Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 165,912 US patients.

Patients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline). Here we present a data science framework to systematically characterize off-label and off-guideline usages using real-world data from de-identified electronic health records (EHR). We analyze treatment patterns in 165,912 US patients with 14 common cancer types. We find that 18.6% and 4.4% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analyses generate hypotheses about patients' response to treatments.

Comparative effectiveness between mosunetuzumab monotherapy clinical trial and real-world data in relapsed/refractory follicular lymphoma in third or subsequent lines of systemic therapy.

A comparison of clinical outcomes in the third or subsequent line (3 L+) of systemic therapy between a real-world data (RWD) external control cohort and a mosunetuzumab single-arm clinical trial cohort is presented. Data for 3 L + patients with relapsed/refractory follicular lymphoma (FL) were obtained from the mosunetuzumab single-arm trial (n = 90) and a US electronic health records database (n = 158), with patients meeting key eligibility criteria from the trial, balanced on pre-specified prognostic factors. Overall response and complete response rates were 80% and 60% in the mosunetuzumab cohort and 75% and 33% in the RWD cohort, odds ratios of 1.23 (95% CI, 0.52-2.93) and 3.18 (95% CI, 1.41-7.17), respectively. Hazard ratios for progression-free survival and overall survival were 0.82 (95% CI, 0.53-1.27) and 0.43 (95% CI, 0.19-0.94). These findings support a clinically meaningful benefit of mosunetuzumab monotherapy as a chemotherapy-free option for the 3 L + FL population.

Penalized regression for left-truncated and right-censored survival data.

High-dimensional data are becoming increasingly common in the medical field as large volumes of patient information are collected and processed by high-throughput screening, electronic health records, and comprehensive genomic testing. Statistical models that attempt to study the effects of many predictors on survival typically implement feature selection or penalized methods to mitigate the undesirable consequences of overfitting. In some cases survival data are also left-truncated which can give rise to an immortal time bias, but penalized survival methods that adjust for left truncation are not commonly implemented. To address these challenges, we apply a penalized Cox proportional hazards model for left-truncated and right-censored survival data and assess implications of left truncation adjustment on bias and interpretation. We use simulation studies and a high-dimensional, real-world clinico-genomic database to highlight the pitfalls of failing to account for left truncation in survival modeling.

A dynamic, ensemble learning approach to forecast dengue fever epidemic years in Brazil using weather and population susceptibility cycles.

Transmission of dengue fever depends on a complex interplay of human, climate and mosquito dynamics, which often change in time and space. It is well known that its disease dynamics are highly influenced by multiple factors including population susceptibility to infection as well as by microclimates: small-area climatic conditions which create environments favourable for the breeding and survival of mosquitoes. Here, we present a novel machine learning dengue forecasting approach, which, dynamically in time and space, identifies local patterns in weather and population susceptibility to make epidemic predictions at the city level in Brazil, months ahead of the occurrence of disease outbreaks. Weather-based predictions are improved when information on population susceptibility is incorporated, indicating that immunity is an important predictor neglected by most dengue forecast models. Given the generalizability of our methodology to any location or input data, it may prove valuable for public health decision-making aimed at mitigating the effects of seasonal dengue outbreaks in locations globally.

Nowcasting for Real-Time COVID-19 Tracking in New York City: An Evaluation Using Reportable Disease Data From Early in the Pandemic.

BACKGROUND: Nowcasting approaches enhance the utility of reportable disease data for trend monitoring by correcting for delays, but implementation details affect accuracy. OBJECTIVE: To support real-time COVID-19 situational awareness, the New York City Department of Health and Mental Hygiene used nowcasting to account for testing and reporting delays. We conducted an evaluation to determine which implementation details would yield the most accurate estimated case counts. METHODS: A time-correlated Bayesian approach called Nowcasting by Bayesian Smoothing (NobBS) was applied in real time to line lists of reportable disease surveillance data, accounting for the delay from diagnosis to reporting and the shape of the epidemic curve. We retrospectively evaluated nowcasting performance for confirmed case counts among residents diagnosed during the period from March to May 2020, a period when the median reporting delay was 2 days. RESULTS: Nowcasts with a 2-week moving window and a negative binomial distribution had lower mean absolute error, lower relative root mean square error, and higher 95% prediction interval coverage than nowcasts conducted with a 3-week moving window or with a Poisson distribution. Nowcasts conducted toward the end of the week outperformed nowcasts performed earlier in the week, given fewer patients diagnosed on weekends and lack of day-of-week adjustments. When estimating case counts for weekdays only, metrics were similar across days when the nowcasts were conducted, with Mondays having the lowest mean absolute error of 183 cases in the context of an average daily weekday case count of 2914. CONCLUSIONS: Nowcasting using NobBS can effectively support COVID-19 trend monitoring. Accounting for overdispersion, shortening the moving window, and suppressing diagnoses on weekends-when fewer patients submitted specimens for testing-improved the accuracy of estimated case counts. Nowcasting ensured that recent decreases in observed case counts were not overinterpreted as true declines and supported officials in anticipating the magnitude and timing of hospitalizations and deaths and allocating resources geographically.

Rates of increase of antibiotic resistance and ambient temperature in Europe: a cross-national analysis of 28 countries between 2000 and 2016.

BackgroundThe rapid increase of bacterial antibiotic resistance could soon render our most effective method to address infections obsolete. Factors influencing pathogen resistance prevalence in human populations remain poorly described, though temperature is known to contribute to mechanisms of spread.AimTo quantify the role of temperature, spatially and temporally, as a mechanistic modulator of transmission of antibiotic resistant microbes.MethodsAn ecologic analysis was performed on country-level antibiotic resistance prevalence in three common bacterial pathogens across 28 European countries, collectively representing over 4 million tested isolates. Associations of minimum temperature and other predictors with change in antibiotic resistance rates over 17 years (2000-2016) were evaluated with multivariable models. The effects of predictors on the antibiotic resistance rate change across geographies were quantified.ResultsDuring 2000-2016, for Escherichia coli and Klebsiella pneumoniae, European countries with 10°C warmer ambient minimum temperatures compared to others, experienced more rapid resistance increases across all antibiotic classes. Increases ranged between 0.33%/year (95% CI: 0.2 to 0.5) and 1.2%/year (95% CI: 0.4 to 1.9), even after accounting for recognised resistance drivers including antibiotic consumption and population density. For Staphylococcus aureus a decreasing relationship of -0.4%/year (95% CI: -0.7 to 0.0) was found for meticillin resistance, reflecting widespread declines in meticillin-resistant S. aureus across Europe over the study period.ConclusionWe found evidence of a long-term effect of ambient minimum temperature on antibiotic resistance rate increases in Europe. Ambient temperature might considerably influence antibiotic resistance growth rates, and explain geographic differences observed in cross-sectional studies. Rising temperatures globally may hasten resistance spread, complicating mitigation efforts.

Evaluation of Nowcasting for Real-Time COVID-19 Tracking - New York City, March-May 2020.

To account for delays between specimen collection and report, the New York City Department of Health and Mental Hygiene used a time-correlated Bayesian nowcasting approach to support real-time COVID-19 situational awareness. We retrospectively evaluated nowcasting performance for case counts among residents diagnosed during March-May 2020, a period when the median reporting delay was 2 days. Nowcasts with a 2-week moving window and a negative binomial distribution had lower mean absolute error, lower relative root mean square error, and higher 95% prediction interval coverage than nowcasts conducted with a 3-week moving window or with a Poisson distribution. Nowcasts conducted toward the end of the week outperformed nowcasts performed earlier in the week, given fewer patients diagnosed on weekends and lack of day-of-week adjustments. When estimating case counts for weekdays only, metrics were similar across days the nowcasts were conducted, with Mondays having the lowest mean absolute error, of 183 cases in the context of an average daily weekday case count of 2,914. Nowcasting ensured that recent decreases in observed case counts were not overinterpreted as true declines and supported health department leadership in anticipating the magnitude and timing of hospitalizations and deaths and allocating resources geographically.

Real-time estimation of disease activity in emerging outbreaks using internet search information.

Understanding the behavior of emerging disease outbreaks in, or ahead of, real-time could help healthcare officials better design interventions to mitigate impacts on affected populations. Most healthcare-based disease surveillance systems, however, have significant inherent reporting delays due to data collection, aggregation, and distribution processes. Recent work has shown that machine learning methods leveraging a combination of traditionally collected epidemiological information and novel Internet-based data sources, such as disease-related Internet search activity, can produce meaningful "nowcasts" of disease incidence ahead of healthcare-based estimates, with most successful case studies focusing on endemic and seasonal diseases such as influenza and dengue. Here, we apply similar computational methods to emerging outbreaks in geographic regions where no historical presence of the disease of interest has been observed. By combining limited available historical epidemiological data available with disease-related Internet search activity, we retrospectively estimate disease activity in five recent outbreaks weeks ahead of traditional surveillance methods. We find that the proposed computational methods frequently provide useful real-time incidence estimates that can help fill temporal data gaps resulting from surveillance reporting delays. However, the proposed methods are limited by issues of sample bias and skew in search query volumes, perhaps as a result of media coverage.

Nowcasting by Bayesian Smoothing: A flexible, generalizable model for real-time epidemic tracking.

Achieving accurate, real-time estimates of disease activity is challenged by delays in case reporting. "Nowcast" approaches attempt to estimate the complete case counts for a given reporting date, using a time series of case reports that is known to be incomplete due to reporting delays. Modeling the reporting delay distribution is a common feature of nowcast approaches. However, many nowcast approaches ignore a crucial feature of infectious disease transmission-that future cases are intrinsically linked to past reported cases-and are optimized to one or two applications, which may limit generalizability. Here, we present a Bayesian approach, NobBS (Nowcasting by Bayesian Smoothing) capable of producing smooth and accurate nowcasts in multiple disease settings. We test NobBS on dengue in Puerto Rico and influenza-like illness (ILI) in the United States to examine performance and robustness across settings exhibiting a range of common reporting delay characteristics (from stable to time-varying), and compare this approach with a published nowcasting software package while investigating the features of each approach that contribute to good or poor performance. We show that introducing a temporal relationship between cases considerably improves performance when the reporting delay distribution is time-varying, and we identify trade-offs in the role of moving windows to accurately capture changes in the delay. We present software implementing this new approach (R package "NobBS") for widespread application and provide practical guidance on implementation.

Forecasting Zika Incidence in the 2016 Latin America Outbreak Combining Traditional Disease Surveillance with Search, Social Media, and News Report Data.

BACKGROUND: Over 400,000 people across the Americas are thought to have been infected with Zika virus as a consequence of the 2015-2016 Latin American outbreak. Official government-led case count data in Latin America are typically delayed by several weeks, making it difficult to track the disease in a timely manner. Thus, timely disease tracking systems are needed to design and assess interventions to mitigate disease transmission. METHODOLOGY/PRINCIPAL FINDINGS: We combined information from Zika-related Google searches, Twitter microblogs, and the HealthMap digital surveillance system with historical Zika suspected case counts to track and predict estimates of suspected weekly Zika cases during the 2015-2016 Latin American outbreak, up to three weeks ahead of the publication of official case data. We evaluated the predictive power of these data and used a dynamic multivariable approach to retrospectively produce predictions of weekly suspected cases for five countries: Colombia, El Salvador, Honduras, Venezuela, and Martinique. Models that combined Google (and Twitter data where available) with autoregressive information showed the best out-of-sample predictive accuracy for 1-week ahead predictions, whereas models that used only Google and Twitter typically performed best for 2- and 3-week ahead predictions. SIGNIFICANCE: Given the significant delay in the release of official government-reported Zika case counts, we show that these Internet-based data streams can be used as timely and complementary ways to assess the dynamics of the outbreak.