123 research outputs found
A multistate model for early decision making in oncology
The development of oncology drugs progresses through multiple phases, where
after each phase a decision is made about whether to move a molecule forward.
Early phase efficacy decisions are often made on the basis of single arm
studies based on RECIST tumor response as endpoint. This decision rules are
implicitly assuming some form of surrogacy between tumor response and long-term
endpoints like progression-free survival (PFS) or overall survival (OS). The
surrogacy is most often assessed as weak, but sufficient to allow a rapid
decision making as early phase studies lack the survival follow up and number
of patients to properly assess PFS or OS. With the emergence of therapies with
new mechanisms of action, for which the link between RECIST tumor response and
long-term endpoints is either not accessible yet because not enough data is
available to perform a meta-regression, or the link is weaker than with
classical chemotherapies, tumor response based rules may not be optimal. In
this paper, we explore the use of a multistate model for decision making based
on single-arm early phase trials. The multistate model allows to account for
more information than the simple RECIST response status, namely, the time to
get to response, the duration of response, the PFS time and time to death. We
propose to base the decision on efficacy on the OS hazard ratio (HR), predicted
from a multistate model based on early phase data with limited survival
follow-up, combined with historical control data. Using three case studies and
simulations, we illustrate the feasibility of the estimation of the OS HR using
a multistate model based on limited data from early phase studies. We argue
that, in the presence of limited follow up and small sample size, and on
assumptions within the multistate model, the OS prediction is acceptable and
may lead to better decisions for continuing the development of a drug
Kinematic analysis of handwriting movements in patients with Alzheimer's disease, mild cognitive impairment, depression and healthy subjects
A variety of studies have demonstrated that motor disorders, parkinsonism and extrapyramidal motor symptoms (EPMS) are common in patients with Alzheimer's disease (AD). Several studies have reported an association of EPMS with severity, progression and poor prognosis of AD. The majority of these studies used clinical assessments for the rating of EPMS. In this study, kinematic handwriting analysis was used to quantify differences in fine hand motor function in patients with probable AD and mild cognitive impairment (MCl, as an assumed initial stage of AD) compared to depressed patients and healthy controls. Both patients with MCl and patients with probable AD exhibited loss of fine motor performance. Movements of AD patients were significantly less regular than those of healthy controls. Copyright (C) 2003 S. Karger AG, Basel
The use of external controls: To what extent can it currently be recommended?
With more and better clinical data being captured outside of clinical studies
and greater data sharing of clinical studies, external controls may become a
more attractive alternative to randomized clinical trials. Both industry and
regulators recognize that in situations where a randomized study cannot be
performed, external controls can provide the needed contextualization to allow
a better interpretation of studies without a randomized control. It is also
agreed that external controls will not fully replace randomized clinical trials
as the gold standard for formal proof of efficacy in drug development and the
yardstick of clinical research. However, it remains unclear in which situations
conclusions about efficacy and a positive benefit/risk can reliably be based on
the use of an external control. This paper will provide an overview on types of
external control, their applications and the different sources of bias their
use may incur, and discuss potential mitigation steps. It will also give
recommendations on how the use of external controls can be justified
Statistical and data reporting guidelines for the European Journal of Cardio-Thoracic Surgery and the Interactive CardioVascular and Thoracic Surgery
As part of the peer review process for the European Journal of Cardio-Thoracic Surgery (EJCTS) and the Interactive CardioVascular and Thoracic Surgery (ICVTS), a statistician reviews any manuscript that includes a statistical analysis. To facilitate authors considering submitting a manuscript and to make it clearer about the expectations of the statistical reviewers, we present up-to-date guidelines for authors on statistical and data reporting specifically in these journals. The number of statistical methods used in the cardiothoracic literature is vast, as are the ways in which data are presented. Therefore, we narrow the scope of these guidelines to cover the most common applications submitted to the EJCTS and ICVTS, focusing in particular on those that the statistical reviewers most frequently comment o
First-dose analgesic effect of the cyclo-oxygenase-2 selective inhibitor lumiracoxib in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled comparison with celecoxib [NCT00267215]
Cyclo-oxygenase-2 selective inhibitors are frequently used to manage osteoarthritis. We compared the analgesic efficacy of the novel cyclo-oxygenase-2 selective inhibitor lumiracoxib (Prexige(®)) versus placebo and celecoxib in patients with knee osteoarthritis. This seven day, double-blind, placebo and active comparator controlled, parallel group study included 364 patients aged ≥50 years with moderate-to-severe symptomatic knee osteoarthritis. Patients received lumiracoxib 400 mg/day (four times the recommended chronic dose in osteoarthritis; n = 144), placebo (n = 75), or celecoxib 200 mg twice daily (n = 145). The primary variable was actual pain intensity difference (100 mm visual–analogue scale) between baseline and the mean of three hour and five hour assessments after the first dose. Actual pain intensity difference, average and worst pain, pain relief and functional status (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC™]) were measured over seven days. Patients also completed a global evaluation of treatment effect at study end or premature discontinuation. For the primary variable, the superiority of lumiracoxib versus placebo, the noninferiority of lumiracoxib versus celecoxib, and the superiority of lumiracoxib versus celecoxib were assessed by closed test procedure adjusting for multiplicity, thereby maintaining the overall 5% significance level. In addition, celecoxib was assessed versus placebo in a predefined exploratory manner to assess trial sensitivity. Lumiracoxib provided better analgesia than placebo 3–5 hours after the first dose (P = 0.004) through to study end. The estimated difference between lumiracoxib and celecoxib 3–5 hours after the first dose was not significant (P = 0.185). Celecoxib was not significantly different from placebo in this analysis (P = 0.069). At study end 13.9% of lumiracoxib-treated patients reported complete pain relief versus 5.5% and 5.3% of celecoxib and placebo recipients, respectively. WOMAC™ total and subscales improved for both active treatments versus placebo except for difficulty in performing daily activities, for which celecoxib just failed to achieve significance (P = 0.056). In the patient's global evaluation of treatment effect, 58.1% of patients receiving lumiracoxib rated treatment as 'excellent' or 'good', versus 48.6% of celecoxib and 25.3% of placebo patients. Lumiracoxib was well tolerated. The overall incidence of adverse events was similar across treatment groups
Diving of Great Shearwaters (Puffinus gravis) in Cold and Warm Water Regions of the South Atlantic Ocean
BACKGROUND: Among the most widespread seabirds in the world, shearwaters of the genus Puffinus are also some of the deepest diving members of the Procellariiformes. Maximum diving depths are known for several Puffinus species, but dive depths or diving behaviour have never been recorded for great shearwaters (P. gravis), the largest member of this genus. This study reports the first high sampling rate (2 s) of depth and diving behaviour for Puffinus shearwaters. METHODOLOGY/PRINCIPAL FINDINGS: Time-depth recorders (TDRs) were deployed on two female great shearwaters nesting on Inaccessible Island in the South Atlantic Ocean, recording 10 consecutive days of diving activity. Remote sensing imagery and movement patterns of 8 males tracked by satellite telemetry over the same period were used to identify probable foraging areas used by TDR-equipped females. The deepest and longest dive was to 18.9 m and lasted 40 s, but most (>50%) dives were <2 m deep. Diving was most frequent near dawn and dusk, with <0.5% of dives occurring at night. The two individuals foraged in contrasting oceanographic conditions, one in cold (8 to 10°C) water of the Sub-Antarctic Front, likely 1000 km south of the breeding colony, and the other in warmer (10 to 16°C) water of the Sub-tropical Frontal Zone, at the same latitude as the colony, possibly on the Patagonian Shelf, 4000 km away. The cold water bird spent fewer days commuting, conducted four times as many dives as the warm water bird, dived deeper on average, and had a greater proportion of bottom time during dives. CONCLUSIONS/SIGNIFICANCE: General patterns of diving activity were consistent with those of other shearwaters foraging in cold and warm water habitats. Great shearwaters are likely adapted to forage in a wide range of oceanographic conditions, foraging mostly with shallow dives but capable of deep diving
Clinical Value of Prognostic Instruments to Identify Patients with an Increased Risk for Osteoporotic Fractures: Systematic Review
There is a plethora of evidence available studying the association of risk profiles and the development of osteoporotic fractures. The small number of out-of-sample validations, the large variety of study characteristics, outcomes and follow-up periods impedes from deriving robust summaries and from conclusions regarding the clinical performance of many tools. First and foremost, future activity in this field should aim at reaching a consensus among clinical experts in respect to the existing instruments. Then we call for careful validations and expedient adaptations for local circumstances of the most promising candidates
Searches at HERA for Squarks in R-Parity Violating Supersymmetry
A search for squarks in R-parity violating supersymmetry is performed in e^+p
collisions at HERA at a centre of mass energy of 300 GeV, using H1 data
corresponding to an integrated luminosity of 37 pb^(-1). The direct production
of single squarks of any generation in positron-quark fusion via a Yukawa
coupling lambda' is considered, taking into account R-parity violating and
conserving decays of the squarks. No significant deviation from the Standard
Model expectation is found. The results are interpreted in terms of constraints
within the Minimal Supersymmetric Standard Model (MSSM), the constrained MSSM
and the minimal Supergravity model, and their sensitivity to the model
parameters is studied in detail. For a Yukawa coupling of electromagnetic
strength, squark masses below 260 GeV are excluded at 95% confidence level in a
large part of the parameter space. For a 100 times smaller coupling strength
masses up to 182 GeV are excluded.Comment: 32 pages, 14 figures, 3 table
Multiplicity Structure of the Hadronic Final State in Diffractive Deep-Inelastic Scattering at HERA
The multiplicity structure of the hadronic system X produced in
deep-inelastic processes at HERA of the type ep -> eXY, where Y is a hadronic
system with mass M_Y< 1.6 GeV and where the squared momentum transfer at the pY
vertex, t, is limited to |t|<1 GeV^2, is studied as a function of the invariant
mass M_X of the system X. Results are presented on multiplicity distributions
and multiplicity moments, rapidity spectra and forward-backward correlations in
the centre-of-mass system of X. The data are compared to results in e+e-
annihilation, fixed-target lepton-nucleon collisions, hadro-produced
diffractive final states and to non-diffractive hadron-hadron collisions. The
comparison suggests a production mechanism of virtual photon dissociation which
involves a mixture of partonic states and a significant gluon content. The data
are well described by a model, based on a QCD-Regge analysis of the diffractive
structure function, which assumes a large hard gluonic component of the
colourless exchange at low Q^2. A model with soft colour interactions is also
successful.Comment: 22 pages, 4 figures, submitted to Eur. Phys. J., error in first
submission - omitted bibliograph
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