34 research outputs found
Anonymising Clinical Data for Secondary Use
Secondary use of data already collected in clinical studies has become more
and more popular in recent years, with the commitment of the pharmaceutical
industry and many academic institutions in Europe and the US to provide access
to their clinical trial data. Whilst this clearly provides societal benefit in
helping to progress medical research, this has to be balanced against
protection of subjects' privacy. There are two main scenarios for sharing
subject data: within Clinical Study Reports and Individual Patient Level Data,
and these scenarios have different associated risks and generally require
different approaches. In any data sharing scenario, there is a trade-off
between data utility and the risk of subject re-identification, and achieving
this balance is key. Quantitative metrics can guide the amount of
de-identification required and new technologies may also start to provide
alternative ways to achieve the risk-utility balance.Comment: 25 page
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
Embracing model-based designs for dose-finding trials
Background: Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM). Methods: We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. Results: We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators’ preference for algorithm-based designs (e.g., 3 þ 3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. Conclusions: There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia
Evaluation and monitoring of terrestrial and aquatic insect biodiversity in forested and cleared watersheds at Camp Atterbury, Indiana.
Executive Summary
Camp Atterbury is a 33,132 ha military installation near Edinburgh, Indiana. Construction of a 80 ha (4,550
ha with safety fan) Multi-Purpose Training Range (MPTR) began in 1998, and supports training for military vehicles
and dismounted infantry, with a variety of stationary and moving targets. This study provides a baseline for long term
monitoring and evaluation of natural communities to assess the impacts of construction of, and training in, the MPTR.
We assessed both aquatic macroinvertebrate and terrestrial insect community diversity, abundance, and
richness and similarity at a series of study plots using quantifiable, repeatable and replicated methods. These data
provide baseline data facilitating long-term monitoring and assessment as a measure of ecosystem health, and allow
evaluation of relationships between community composition and habitat metrics.
Methods
Eight terrestrial study sites, each comprised of a 30 m square plot, were randomly selected, with four of
these placed in the cleared portions of the MPTR and four placed in adjacent upland forest. We used several
sampling methods, with focus on three groups of taxa (all insect taxa, ants, and leafhoppers and kin) and compared
the efficacy of both the methods and the groups as monitoring tools. Sampling methods included: 1) a Malaise trap
(mesh tent-like device that captures flying insects) at each site; 2) four sweep sample transects at each site; 3) four
leaf litter samples from each site, with invertebrates extracted using the Winkler method; and 4) Nine pitfall traps at
each site. Samples were collect during Summer and Fall study periods, and this report gives results from the
Summer sample period. Several habitat parameters were recorded, including a vegetation index, canopy cover,
ground cover, and leaf litter depth. Dominant plant taxa were collected, and data loggers recorded soil and air
temperature during the study.
We sampled aquatic macroinvertebrates at three stream sites draining the MPTR. Invertebrates were
collected in replicate samples with a dipnet and these were sorted and subsampled in the laboratory. Canopy cover
and basic water chemistry data were collected, and data loggers recorded changes in terrestrial and aquatic
temperature. An index of biotic integrity and taxon richness were used to evaluate the aquatic communities.
Results and Discussion
At least 409 taxa and 3776 specimens were collected at terrestrial sample sites during the Summer sampling
period. In general, there were some differences among sites, among sampling methods, and among treatments
(cleared MPTR versus forested) when we examined taxon richness and species diversity, but these differences could
not always be fully resolved. While taxon richness and species diversity differed among treatments, and, in general,
plots in the two treatments harbored different insect communities. Species accumulation curves and various
estimators of taxon richness were used to evaluate the four sampling methods and the three groups of taxa (all taxa,
ants, leafhoppers). Based on the performance of the different taxa (all, ants, leafhoppers) compared across the
different methods (malaise sampling, Winkler extracted leaf litter samples, pitfall traps, and sweep samples), the
single most effective taxon for monitoring was found to be the ants (Formicidae), and the single best method for
monitoring was found to be pitfall trapping.
We collected 818 specimens, primarily aquatic macroinvertebrates, from the three stream sites during
Summer sampling. All three streams were dry during the fall sample period, and thus no aquatic macroinvertebrates
were collected. Using Hilsenhoff’s (1988) family-level index of biotic integrity, water quality was classified as “good”
at one site, and “fair” at the other two, although taxon richness was lowest at the site classified as good. In addition
to invertebrates, numerous salamanders (Eurycea cirrigera, the Two-lined Salamander) were observed in the
streams.
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For aquatic invertebrates, we found that the small upstream portions that directly drained the MPTR only
held water seasonally, and thus were not effective sites for monitoring of stream macroinvertebrates. There was
insufficient separation between MPTR-influenced stream sites and control sites, and a lack of replication (few
streams flowing away from the MPTR) precluded robust statistical analysis of the data we did obtain. The community
of aquatic macroinvertebrates collected during this study appeared similar to the communities reported by Robinson
(2004) elsewhere at Camp Atterbury in larger streams, and includes taxa typical of rocky bottom Midwestern forest
streams. Fish were largely absent due to the intermittent nature of the streams. Salamanders were abundant in the
streams, and because they are top predators in this seasonal habitat, they may be suitable subjects for studies of
potential bioaccumulation of toxins.
This study provides a snapshot of insect biodiversity at a point in time, thus providing baseline for any
possible future monitoring of insect biodiversity. Sampling methods and analyses developed in this study could
easily be implemented at a wide variety of other military installations to facilitate inventory and/or monitoring of insect
biodiversity.Ope
Accelerated Model Checking of Parametric Markov Chains
Parametric Markov chains occur quite naturally in various applications: they
can be used for a conservative analysis of probabilistic systems (no matter how
the parameter is chosen, the system works to specification); they can be used
to find optimal settings for a parameter; they can be used to visualise the
influence of system parameters; and they can be used to make it easy to adjust
the analysis for the case that parameters change. Unfortunately, these
advancements come at a cost: parametric model checking is---or rather
was---often slow. To make the analysis of parametric Markov models scale, we
need three ingredients: clever algorithms, the right data structure, and good
engineering. Clever algorithms are often the main (or sole) selling point; and
we face the trouble that this paper focuses on -- the latter ingredients to
efficient model checking. Consequently, our easiest claim to fame is in the
speed-up we have often realised when comparing to the state of the art
Minimal Residual Disease Status Predicts Outcome in Patients With Previously Untreated Follicular Lymphoma
Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients
Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control
A flexible method for determining a biomarker positive population based on an efficacy target within a confirmatory study
Alternative graphical representations of genotypes in a pedigree
Three representations of the conditional independences due to Mendelian segregation of genes in a pedigree are proposed. The computational costs of performing calculations using the technique of peeling with each of these representations is compared by considering the weights of triangulations of the graph produced by each representation