Design of a clinical trial using generalized pairwise comparisons to test a less intensive treatment regimen.

BACKGROUND/AIMS: Showing "similar efficacy" of a less intensive treatment typically requires a non-inferiority trial. Yet such trials may be challenging to design and conduct. In acute promyelocytic leukemia, great progress has been achieved with the introduction of targeted therapies, but toxicity remains a major clinical issue. There is a pressing need to show the favorable benefit/risk of less intensive treatment regimens. METHODS: We designed a clinical trial that uses generalized pairwise comparisons of five prioritized outcomes (alive and event-free at 2 years, grade 3/4 documented infections, differentiation syndrome, hepatotoxicity, and neuropathy) to confirm a favorable benefit/risk of a less intensive treatment regimen. We conducted simulations based on historical data and assumptions about the differences expected between the standard of care and the less intensive treatment regimen to calculate the sample size required to have high power to show a positive Net Treatment Benefit in favor of the less intensive treatment regimen. RESULTS: Across 10,000 simulations, average sample sizes of 260 to 300 patients are required for a trial using generalized pairwise comparisons to detect typical Net Treatment Benefits of 0.19 (interquartile range 0.14-0.23 for a sample size of 280). The Net Treatment Benefit is interpreted as a difference between the probability of doing better on the less intensive treatment regimen than on the standard of care, minus the probability of the opposite situation. A Net Treatment Benefit of 0.19 translates to a number needed to treat of about 5.3 patients (1/0.19 ≃ 5.3). CONCLUSION: Generalized pairwise comparisons allow for simultaneous assessment of efficacy and safety, with priority given to the former. The sample size required would be of the order of 300 patients, as compared with more than 700 patients for a non-inferiority trial using a margin of 4% against the less intensive treatment regimen for the absolute difference in event-free survival at 2 years, as considered here.

Generalized pairwise comparisons of prioritized outcomes are a powerful and patient-centric analysis of multi-domain scores.

BACKGROUND: Generalized pairwise comparisons (GPC) can be used to assess the net benefit of new treatments for rare diseases. We show the potential of GPC through simulations based on data from a natural history study in mucopolysaccharidosis type IIIA (MPS IIIA). METHODS: Using data from a historical series of untreated children with MPS IIIA aged 2 to 9 years at the time of enrolment and followed for 2 years, we performed simulations to assess the operating characteristics of GPC to detect potential (simulated) treatment effects on a multi-domain symptom assessment. Two approaches were used for GPC: one in which the various domains were prioritized, the other with all domains weighted equally. The net benefit was used as a measure of treatment effect. We used increasing thresholds of clinical relevance to reflect the magnitude of the desired treatment effects, relative to the standard deviation of the measurements in each domain. RESULTS: GPC were shown to have adequate statistical power (80% or more), even with small sample sizes, to detect treatment effects considered to be clinically worthwhile on a symptom assessment covering five domains (expressive language, daily living skills, and gross-motor, sleep and pain). The prioritized approach generally led to higher power as compared with the non-prioritized approach. CONCLUSIONS: GPC of prioritized outcomes is a statistically powerful as well as a patient-centric approach for the analysis of multi-domain scores in MPS IIIA and could be applied to other heterogeneous rare diseases.

Generalized Pairwise Comparisons to Assess Treatment Effects: JACC Review Topic of the Week.

A time-to-first-event composite endpoint analysis has well-known shortcomings in evaluating a treatment effect in cardiovascular clinical trials. It does not fully describe the clinical benefit of therapy because the severity of the events, events repeated over time, and clinically relevant nonsurvival outcomes cannot be considered. The generalized pairwise comparisons (GPC) method adds flexibility in defining the primary endpoint by including any number and type of outcomes that best capture the clinical benefit of a therapy as compared with standard of care. Clinically important outcomes, including bleeding severity, number of interventions, and quality of life, can easily be integrated in a single analysis. The treatment effect in GPC can be expressed by the net treatment benefit, the success odds, or the win ratio. This review provides guidance on the use of GPC and the choice of treatment effect measures for the analysis and reporting of cardiovascular trials.

Pupil size variations reveal covert shifts of attention induced by numbers.

The pupil light response is more than a pure reflexive mechanism that reacts to the amount of light entering the eye. The pupil size may also react to the luminance of objects lying in the visual periphery, revealing the locus of covert attention. In the present study, we took advantage of this response to study the spatial coding of abstract concepts with no physical counterpart: numbers. The participants' gaze was maintained fixed in the middle of a screen whose left and right parts were dark or bright, and variations in pupil size were recorded during an auditory number comparison task. The results showed that small numbers accentuated pupil dilation when the darker part of the screen was on the left, while large numbers accentuated pupil dilation when the darker part of the screen was on the right. This finding provides direct evidence for covert attention shifts on a left-to-right oriented mental spatial representation of numbers. From a more general perspective, it shows that the pupillary response to light is subject to modulation from spatial attention mechanisms operating on mental contents.

The predictive role of eye movements in mental arithmetic.

Behavioural studies have suggested that number manipulation involves shifting attention along a left-to-right oriented continuum. However, these studies provide little evidence about the time course of attention shifts during number processing. We used an eye-tracker with high spatio-temporal resolution to measure eye movements during the mental solving of addition (e.g., 43 + 4) and subtraction problems (e.g., 53 - 6), as a proxy for the rightward and leftward attention shifts that accompany these operations. A first difference in eye position was observed as soon as the operator was heard: the hearing of "plus" shifted the eye rightward compared to "minus". A second difference was observed later between problem offset and response onset: addition shifted the eye rightward and upward compared to subtraction, suggesting that the space used to represent the problem is bidimensional. Further analyses confirmed the fast deployment of spatial attention and evidenced its relationship with the carrying and borrowing procedures triggered by the problem presentation. The predictive role of horizontal eye movements, in particular, is essential to understand how attention contributes to narrow down the range of plausible answers. We propose that attention illuminates significant portions of the numerical continuum anticipatively to guide the search of the answer and facilitate the implementation of solving procedures in verbal working memory.

Craving is everything: An eye-tracking exploration of attentional bias in binge drinking.

BACKGROUND: Attentional bias towards alcohol-related stimuli is a core characteristic of severe alcohol use disorders (AUD), directly linked to clinical variables (e.g. alcohol consumption, relapse). Nevertheless, the extent of this bias in subclinical populations remains poorly documented. This is particularly true for binge drinking, an alcohol consumption pattern highly prevalent in youth, characterised by an alternation between excessive intakes and withdrawal periods. AIMS: We used eye-tracking to: (a) measure attentional bias in binge drinking, (b) determine its time course by dissociating early/late processing stages, (c) clarify its specificity for alcohol-related stimuli compared to other appetitive stimulations and (d) explore its modulation by current craving intensity. METHODS: Binge drinkers (n=42) and matched controls (n=43) performed a visual probe task, requiring visual targets preceded by pairs of pictures to be processed, with three conditions (i.e. alcohol vs. soft drink, alcohol vs. high-calorie food, high-calorie food vs. low-calorie food). RESULTS: No group difference was observed for early processing (i.e. first area of interest visited). Dwell times highlighted a bias towards soft drinks and healthy food among controls, without any global bias towards alcohol in binge drinkers. Centrally, a comparison of binge drinkers with low versus high current craving intensity indicated that binge drinking was associated with a bias towards alcohol and high-calorie food only in the presence of a high craving towards these stimuli. CONCLUSION: Attentional bias towards alcohol reported in severe AUD is only found in binge drinkers in the presence of high craving and is generalised to other appetitive cues.

Semantic associations between arithmetic and space: Evidence from temporal order judgements.

Spatial biases associated with subtraction or addition problem solving are generally considered as reflecting leftward or rightward attention shifts along a mental numerical continuum, but an alternative hypothesis not implying spatial attention proposes that the operator (plus or minus sign) may favour a response to one side of space (left or right) because of semantic associations. We tested these two accounts in a series of temporal order judgement experiments that consisted in the auditory presentation of addition or subtraction problems followed 200 ms (Experiments 1-2) or 800 ms (Experiment 3) later by the display of two lateralized targets in close temporal succession. To dissociate the side where the operation first brought their attention from the side they had to respond to, we asked participants to report which of the left or right target appeared first or last on screen. Under the attention-orienting account, addition should elicit more rightward responses than subtraction when participants have to focus on the first target, but more leftward responses when they have to focus on the last target, because the latter is opposite to the side where the operation first brought their attention. Under the semantic account, addition should elicit more rightward responses than subtraction, no matter the focus is on the first or last target, because participants should systematically favour the side conceptually linked to the operator. The results of the three experiments converge to indicate that, in lateralized target detection tasks, the spatial biases induced by arithmetic operations stem from semantic associations.

Eye position reflects the spatial coding of numbers during magnitude comparison.

Behavioral studies have reported interactions between number processing and spatial attention, suggesting that number processing involves shifting attention along a mental continuum on which numbers are represented in ascending order. However, direct evidence for attention shifts remains scarce, the respective contribution of the horizontal and vertical axes is unclear, and little is known about the time course of attention shifts during mental manipulation of numbers. In the present study, we used an eye-tracking device with a high spatiotemporal resolution to measure gaze patterns in a task that required participants to compare number words (20 to 70) to a fixed reference (45) while looking at a blank screen (Experiment 1) or at colorful pictures (Experiment 2). Experiment 1 revealed late attention shifts evoking an epiphenomenon rather than a functional process because they occurred after the response. Experiment 2 revealed horizontal and vertical attention shifts emerging during the first stages of the comparison process. A leftward and downward ocular drift was observed while participants were listening to numbers smaller than the reference compared to numbers larger than the reference. The results showed that earlier shifts were observed when numbers were far from the reference because the decade was sufficiently discriminating to allow a fast decision. In contrast, close numbers were associated with later attention shifts because their proximity with the reference required processing the unit. We conclude that number comparison is a dynamic process that exploits visual imagery mechanisms to magnify the position of numbers on a two-dimensional space representing their magnitude. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The development of a new questionnaire for cognitive complaints in vertigo: the Neuropsychological Vertigo Inventory (NVI).

Vertigo patients frequently complain of emotional and associated cognitive problems, yet currently, there is no satisfactory questionnaire to measure these associated problems. In the present paper, we propose a new internet-based Neuropsychological Vertigo Inventory (NVI; French) that evaluates attention, memory, emotion, space perception, time perception, vision, and motor abilities. The questionnaire was created using four steps: (1) open interviews with patients suffering from vertigo; (2) semi-structured interviews with an analysis grid to quantify and define the various cognitive and emotional problems reported by the patients; (3) a first version of an internet questionnaire tested on 108 vertigo participants; and (4) the selection of subscale items using principal component analyses (PCA). From the development phase, the revised NVI was composed of seven subscales, each with four items (28 items). In the validation phase, Cronbach's alphas were performed on the revised NVI for total and each subscale score, and to test extreme groups validity, the analyses of covariance (ANCOVAs) taking into account age were performed between 108 vertigo and 104 non-vertigo participants. The Cronbach's alphas showed good to satisfactory coefficients for the total and for all subscale scores, demonstrating acceptable reliability. The extreme groups validity analyses (ANCOVAs) were reliable for the total scale and for four subscales. Supplementary analyses showed no effect of hearing difficulties and an inverse age effect for attention and emotion subscales, with reduced problems with increased age in the vertigo participants. The NVI provides a useful new questionnaire to determine cognitive and emotional neuropsychological complaints that are associated with vertigo.