Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up

Objectives: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non–small-cell lung cancer (NSCLC). Methods: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs—landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)—were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. Results: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). Conclusions: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up. Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes. Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data. Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting. Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup

Simpson's Paradox, Lord's Paradox, and Suppression Effects are the same phenomenon – the reversal paradox

This article discusses three statistical paradoxes that pervade epidemiological research: Simpson's paradox, Lord's paradox, and suppression. These paradoxes have important implications for the interpretation of evidence from observational studies. This article uses hypothetical scenarios to illustrate how the three paradoxes are different manifestations of one phenomenon – the reversal paradox – depending on whether the outcome and explanatory variables are categorical, continuous or a combination of both; this renders the issues and remedies for any one to be similar for all three. Although the three statistical paradoxes occur in different types of variables, they share the same characteristic: the association between two variables can be reversed, diminished, or enhanced when another variable is statistically controlled for. Understanding the concepts and theory behind these paradoxes provides insights into some controversial or contradictory research findings. These paradoxes show that prior knowledge and underlying causal theory play an important role in the statistical modelling of epidemiological data, where incorrect use of statistical models might produce consistent, replicable, yet erroneous results

The development of a brief and objective method for evaluating moral sensitivity and reasoning in medical students

BACKGROUND: Most medical schools in Japan have incorporated mandatory courses on medical ethics. To this date, however, there is no established means of evaluating medical ethics education in Japan. This study looks 1) To develop a brief, objective method of evaluation for moral sensitivity and reasoning; 2) To conduct a test battery for the PIT and the DIT on medical students who are either currently in school or who have recently graduated (residents); 3) To investigate changes in moral sensitivity and reasoning between school years among medical students and residents. METHODS: Questionnaire survey: Two questionnaires were employed, the Problem Identification Test (PIT) for evaluation of moral sensitivity and a portion of the Defining Issues Test (DIT) for moral reasoning. Subjects consisted of 559 medical school students and 272 residents who recently graduated from the same medical school located in an urban area of Japan. RESULTS: PIT results showed an increase in moral sensitivity in 4(th )and 5(th )year students followed by a decrease in 6(th )year students and in residents. No change in moral development stage was observed. However, DIT results described a gradual rising shift in moral decision-making concerning euthanasia between school years. No valid correlation was observed between PIT and DIT questionnaires. CONCLUSION: This study's questionnaire survey, which incorporates both PIT and DIT, could be used as a brief and objective means of evaluating medical students' moral sensitivity and reasoning in Japan

The rolling problem: overview and challenges

In the present paper we give a historical account -ranging from classical to modern results- of the problem of rolling two Riemannian manifolds one on the other, with the restrictions that they cannot instantaneously slip or spin one with respect to the other. On the way we show how this problem has profited from the development of intrinsic Riemannian geometry, from geometric control theory and sub-Riemannian geometry. We also mention how other areas -such as robotics and interpolation theory- have employed the rolling model.Comment: 20 page

Lattice QCD determination of m_b, f_B and f_Bs with twisted mass Wilson fermions

We present a lattice QCD determination of the b quark mass and of the B and B_s decay constants, performed with N_f=2 twisted mass Wilson fermions, by simulating at four values of the lattice spacing. In order to study the b quark on the lattice, two methods are adopted in the present work, respectively based on suitable ratios with exactly known static limit and on the interpolation between relativistic data, evaluated in the charm mass region, and the static point, obtained by simulating the HQET on the lattice. The two methods provide results in good agreement. For the b quark mass in the MSbar scheme and for the decay constants we obtain m_b(m_b)=4.29(14) GeV, f_B=195(12) MeV, f_Bs=232(10) MeV and f_Bs/f_B=1.19(5). As a byproduct of the analysis we also obtain the results for the f_D and f_Ds decay constants: f_D=212(8) MeV, f_Ds=248(6) MeV and f_Ds/f_D=1.17(5).Comment: 23 pages, 10 figures, 2 tables. Added appendix showing the agreement of the data for the ratios with the HQE prediction. Matching JHEP published versio

Cue Reactivity in Active Pathological, Abstinent Pathological, and Regular Gamblers

Twenty-one treatment-seeking pathological gamblers, 21 pathological gamblers in recovery, and 21 recreational gamblers watched two video-taped exciting gambling scenarios and an exciting roller-coaster control scenario while their arousal (heart rate and subjective excitement) and urge to gamble were being measured. The gamblers did not differ significantly in cue-elicited heart rate elevations or excitement. However, the active pathological gamblers reported significantly greater urges to gamble across all cues compared to the abstinent pathological gamblers and, with marginal significance (p = 0.06), also compared to the social gamblers. Further exploration of these findings revealed that active pathological gamblers experience urges to gamble in response to exciting situations, whether or not they are gambling related, whereas abstinent and social gamblers only report urges to an exciting gambling-related cue. This suggests that for pathological gamblers excitement itself, irrespective of its source, may become a conditioned stimulus capable of triggering gambling behavior. Implications for treatment and future research are discussed

Inter-Relationship between Testicular Dysgenesis and Leydig Cell Function in the Masculinization Programming Window in the Rat

The testicular dysgenesis syndrome (TDS) hypothesis proposes that maldevelopment of the testis, irrespective of cause, leads to malfunction of the somatic (Leydig, Sertoli) cells and consequent downstream TDS disorders. Studies in rats exposed in utero to di(n-butyl) phthalate (DBP) have strongly supported the TDS concept, but so far no direct evidence has been produced that links dysgenesis per se to somatic cell dysfunction, in particular to androgen production/action during the ‘masculinization programming window’ (MPW; e15.5–e18.5). Normal reproductive tract development and anogenital distance (AGD) are programmed within the MPW, and TDS disorders arise because of deficiencies in this programming. However, DBP-induced focal testicular dysgenesis (Leydig cell aggregation, ectopic Sertoli cells, malformed seminiferous cords) is not evident until after the MPW. Therefore, we used AGD as a read-out of androgen exposure in the MPW, and investigated if this measure was related to objectively quantified dysgenesis (Leydig cell aggregation) at e21.5 in male fetuses exposed to vehicle, DBP (500 or 750 mg/kg/day) or the synthetic glucocorticoid dexamethasone (Dex; alone or plus DBP-500) from e15.5–e18.5 (MPW), e13.5–e20.5 or e19.5–e20.5 (late window). Dysgenesis was found only in animals exposed to DBP during the MPW, and was negatively correlated (R2 = −0.5) with AGD at e21.5 and at postnatal day 8, irrespective of treatment period. Dysgenesis was also negatively correlated (R2 = –0.5) with intratesticular testosterone (ITT) at e21.5, but only when treatments in short windows (MPW, late window) were excluded; the same was true for correlation between AGD and ITT. We conclude that AGD, reflecting Leydig cell function solely within the MPW, is strongly related to focal dysgenesis. Our results point to this occurring because of a common early mechanism, targeted by DBP that determines both dysgenesis and early (during the MPW) fetal Leydig cell dysfunction. The findings provide strong validation of the TDS hypothesis

Numerical Hermitian Yang-Mills Connections and Vector Bundle Stability in Heterotic Theories

A numerical algorithm is presented for explicitly computing the gauge connection on slope-stable holomorphic vector bundles on Calabi-Yau manifolds. To illustrate this algorithm, we calculate the connections on stable monad bundles defined on the K3 twofold and Quintic threefold. An error measure is introduced to determine how closely our algorithmic connection approximates a solution to the Hermitian Yang-Mills equations. We then extend our results by investigating the behavior of non slope-stable bundles. In a variety of examples, it is shown that the failure of these bundles to satisfy the Hermitian Yang-Mills equations, including field-strength singularities, can be accurately reproduced numerically. These results make it possible to numerically determine whether or not a vector bundle is slope-stable, thus providing an important new tool in the exploration of heterotic vacua.Comment: 52 pages, 15 figures. LaTex formatting of figures corrected in version 2

Numerical Hermitian Yang-Mills Connections and Kahler Cone Substructure

We further develop the numerical algorithm for computing the gauge connection of slope-stable holomorphic vector bundles on Calabi-Yau manifolds. In particular, recent work on the generalized Donaldson algorithm is extended to bundles with Kahler cone substructure on manifolds with h^{1,1}>1. Since the computation depends only on a one-dimensional ray in the Kahler moduli space, it can probe slope-stability regardless of the size of h^{1,1}. Suitably normalized error measures are introduced to quantitatively compare results for different directions in Kahler moduli space. A significantly improved numerical integration procedure based on adaptive refinements is described and implemented. Finally, an efficient numerical check is proposed for determining whether or not a vector bundle is slope-stable without computing its full connection.Comment: 38 pages, 10 figure