Multiply robust estimation for causal survival analysis with treatment noncompliance

Comparative effectiveness research with randomized trials or observational studies frequently addresses a time-to-event outcome and can require unique considerations in the presence of treatment noncompliance. Motivated by the challenges in addressing noncompliance in the ADAPTABLE pragmatic trial, we develop a multiply robust estimator to estimate the principal survival causal effects under the principal ignorability and monotonicity assumption. The multiply robust estimator involves several working models including that for the treatment assignment, the compliance strata, censoring, and time to event of interest. We demonstrate that the proposed estimator is consistent even if one, and sometimes two, of the working models are incorrectly specified. We further contribute sensitivity analysis strategies for investigating the robustness of the multiply robust estimator under violation of two identification assumptions specific to noncompliance. We implement the multiply robust method in the ADAPTABLE trial to evaluate the effect of low- versus high-dose aspirin assignment on patients' death and hospitalization from cardiovascular diseases, and further obtain the causal effect estimates when the identification assumptions fail to hold. We find that, comparing to low-dose assignment, assignment to the high-dose leads to differential effects among always high-dose takers, compliers, and always low-dose takers. Such treatment effect heterogeneity contributes to the null intention-to-treatment effect, and suggests that policy makers should design personalized strategies based on potential compliance patterns to maximize treatment benefits to the entire study population

The Dynamic Transcriptional Cell Atlas of Testis Development during Human Puberty

The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of similar to 10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty

Neuromatch Academy: Teaching Computational Neuroscience with global accessibility

Neuromatch Academy designed and ran a fully online 3-week Computational Neuroscience summer school for 1757 students with 191 teaching assistants working in virtual inverted (or flipped) classrooms and on small group projects. Fourteen languages, active community management, and low cost allowed for an unprecedented level of inclusivity and universal accessibility.Comment: 10 pages, 3 figures. Equal contribution by the executive committee members of Neuromatch Academy: Tara van Viegen, Athena Akrami, Kate Bonnen, Eric DeWitt, Alexandre Hyafil, Helena Ledmyr, Grace W. Lindsay, Patrick Mineault, John D. Murray, Xaq Pitkow, Aina Puce, Madineh Sedigh-Sarvestani, Carsen Stringer. and equal contribution by the board of directors of Neuromatch Academy: Gunnar Blohm, Konrad Kording, Paul Schrater, Brad Wyble, Sean Escola, Megan A. K. Peter

Neuromatch Academy: a 3-week, online summer school in computational neuroscience

Neuromatch Academy (https://academy.neuromatch.io; (van Viegen et al., 2021)) was designed as an online summer school to cover the basics of computational neuroscience in three weeks. The materials cover dominant and emerging computational neuroscience tools, how they complement one another, and specifically focus on how they can help us to better understand how the brain functions. An original component of the materials is its focus on modeling choices, i.e. how do we choose the right approach, how do we build models, and how can we evaluate models to determine if they provide real (meaningful) insight. This meta-modeling component of the instructional materials asks what questions can be answered by different techniques, and how to apply them meaningfully to get insight about brain function

FUNCTIONAL ORGANIZATIONS IN THE AUDITORY CORTEX OF THE COMMON MARMOSET INVESTIGATED BY OPTICAL IMAGING METHODS

The auditory cortex of non-human primates is composed of three hierarchies: core, belt and parabelt. While previous studies have extensively investigated the core region of the auditory cortex with tonal stimuli, how the auditory cortex is spatially organized to represent complex sounds, especially in the secondary auditory regions (belt and parabelt), is still poorly understood. In this study, we sought to address this fundamental question in the common marmoset (Callithrix jacchus), a highly vocal New World monkey species that has garnered considerable interest in recent years as a promising non-human primate model in neuroscience. We developed chronic optical imaging techniques to obtain wide-field intrinsic and calcium signals from the auditory cortex in awake marmosets through a removable imaging window. Using this method, we recorded neural responses over a large area of the auditory cortex to different acoustic stimuli, including synthetic sounds (pure tones and dynamic ripples), natural sounds, and conspecific vocalizations. First, we mapped out the tuning for pure tone frequencies and revealed a reliable new gradient from RT to parabelt. We also uncovered a spectral modulation gradient along the lateral-medial axis with dynamic ripple stimuli and natural sounds. We then applied an unsupervised matrix decomposition method to analyze natural sound responses to identify canonical functional components (subregions) in the auditory cortex. These components were shown to be selective to different acoustic features and relatively consistent across subjects, thus providing new views on how the auditory cortex could be divided based on its functional characteristics. Finally, we identified areas in the auditory cortex that were selective to marmoset vocalizations, and observed distinct representations of different marmoset call types. The newly discovered high frequency sensitive area in parabelt was further investigated by two-photon calcium imaging, which revealed spatially clustered neural populations that were selective to phee and twitter calls. Our chronic optical imaging results provided new insights to the functional organization principles of the primate auditory cortex beyond the traditional description of tonotopy

A Study of Auditory Perceptual Capacity of Certain Musical Elements in a Non-human Primate Species, the Common Marmoset (Callithix jacchus)

It has long been debated whether music is unique to human, as man is the only species that actively produces and listens to music for entertainment and social interaction purposes. In this thesis, I investigated the ability of perceiving and innate preference for music elements in the common marmosets (callithrix jacchus), a highly vocal New-World monkey, which has emerged in recent years as a promising animal model in auditory research. We first characterized marmoset’s fundamental auditory perceptual abilities of discriminating pitch, the most fundamental element in music. Marmosets were trained on a discrimination task using operant conditioning procedures. We then measured the minimum change in frequency (i.e., the frequency difference limen, or FDL) that marmosets could detect using pure tones at eight frequencies with an octave spacing, covering their entire hearing range. We also tested with harmonic complex tones, a common sound type in music, at four different fundamental frequencies to measure their fundamental frequency difference limen (F0DL). These results revealed that marmosets have relatively fine pitch discrimination capacities, with FDL ranging from ~2.6 semitones to ~0.4 semitones, and F0DL ranging from ~1.6 semitones to ~0.4 semitones, depending on the test frequency. These characterizations help guide further studies of auditory behaviors of this species. Given marmoset’s capacity of discriminating musical pitch, I further investigated their high-level cognition about innate preferences in music aesthetics in terms of musical consonance and dissonance. Spontaneous behaviors were measured using a V-shaped maze with two branches, to test whether marmosets prefer consonant over dissonant music as we humans do. A customized program was used to detect and record an animal’s location in the maze (left or right branch), then select a stimulus to play through a speaker. One sound was played when the test subject moved into one branch, and a different sound was played when the test subject moved into the other branch. Thus the proportion of time an animal spent at each side serves as an indicator of its preference for the associated sound. The results showed that marmosets did not prefer consonant over dissonant stimuli in this test setting, although they did show preference of silence over white noise in the same setting. Further studies are needed to confirm this finding. Nevertheless, these results provide more insights into the evolutionary origin of music