Estimating causal effects for binary outcomes using per-decision inverse probability weighting.

Micro-randomized trials are commonly conducted for optimizing mobile health interventions such as push notifications for behavior change. In analyzing such trials, causal excursion effects are often of primary interest, and their estimation typically involves inverse probability weighting (IPW). However, in a micro-randomized trial, additional treatments can often occur during the time window over which an outcome is defined, and this can greatly inflate the variance of the causal effect estimator because IPW would involve a product of numerous weights. To reduce variance and improve estimation efficiency, we propose two new estimators using a modified version of IPW, which we call "per-decision IPW." The second estimator further improves efficiency using the projection idea from the semiparametric efficiency theory. These estimators are applicable when the outcome is binary and can be expressed as the maximum of a series of sub-outcomes defined over sub-intervals of time. We establish the estimators' consistency and asymptotic normality. Through simulation studies and real data applications, we demonstrate substantial efficiency improvement of the proposed estimator over existing estimators. The new estimators can be used to improve the precision of primary and secondary analyses for micro-randomized trials with binary outcomes.

The influence of the topographic location of geographic atrophy on vision-related quality of life in nonexudative age-related macular degeneration.

PURPOSE: To examine associations between the topographic distribution of geographic atrophy (GA) and vision-related quality of life (VRQoL). METHODS: This study included 237 eyes from 161 participants in the Age-Related Eye Disease Study (AREDS). GA lesions were manually delineated with color fundus photographs obtained by the AREDS Research Group and atrophic area was measured in an Early Treatment Diabetic Retinopathy Study (ETDRS) grid. VRQoL was measured using the National Eye Institute Visual Function Questionnaire (NEI-VFQ). Area of atrophy in the ETDRS grid subfields was correlated with VRQoL by linear regression modeling. RESULTS: The average area of atrophy in the better and worse eye was 3.43mm2 and 7.15mm2 respectively. In multivariable analysis, VRQoL was not associated with total area of atrophy in the better eye (ß, - 0.53; 95% confidence interval [CI], - 1.11 to 0.05; P = 0.07) or worse eye (ß, 0.12; 95% CI, - 0.32 to 0.55; P = 0.59). However, area of atrophy in the central 1-mm-diameter zone of the better eye was significantly associated with VRQoL when the ETDRS subfields were examined individually (ß, - 14.57; 95% CI, - 27.12 to - 2.02; P = 0.023), grouped into quadrants (ß, - 18.35; 95% CI, - 30.03 to - 6.67; P = 0.002), inner and outer zones (ß, - 17.26; 95% CI, - 29.38 to - 5.14; P = 0.006), or vertical and horizontal zones (ß, - 18.97; 95% CI, - 30.18 to - 7.77; P = 0.001). CONCLUSION: In patients with GA, greater area of atrophy in the central 1-mm-diameter zone of the better eye was independently associated with lower VRQoL, while total area of atrophy in the better or worse eye was not.

A base editor for the long-term restoration of auditory function in mice with recessive profound deafness.

A prevalent recessive mutation (c.2485C>T, p.Q829X) within the OTOF gene leads to profound prelingual hearing loss. Here we show that in Otof mice harbouring a mutation (c.2482C>T, p.Q828X) homozygous to human OTOF that faithfully mimics the hearing-loss phenotype, a base editor (consisting of the deaminase ABE7.10max and the Cas9 variant SpCas9-NG) packaged in adeno-associated viruses and injected into the inner ear of the mice via the round-window membrane effectively corrected the pathogenic mutation, with no apparent off-target effects. The treatment restored the levels of the otoferlin protein in 88% of the inner hair cells and stably rescued the auditory function of the mice to near-wild-type levels for over 1.5 years while improving synaptic exocytosis in the inner hair cells. We also show that an adenine base editor that targets the prevalent human OTOF mutation restored hearing in humanized mice to levels comparable to those of the wild-type counterparts. Base editors may be effective for the treatment of hereditary deafness.

How Notifications Affect Engagement With a Behavior Change App: Results From a Micro-Randomized Trial.

BACKGROUND: Drink Less is a behavior change app to help higher-risk drinkers in the United Kingdom reduce their alcohol consumption. The app includes a daily notification asking users to "Please complete your drinks and mood diary," yet we did not understand the causal effect of the notification on engagement nor how to improve this component of Drink Less. We developed a new bank of 30 new messages to increase users' reflective motivation to engage with Drink Less. This study aimed to determine how standard and new notifications affect engagement. OBJECTIVE: Our objective was to estimate the causal effect of the notification on near-term engagement, to explore whether this effect changed over time, and to create an evidence base to further inform the optimization of the notification policy. METHODS: We conducted a micro-randomized trial (MRT) with 2 additional parallel arms. Inclusion criteria were Drink Less users who consented to participate in the trial, self-reported a baseline Alcohol Use Disorders Identification Test score of ≥8, resided in the United Kingdom, were aged ≥18 years, and reported interest in drinking less alcohol. Our MRT randomized 350 new users to test whether receiving a notification, compared with receiving no notification, increased the probability of opening the app in the subsequent hour, over the first 30 days since downloading Drink Less. Each day at 8 PM, users were randomized with a 30% probability of receiving the standard message, a 30% probability of receiving a new message, or a 40% probability of receiving no message. We additionally explored time to disengagement, with the allocation of 60% of eligible users randomized to the MRT (n=350) and 40% of eligible users randomized in equal number to the 2 parallel arms, either receiving the no notification policy (n=98) or the standard notification policy (n=121). Ancillary analyses explored effect moderation by recent states of habituation and engagement. RESULTS: Receiving a notification, compared with not receiving a notification, increased the probability of opening the app in the next hour by 3.5-fold (95% CI 2.91-4.25). Both types of messages were similarly effective. The effect of the notification did not change significantly over time. A user being in a state of already engaged lowered the new notification effect by 0.80 (95% CI 0.55-1.16), although not significantly. Across the 3 arms, time to disengagement was not significantly different. CONCLUSIONS: We found a strong near-term effect of engagement on the notification, but no overall difference in time to disengagement between users receiving the standard fixed notification, no notification at all, or the random sequence of notifications within the MRT. The strong near-term effect of the notification presents an opportunity to target notifications to increase "in-the-moment" engagement. Further optimization is required to improve the long-term engagement. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/18690.