the re
sults to those obtained by a traditional multivariate regression approach.
\n CONCLUSION: The proposed analytical approach ma
y be especially useful to quantify complex immune responses in immuno-epid
emiological studies\, where investigators examine the relationship among e
pidemiological patterns\, immune response\, and disease outcomes
\; |
Nicola Scott \
;
\n GSK | Leveraging Data across Multiple Immuno-Inflammation Indications: Earl
y Clinical Development of a Novel Compound | \;Recent research has identified that necrop
tosis is the major driver of TNF-&alpha\; dependent inflammation and disea
se. A clinical development program for a first in class compound is curren
tly assessing a target which blocks solely the TNF-&alpha\; necroptosis pa
thway. Following completion of the First Time in Human study\, we will nex
t focus in on the human validation of blocking this pathway\, which in tur
n will result in a greater understanding of the compound and mechanism ear
ly in clinical development. \;This will be achieved through experimen
tal medicine (EM) studies in three Immuno Inflammation indications that ar
e treated with anti-TNFs: Psoriasis\, Rheumatoid Arthritis and Ulcerative
Colitis. \;Each study is extremely data rich due to the number of bio
markers\, mechanistic and efficacy endpoints that will be collected.
\;These EM studies will be conducted in parallel\, thus providing a unique
opportunity to leverage data across the three indications in order to ben
chmark against anti-TNFs\, and thus inform the clinical development of thi
s compound |
Karine Lheritier PhD
\n Novartis | Complex study design in patients with Hereditary Periodic Fevers (HP
F)\, an orphan autoimmune disease. | \;Familial Mediterranean fever (FMF)\, Hyperimmunogl
obulinemia D with periodic fever syndrome (HIDS) and TNF-receptor&ndash\;a
ssociated periodic syndrome (TRAPS) are a cluster of autoimmune disease ca
lled HPF syndromes. These are rare and distinct heritable disorders charac
terized by short and recurrent attacks of fever and severe localized infla
mmation that occur periodically or irregularly. \;
\n
The planning of a single study within this cluster of autoimmune di
sease presents multiple and complex design challenges. Canakinumab is an a
nti-interleukin-1&beta\; monoclonal antibody being developed for the treat
ment of IL-1&beta\; - driven inflammatory diseases and has already been sh
own to be effective in patients with CAPS which is also classified under t
his single term of HPF syndromes.
\n Efficacy and s
afety of Canakinumab in colchicine resistant FMF\, HIDS and TRAPS patients
have been shown in phase II studies. However\, there are currently no app
roved treatments for \;
\n these conditions. Our chall
enge was to design a single study on patients suffering from these 3 rare
conditions. This required inclusion of a randomised\, double-blind\, place
bo-control and a randomized withdrawal element\, a long-term follow-up par
t\, in addition to clinical constraints such as up-titration of the dose\,
change in the dose frequency\, co-primary efficacy endpoints with differe
nt timepoints. Requests from different health authorities such as the Paed
iatric Committee at the European to include patients >\;28 days in this
clinical trial were also built into the design.
\; <
/td> |
\n Jen Pulley
\n Roche |
\;\n A
bioequivalence study design which includes the option for sample size re-
estimation (SSR) at the Interim Analysis | \;In Immunology we are currently designin
g a bio-equivalence study using a two stage sample size re-estimation adap
tive design. This design will allow the sample size assumptions to be re-e
valuated once approximately half the subjects have completed the study.
\n Our initial study design used overall power and fixed ana
lysis with no adjustment for type I error. This design was rejected by the
health authorities so the team revised the study design. Two revised stud
y designs using conditional power with a promising zone was proposed to he
alth authorities. Each of the two revised designs made the adjustment for
the type I error within the 90% CI calculation using either the t-distribu
tion method or adjusted normal method.
\n This presentatio
n will discuss the methods used for the revised SSR study designs and the
ongoing interactions with health authorities.
\; |
\;
\n
Kieran Alden
York Computational Immunology Lab
| Engineering simulations to understand and gain inspiration from bi
ological systems | S
imulation is increasingly providing relevant tools to interrogate human bi
ology\, to counter a continued reliance on predictions from animal experim
ents. Yet simulations designed to explore complex biological mechanisms ca
pture a range of uncertain factors that impact the relationship between a
prediction and the real world: factors that together act as a barrier to w
ider simulation use and acceptance in laboratory or clinical studies. Deve
loping robust\, evidence-based engineering approaches to simulation compos
ition\, implementation\, analysis\, and application has been a key feature
of research in the York Computational Immunology Lab for a number of year
s\, within significant immunological case studies. In this talk I will pro
vide an overview of the techniques we have been developing to overcome bar
riers to simulation acceptance and increase belief in predictions these si
mulations derive\, in the context of a number of ongoing immunological res
earch studies.
|
\;\n
\n Jacquie Chris
tie
GSK<
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| \; | \;Across immunology indication
s\, a common question is how long should a patient persevere with a treatm
ent if they not initially receive sufficient benefit. \; In this talk
statistical approaches to address this question will be discussed
|
Brian Tom
\n MRC Bi
ostatistics Unit | RA-
MAP Project - Towards an improved understanding of immune function and res
ponse in RA | \
;There is compelling evidence to implicate dysregulated immune function i
n the pathogenesis (origin and progression) of rheumatoid arthritis (RA).
The RA-MAP Project is an MRC/ABPI Inflammation and Immunology Initiative t
hat aims to improve understanding of the human immune system in rheumatoid
arthritis\, using ex vivo and functional read outs\, through the applicat
ion of established and new technologies and through different complementar
y studies. We conjecture that discrete\, dynamic immunological profiles ar
e 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 thereby relevant immune function.
\n In this
talk\, I will describe the plan of investigation adopted\, the data collec
ted and the statistical methodology that may be used to investigate immune
dysregulation in RA by the RA-MAP consortium. |