Comparison of design strategies for a three‐arm clinical trial with time‐to‐event endpoint: Power,time‐to‐analysis,and operational aspects

To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three‐arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time‐to‐event endpoint. The inference strategy of this trial was based on a closed testing procedure. We compare this strategy to three potential alternatives to run a three‐arm clinical trial with a time‐to‐event endpoint. The primary goal is to quantify the differences between these strategies in terms of the time it takes until the first analysis and thus potential approval of a new drug, number of required events, and power. Operational aspects of implementing the various strategies are discussed. In conclusion, using a closed testing procedure results in the shortest time to the first analysis with a minimal loss in power. Therefore, closed testing procedures should be part of the statistician's standard clinical trials toolbox when planning multiarm clinical trials.     

MOSFET dose measurements for proton SOBP beam

PurposeThe aim of this work was to develop a computational scheme for the correction of the LET dependence on the MOSFET response in water phantom dose measurements for a spread-out Bragg peak (SOBP) proton beam.MethodsThe LET dependence of MOSFET was attributed to the stopping power ratio of SiO₂ to H₂O and to the fractional hole yield in the SiO₂ layer. Using literature values for the stopping powers of the continuous slowing down approximation and measured fractional hole yields vs. electric field and LET, formulas were derived for the computation of a dose-weighted correction factor of a SOBP beam.ResultsDose-weighted correction factors were computed for a clinical 190-MeV proton SOBP beam in a high-density polyethylene phantom. By applying correction factors to the SOBP beam, which consisted of weighted monoenergetic Bragg peaks, the MOSFET outputs were predicted and agreed well with the measured MOSFET responses.ConclusionBy applying LET dependent correction factors to MOSFET data, quality assurance of dose verification based on MOSFET measurements becomes possible for proton therapy.     

Quantitative 177Lu SPECT imaging using advanced correction algorithms in non-reference geometry

Peptide receptor therapy with ¹⁷⁷Lu-labelled somatostatin analogues is a promising tool in the management of patients with inoperable or metastasized neuroendocrine tumours. The aim of this work was to perform accurate activity quantification of ¹⁷⁷Lu in complex anthropomorphic geometry using advanced correction algorithms.Acquisitions were performed on the higher ¹⁷⁷Lu photopeak (208 keV) using a Philips IRIX gamma camera provided with medium-energy collimators. System calibration was performed using a 16 mL Jaszczak sphere surrounded by non-radioactive water. Attenuation correction was performed using μ-maps derived from CT data, while scatter and septal penetration corrections were performed using the transmission-dependent convolution-subtraction method. SPECT acquisitions were finally corrected for dead time and partial volume effects. Image analysis was performed using the commercial QSPECT software.The quantitative SPECT approach was validated on an anthropomorphic phantom provided with a home-made insert simulating a hepatic lesion. Quantitative accuracy was studied using three tumour-to-background activity concentration ratios (6:1, 9:1, 14:1).For all acquisitions, the recovered total activity was within 12% of the calibrated activity both in the background region and in the tumour. Using a 6:1 tumour-to-background ratio the recovered total activity was within 2% in the tumour and within 5% in the background. Partial volume effects, if not properly accounted for, can lead to significant activity underestimations in clinical conditions.In conclusion, accurate activity quantification of ¹⁷⁷Lu can be obtained if activity measurements are performed with equipment traceable to primary standards, advanced correction algorithms are used and acquisitions are performed at the 208 keV photopeak using medium-energy collimators.     

Use of uniform shots for robust planning of mask-based treatment in Gamma Knife Icon

PurposeTo verify whether Icon automatic correction is robust in preserving plan quality.Materials/methodsAn end-to-end phantom was used to verify Icon’s correction accuracy qualitatively. For quantitative assessment, two plans, a composite- and a uniform-shot-only, were created for an elliptical- (E) and a sausage-shaped (S) lesion inside a PseudoPatient head phantom with a film insert. The phantom was irradiated in the planned and three other positions under each plan: 14° pitch (B); 14° rotation + 8° pitch (C); 95° rotation + 4-cm shift (D).ResultsIcon accurately corrects the locations of the shots. For the uniform-shot plans: all gamma index passing rates were >97%, and the differences between the planned and the delivery doses (minimum, maximum, and mean) were all ≤0.1 Gy. For the composite-shot plans, however, the dose differences increased as the phantom was shifted through positions B-D, with a gamma index passing rate of 61% for lesion-E in position D, and 92%, 79%, and 45% for lesion-S in positions B, C, and D, respectively.ConclusionsPlans using only uniform shots are more robust to deviations in treatment position. The tolerance for such deviations may be lower for plans using composite shots.     

Geographic,seasonal, and diurnal surface behavior of harbor porpoises

During ship surveys harbor porpoises are only visible when breaking the sea surface to breathe, while during aerial surveys they may be seen down to 2 m below the surface. The fractions of time spent at these two depths can be used for correcting visual surveys to actual population estimates, which are essential information on the status and management of the species. Thirty‐five free‐ranging harbor porpoises (Phocoena phocoena) were tracked in the region between the Baltic and the North Sea for 25–349 d using Argos satellite transmitters. No differences were found in surface behavior between geographical areas or the size of the animals. Slight differences were found between the two sexes and time of day. Surface time peaked in April, where 6% was spent with the transmitter above surface and 61.5% between 0 and 2 m depth, while the minimum values occurred in February (3.4% and 42.5%, respectively). The analyses reveal that individual variation among porpoises is the most important factor in explaining variation in surface rates. However, the large number of animals documented in the present study covering a wide range of age and sex groups justifies the use of the seasonal average surface times for correcting abundance surveys.     

On the utility of aPost Hoc correction procedure for one-zero sampling duration estimates

Numerous previous studies have shown that one-zero sampling in direct observation systematically overestimates behavioral durations. Apost hoc correction procedure has been proposed and demonstrated to be capable of removing most of the systematic errors found in one-zero duration estimates. However, the remaining errors for some individual observation sessions can still be quite substantial in practical terms. In this paper, the condition under which thepost hoc correction procedure will produce results with negligible systematic errors in one-zero duration estimates is identified.     

Comparing two independent binomial proportions by a modified chi square test

When using the chi square test to compare the proportions of successes in two independent binomial samples, a new continuity correction is proposed, which equals half the size of the smaller sample. Exact computations of unconditional tail-probabilities, together with a theoretical argument, show that this correction is more appropriate than the YATES correction. This version of the chi square test is still conservative, but less so, and as a consequence more powerful, than the YATES corrected test.     

The origin and theoretical correction of thermal gradients in thermocouple psychrometers

Temperature-compensated psychrometers are explained and a theoretical correction for temperature gradients, with its boundaries, is given. The correction was elaborated for in situ determination of water potential on soybean and tomato stems where it was indispensable. The origin of the thermal gradients in the psychrometric chamber is then discussed. Cooling of the conducting tissue by the circulation of xylem sap seemed to be the major cause for these gradients, while the heating of the psychrometer (thermally insulated) by the surroundings through radiative or conductive transfer was negligible.