Statistical controversies in clinical research: futility analyses in oncology-lessons on potential pitfalls from a randomized controlled trial.

BACKGROUND: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER: NCT00806819.

Lateralized auditory spatial perception and the contralaterality of cortical processing as studied with functional magnetic resonance imaging and magnetoencephalography.

Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) were used to study the relationships between lateralized auditory perception in humans and the contralaterality of processing in auditory cortex. Subjects listened to rapidly presented streams of short FM-sweep tone bursts to detect infrequent, slightly deviant tone bursts. The stimulus streams consisted of either monaural stimuli to one ear or the other or binaural stimuli with brief interaural onset delays. The onset delay gives the binaural sounds a lateralized auditory perception and is thought to be a key component of how our brains localize sounds in space. For the monaural stimuli, fMRI revealed a clear contralaterality in auditory cortex, with a contralaterality index (contralateral activity divided by the sum of contralateral and ipsilateral activity) of 67%. In contrast, the fMRI activations from the laterally perceived binaural stimuli indicated little or no contralaterality (index of 51%). The MEG recordings from the same subjects performing the same task converged qualitatively with the fMRI data, confirming a clear monaural contralaterality, with no contralaterality for the laterally perceived binaurals. However, the MEG monaural contralaterality (55%) was less than the fMRI and decreased across the several hundred millisecond poststimulus time period, going from 57% in the M50 latency range (20-70 ms) to 53% in the M200 range (170-250 ms). These data sets provide both quantification of the degree of contralaterality in the auditory pathways and insight into the locus and mechanism of the lateralized perception of spatially lateralized sounds.

Electrodynamic headphones and woofers for application in magnetic resonance imaging scanners.

Electrodynamic speakers compatible with (functional) magnetic resonance imaging (MRI) are described. The speakers magnets are removed, their function is replaced by the scanner's magnetic field, resulting in an uncommon but efficient operation. The method can be used with headphones as well as woofers. Functional MRI is not associated with any known biological risks, but as a method for visualization of task-specific activation of brain regions it is undesirably noisy. Thus, it requires both noise protection and efficient sound transmission systems for delivering acoustic stimuli to subjects. Woofers could possibly be used in active noise-control systems. The speakers described in this paper can be used for either task.

Functional magnetic resonance imaging of a human auditory cortex area involved in foreground-background decomposition.

Auditory foreground-background decomposition is a pattern recognition process which combines simultaneous and sequential grouping in complex sound sequences. Using functional magnetic resonance imaging with reduced scanner noise and stimulation through a new type of earphones, we investigated the possibility that this process activates topographically distinct areas of human auditory cortex. A basic matching-to-sample task with variable tones (sequential grouping) caused significant activity in three separate landmark-related territories on the supratemporal plane. A similar task in the presence of a strongly masking acoustic background pattern to challenge simultaneous grouping led to the distinction of the subterritory in which foreground signal-related or task-related signal properties were exclusively seen. In contrast to the remainder of territories the level of activity and the periodicity of the signal time-course was resistant to the masking influence of the background. This suggests that auditory foreground-background decomposition involves a specialized non-primary auditory cortex field. Generally, the findings demonstrate functional parcellation of auditory cortex for which the evidence in humans, in contrast to other primates, is only indirect to date.

Activation of human auditory cortex in retrieval experiments: an fMRI study.

In a previous functional magnetic resonance (fMRI) study, a subdivision of the human auditory cortex into four distinct territories was achieved. One territory (T1a) exhibited functional specialization in terms of a foreground-background decomposition task involving matching-to-sample monitoring on tone sequences. The present study more specifically determined whether memory-guided analysis of tone sequences is part of the T1a specialization. During the encoding periods, an arbitrary and unfamiliar four-tone-sequence (melody) played by one instrument was presented. The melody-instrument-combination was different in each period. During subsequent retrieval periods, learned and additional combinations were presented, and the tasks were either to detect the target melodies (experiment I) or the target instruments (experiment II). T1a showed larger activation during the melody retrieval. The results generally suggest that (1) activation of T1a during retrieval is determined less by the sound material than by the executed task, and (2) more specifically, that memory-guided sequential analysis in T1a is dominant over recognition of characteristic complex sounds.

Statistical methods in functional magnetic resonance imaging with respect to nonstationary time-series: auditory cortex activity.

In awake animal and human auditory cortices, it is a common experience with electrophysiological and suitable imaging methods for responses to steady stimulation to be strongly state-dependent and to exhibit nonstationarities, even over short periods of observation. If such nonstationary behavior is also reflected by hemodynamic responses in the human auditory cortex, conventional methods of analysis of fMRI data, although applicable for instance to largely stationary responses in visual and other cortices, may be misleading in attempts to parcellate auditory cortex into fields and to demonstrate functional maps. Time-Windows, described in this article as a convenient tool for the detection and analysis of time-variant brain activities, solves some of these problems. Time-Windows demonstrates that activity is evoked reliably in three separate territories of human auditory cortex, parts of which may show nonstationary behavior, depending on the auditory stimuli and tasks.

Lateralized processing of speech prosodies in the temporal cortex: a 3-T functional magnetic resonance imaging study.

Prosodic modulation of speech provides information about emotional states of speakers (affective prosodies) or serves as syntactic markers to change linguistic aspects of speech (linguistic prosodies). Previous electrophysiological investigations and studies on patients with right or left hemisphere damage showed nonuniform results with respect to lateralization of prosodic processing. In this study 20 healthy right-handed volunteers were investigated with functional magnetic resonance imaging of the acoustically responsive areas on the supratemporal plane while detecting phonemes as control targets or prosodies in strings of nonsense syllables and adjectives, the latter randomly intonated in a declarative, interrogative, commanding, happy, or sad fashion. In control task A the phoneme /a/ was detected in the syllables. In control task B the phoneme /a/ was detected in the adjectives, and in the experimental task C the sad intonations (affective) and in the experimental task D the interrogative intonations (linguistic) had to be detected in the same material. In task A intensity-weighted volumes of activated voxels were not different in the two hemispheres (laterality index 0). In task B with an irrelevant phoneme detection with respect to prosodic material, the population split into two subgroups with similar right or left hemispheric lateralization of activity leading to an absolute laterality index of 26.8 across all subjects. During detection of affective prosodies (task C), lateralization was maintained yet the absolute laterality index reduced to 14.5, while there was no lateralization during detection of linguistic prosodies. The sum of activations in the two hemispheres was the same across all tasks and subgroups, which suggests that the lateralizations occurring with presentation and detection of prosodic material depend on a redistribution of activity between hemispheres.