The US COVID-19 Trends and Impact Survey: Continuous real-time measurement of COVID-19 symptoms, risks, protective behaviors, testing, and vaccination.

The US COVID-19 Trends and Impact Survey (CTIS) is a large, cross-sectional, internet-based survey that has operated continuously since April 6, 2020. By inviting a random sample of Facebook active users each day, CTIS collects information about COVID-19 symptoms, risks, mitigating behaviors, mental health, testing, vaccination, and other key priorities. The large scale of the survey-over 20 million responses in its first year of operation-allows tracking of trends over short timescales and allows comparisons at fine demographic and geographic detail. The survey has been repeatedly revised to respond to emerging public health priorities. In this paper, we describe the survey methods and content and give examples of CTIS results that illuminate key patterns and trends and help answer high-priority policy questions relevant to the COVID-19 epidemic and response. These results demonstrate how large online surveys can provide continuous, real-time indicators of important outcomes that are not subject to public health reporting delays and backlogs. The CTIS offers high value as a supplement to official reporting data by supplying essential information about behaviors, attitudes toward policy and preventive measures, economic impacts, and other topics not reported in public health surveillance systems.

Recalibrating probabilistic forecasts of epidemics.

Distributional forecasts are important for a wide variety of applications, including forecasting epidemics. Often, forecasts are miscalibrated, or unreliable in assigning uncertainty to future events. We present a recalibration method that can be applied to a black-box forecaster given retrospective forecasts and observations, as well as an extension to make this method more effective in recalibrating epidemic forecasts. This method is guaranteed to improve calibration and log score performance when trained and measured in-sample. We also prove that the increase in expected log score of a recalibrated forecaster is equal to the entropy of the PIT distribution. We apply this recalibration method to the 27 influenza forecasters in the FluSight Network and show that recalibration reliably improves forecast accuracy and calibration. This method, available on Github, is effective, robust, and easy to use as a post-processing tool to improve epidemic forecasts.

A collaborative multiyear, multimodel assessment of seasonal influenza forecasting in the United States.

Influenza infects an estimated 9-35 million individuals each year in the United States and is a contributing cause for between 12,000 and 56,000 deaths annually. Seasonal outbreaks of influenza are common in temperate regions of the world, with highest incidence typically occurring in colder and drier months of the year. Real-time forecasts of influenza transmission can inform public health response to outbreaks. We present the results of a multiinstitution collaborative effort to standardize the collection and evaluation of forecasting models for influenza in the United States for the 2010/2011 through 2016/2017 influenza seasons. For these seven seasons, we assembled weekly real-time forecasts of seven targets of public health interest from 22 different models. We compared forecast accuracy of each model relative to a historical baseline seasonal average. Across all regions of the United States, over half of the models showed consistently better performance than the historical baseline when forecasting incidence of influenza-like illness 1 wk, 2 wk, and 3 wk ahead of available data and when forecasting the timing and magnitude of the seasonal peak. In some regions, delays in data reporting were strongly and negatively associated with forecast accuracy. More timely reporting and an improved overall accessibility to novel and traditional data sources are needed to improve forecasting accuracy and its integration with real-time public health decision making.

An open challenge to advance probabilistic forecasting for dengue epidemics.

A wide range of research has promised new tools for forecasting infectious disease dynamics, but little of that research is currently being applied in practice, because tools do not address key public health needs, do not produce probabilistic forecasts, have not been evaluated on external data, or do not provide sufficient forecast skill to be useful. We developed an open collaborative forecasting challenge to assess probabilistic forecasts for seasonal epidemics of dengue, a major global public health problem. Sixteen teams used a variety of methods and data to generate forecasts for 3 epidemiological targets (peak incidence, the week of the peak, and total incidence) over 8 dengue seasons in Iquitos, Peru and San Juan, Puerto Rico. Forecast skill was highly variable across teams and targets. While numerous forecasts showed high skill for midseason situational awareness, early season skill was low, and skill was generally lowest for high incidence seasons, those for which forecasts would be most valuable. A comparison of modeling approaches revealed that average forecast skill was lower for models including biologically meaningful data and mechanisms and that both multimodel and multiteam ensemble forecasts consistently outperformed individual model forecasts. Leveraging these insights, data, and the forecasting framework will be critical to improve forecast skill and the application of forecasts in real time for epidemic preparedness and response. Moreover, key components of this project-integration with public health needs, a common forecasting framework, shared and standardized data, and open participation-can help advance infectious disease forecasting beyond dengue.

Accuracy of real-time multi-model ensemble forecasts for seasonal influenza in the U.S.

Seasonal influenza results in substantial annual morbidity and mortality in the United States and worldwide. Accurate forecasts of key features of influenza epidemics, such as the timing and severity of the peak incidence in a given season, can inform public health response to outbreaks. As part of ongoing efforts to incorporate data and advanced analytical methods into public health decision-making, the United States Centers for Disease Control and Prevention (CDC) has organized seasonal influenza forecasting challenges since the 2013/2014 season. In the 2017/2018 season, 22 teams participated. A subset of four teams created a research consortium called the FluSight Network in early 2017. During the 2017/2018 season they worked together to produce a collaborative multi-model ensemble that combined 21 separate component models into a single model using a machine learning technique called stacking. This approach creates a weighted average of predictive densities where the weight for each component is determined by maximizing overall ensemble accuracy over past seasons. In the 2017/2018 influenza season, one of the largest seasonal outbreaks in the last 15 years, this multi-model ensemble performed better on average than all individual component models and placed second overall in the CDC challenge. It also outperformed the baseline multi-model ensemble created by the CDC that took a simple average of all models submitted to the forecasting challenge. This project shows that collaborative efforts between research teams to develop ensemble forecasting approaches can bring measurable improvements in forecast accuracy and important reductions in the variability of performance from year to year. Efforts such as this, that emphasize real-time testing and evaluation of forecasting models and facilitate the close collaboration between public health officials and modeling researchers, are essential to improving our understanding of how best to use forecasts to improve public health response to seasonal and emerging epidemic threats.

Active deep learning to detect demographic traits in free-form clinical notes.

The free-form portions of clinical notes are a significant source of information for research, but before they can be used, they must be de-identified to protect patients' privacy. De-identification efforts have focused on known identifier types (names, ages, dates, addresses, ID's, etc.). However, a note can contain residual "Demographic Traits" (DTs), unique enough to re-identify the patient when combined with other such facts. Here we examine whether any residual risks remain after removing these identifiers. After manually annotating over 140,000 words worth of medical notes, we found no remaining directly identifying information, and a low prevalence of demographic traits, such as marital status or housing type. We developed an annotation guide to the discovered Demographic Traits (DTs) and used it to label MIMIC-III and i2b2-2006 clinical notes as test sets. We then designed a "bootstrapped" active learning iterative process for identifying DTs: we tentatively labeled as positive all sentences in the DT-rich note sections, used these to train a binary classifier, manually corrected acute errors, and retrained the classifier. This train-and-correct process may be iterated. Our active learning process significantly improved the classifier's accuracy. Moreover, our BERT-based model outperformed non-neural models when trained on both tentatively labeled data and manually relabeled examples. To facilitate future research and benchmarking, we also produced and made publicly available our human annotated DT-tagged datasets. We conclude that directly identifying information is virtually non-existent in the multiple medical note types we investigated. Demographic traits are present in medical notes, but can be detected with high accuracy using a cost-effective human-in-the-loop active learning process, and redacted if desired.2.

Nonmechanistic forecasts of seasonal influenza with iterative one-week-ahead distributions.

Accurate and reliable forecasts of seasonal epidemics of infectious disease can assist in the design of countermeasures and increase public awareness and preparedness. This article describes two main contributions we made recently toward this goal: a novel approach to probabilistic modeling of surveillance time series based on "delta densities", and an optimization scheme for combining output from multiple forecasting methods into an adaptively weighted ensemble. Delta densities describe the probability distribution of the change between one observation and the next, conditioned on available data; chaining together nonparametric estimates of these distributions yields a model for an entire trajectory. Corresponding distributional forecasts cover more observed events than alternatives that treat the whole season as a unit, and improve upon multiple evaluation metrics when extracting key targets of interest to public health officials. Adaptively weighted ensembles integrate the results of multiple forecasting methods, such as delta density, using weights that can change from situation to situation. We treat selection of optimal weightings across forecasting methods as a separate estimation task, and describe an estimation procedure based on optimizing cross-validation performance. We consider some details of the data generation process, including data revisions and holiday effects, both in the construction of these forecasting methods and when performing retrospective evaluation. The delta density method and an adaptively weighted ensemble of other forecasting methods each improve significantly on the next best ensemble component when applied separately, and achieve even better cross-validated performance when used in conjunction. We submitted real-time forecasts based on these contributions as part of CDC's 2015/2016 FluSight Collaborative Comparison. Among the fourteen submissions that season, this system was ranked by CDC as the most accurate.

A human judgment approach to epidemiological forecasting.

Infectious diseases impose considerable burden on society, despite significant advances in technology and medicine over the past century. Advanced warning can be helpful in mitigating and preparing for an impending or ongoing epidemic. Historically, such a capability has lagged for many reasons, including in particular the uncertainty in the current state of the system and in the understanding of the processes that drive epidemic trajectories. Presently we have access to data, models, and computational resources that enable the development of epidemiological forecasting systems. Indeed, several recent challenges hosted by the U.S. government have fostered an open and collaborative environment for the development of these technologies. The primary focus of these challenges has been to develop statistical and computational methods for epidemiological forecasting, but here we consider a serious alternative based on collective human judgment. We created the web-based "Epicast" forecasting system which collects and aggregates epidemic predictions made in real-time by human participants, and with these forecasts we ask two questions: how accurate is human judgment, and how do these forecasts compare to their more computational, data-driven alternatives? To address the former, we assess by a variety of metrics how accurately humans are able to predict influenza and chikungunya trajectories. As for the latter, we show that real-time, combined human predictions of the 2014-2015 and 2015-2016 U.S. flu seasons are often more accurate than the same predictions made by several statistical systems, especially for short-term targets. We conclude that there is valuable predictive power in collective human judgment, and we discuss the benefits and drawbacks of this approach.

Flexible Modeling of Epidemics with an Empirical Bayes Framework.

Seasonal influenza epidemics cause consistent, considerable, widespread loss annually in terms of economic burden, morbidity, and mortality. With access to accurate and reliable forecasts of a current or upcoming influenza epidemic's behavior, policy makers can design and implement more effective countermeasures. This past year, the Centers for Disease Control and Prevention hosted the "Predict the Influenza Season Challenge", with the task of predicting key epidemiological measures for the 2013-2014 U.S. influenza season with the help of digital surveillance data. We developed a framework for in-season forecasts of epidemics using a semiparametric Empirical Bayes framework, and applied it to predict the weekly percentage of outpatient doctors visits for influenza-like illness, and the season onset, duration, peak time, and peak height, with and without using Google Flu Trends data. Previous work on epidemic modeling has focused on developing mechanistic models of disease behavior and applying time series tools to explain historical data. However, tailoring these models to certain types of surveillance data can be challenging, and overly complex models with many parameters can compromise forecasting ability. Our approach instead produces possibilities for the epidemic curve of the season of interest using modified versions of data from previous seasons, allowing for reasonable variations in the timing, pace, and intensity of the seasonal epidemics, as well as noise in observations. Since the framework does not make strict domain-specific assumptions, it can easily be applied to some other diseases with seasonal epidemics. This method produces a complete posterior distribution over epidemic curves, rather than, for example, solely point predictions of forecasting targets. We report prospective influenza-like-illness forecasts made for the 2013-2014 U.S. influenza season, and compare the framework's cross-validated prediction error on historical data to that of a variety of simpler baseline predictors.

Results from the centers for disease control and prevention's predict the 2013-2014 Influenza Season Challenge.

BACKGROUND: Early insights into the timing of the start, peak, and intensity of the influenza season could be useful in planning influenza prevention and control activities. To encourage development and innovation in influenza forecasting, the Centers for Disease Control and Prevention (CDC) organized a challenge to predict the 2013-14 Unites States influenza season. METHODS: Challenge contestants were asked to forecast the start, peak, and intensity of the 2013-2014 influenza season at the national level and at any or all Health and Human Services (HHS) region level(s). The challenge ran from December 1, 2013-March 27, 2014; contestants were required to submit 9 biweekly forecasts at the national level to be eligible. The selection of the winner was based on expert evaluation of the methodology used to make the prediction and the accuracy of the prediction as judged against the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet). RESULTS: Nine teams submitted 13 forecasts for all required milestones. The first forecast was due on December 2, 2013; 3/13 forecasts received correctly predicted the start of the influenza season within one week, 1/13 predicted the peak within 1 week, 3/13 predicted the peak ILINet percentage within 1 %, and 4/13 predicted the season duration within 1 week. For the prediction due on December 19, 2013, the number of forecasts that correctly forecasted the peak week increased to 2/13, the peak percentage to 6/13, and the duration of the season to 6/13. As the season progressed, the forecasts became more stable and were closer to the season milestones. CONCLUSION: Forecasting has become technically feasible, but further efforts are needed to improve forecast accuracy so that policy makers can reliably use these predictions. CDC and challenge contestants plan to build upon the methods developed during this contest to improve the accuracy of influenza forecasts.

A large-scale immuno-epidemiological simulation of influenza A epidemics.

BACKGROUND: Agent based models (ABM) are useful to explore population-level scenarios of disease spread and containment, but typically characterize infected individuals using simplified models of infection and symptoms dynamics. Adding more realistic models of individual infections and symptoms may help to create more realistic population level epidemic dynamics. METHODS: Using an equation-based, host-level mathematical model of influenza A virus infection, we develop a function that expresses the dependence of infectivity and symptoms of an infected individual on initial viral load, age, and viral strain phenotype. We incorporate this response function in a population-scale agent-based model of influenza A epidemic to create a hybrid multiscale modeling framework that reflects both population dynamics and individualized host response to infection. RESULTS: At the host level, we estimate parameter ranges using experimental data of H1N1 viral titers and symptoms measured in humans. By linearization of symptoms responses of the host-level model we obtain a map of the parameters of the model that characterizes clinical phenotypes of influenza infection and immune response variability over the population. At the population-level model, we analyze the effect of individualizing viral response in agent-based model by simulating epidemics across Allegheny County, Pennsylvania under both age-specific and age-independent severity assumptions. CONCLUSIONS: We present a framework for multi-scale simulations of influenza epidemics that enables the study of population-level effects of individual differences in infections and symptoms, with minimal additional computational cost compared to the existing population-level simulations.

FRED (a Framework for Reconstructing Epidemic Dynamics): an open-source software system for modeling infectious diseases and control strategies using census-based populations.

BACKGROUND: Mathematical and computational models provide valuable tools that help public health planners to evaluate competing health interventions, especially for novel circumstances that cannot be examined through observational or controlled studies, such as pandemic influenza. The spread of diseases like influenza depends on the mixing patterns within the population, and these mixing patterns depend in part on local factors including the spatial distribution and age structure of the population, the distribution of size and composition of households, employment status and commuting patterns of adults, and the size and age structure of schools. Finally, public health planners must take into account the health behavior patterns of the population, patterns that often vary according to socioeconomic factors such as race, household income, and education levels. RESULTS: FRED (a Framework for Reconstructing Epidemic Dynamics) is a freely available open-source agent-based modeling system based closely on models used in previously published studies of pandemic influenza. This version of FRED uses open-access census-based synthetic populations that capture the demographic and geographic heterogeneities of the population, including realistic household, school, and workplace social networks. FRED epidemic models are currently available for every state and county in the United States, and for selected international locations. CONCLUSIONS: State and county public health planners can use FRED to explore the effects of possible influenza epidemics in specific geographic regions of interest and to help evaluate the effect of interventions such as vaccination programs and school closure policies. FRED is available under a free open source license in order to contribute to the development of better modeling tools and to encourage open discussion of modeling tools being used to evaluate public health policies. We also welcome participation by other researchers in the further development of FRED.

Evaluation of FluSight influenza forecasting in the 2021-22 and 2022-23 seasons with a new target laboratory-confirmed influenza hospitalizations.

Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. Forecasting teams were asked to provide national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one through four weeks ahead for the 2021-22 and 2022-23 influenza seasons. Across both seasons, 26 teams submitted forecasts, with the submitting teams varying between seasons. Forecast skill was evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperformed the baseline model across forecast weeks and locations in 2021-22 and 12 out of 18 models in 2022-23. Averaging across all forecast targets, the FluSight ensemble was the 2nd most accurate model measured by WIS in 2021-22 and the 5th most accurate in the 2022-23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degraded over longer forecast horizons and during periods of rapid change. Current influenza forecasting efforts help inform situational awareness, but research is needed to address limitations, including decreased performance during periods of changing epidemic dynamics.

A probabilistic generative model for GO enrichment analysis.

The Gene Ontology (GO) is extensively used to analyze all types of high-throughput experiments. However, researchers still face several challenges when using GO and other functional annotation databases. One problem is the large number of multiple hypotheses that are being tested for each study. In addition, categories often overlap with both direct parents/descendents and other distant categories in the hierarchical structure. This makes it hard to determine if the identified significant categories represent different functional outcomes or rather a redundant view of the same biological processes. To overcome these problems we developed a generative probabilistic model which identifies a (small) subset of categories that, together, explain the selected gene set. Our model accommodates noise and errors in the selected gene set and GO. Using controlled GO data our method correctly recovered most of the selected categories, leading to dramatic improvements over current methods for GO analysis. When used with microarray expression data and ChIP-chip data from yeast and human our method was able to correctly identify both general and specific enriched categories which were overlooked by other methods.

Differences in Regional Patterns of Influenza Activity Across Surveillance Systems in the United States: Comparative Evaluation.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) tracks influenza-like illness (ILI) using information on patient visits to health care providers through the Outpatient Influenza-like Illness Surveillance Network (ILINet). As participation in this system is voluntary, the composition, coverage, and consistency of health care reports vary from state to state, leading to different measures of ILI activity between regions. The degree to which these measures reflect actual differences in influenza activity or systematic differences in the methods used to collect and aggregate the data is unclear. OBJECTIVE: The objective of our study was to qualitatively and quantitatively compare national and region-specific ILI activity in the United States across 4 surveillance data sources-CDC ILINet, Flu Near You (FNY), athenahealth, and HealthTweets.org-to determine whether these data sources, commonly used as input in influenza modeling efforts, show geographical patterns that are similar to those observed in CDC ILINet's data. We also compared the yearly percentage of FNY participants who sought health care for ILI symptoms across geographical areas. METHODS: We compared the national and regional 2018-2019 ILI activity baselines, calculated using noninfluenza weeks from previous years, for each surveillance data source. We also compared measures of ILI activity across geographical areas during 3 influenza seasons, 2015-2016, 2016-2017, and 2017-2018. Geographical differences in weekly ILI activity within each data source were also assessed using relative mean differences and time series heatmaps. National and regional age-adjusted health care-seeking percentages were calculated for each influenza season by dividing the number of FNY participants who sought medical care for ILI symptoms by the total number of ILI reports within an influenza season. Pearson correlations were used to assess the association between the health care-seeking percentages and baselines for each surveillance data source. RESULTS: We observed consistent differences in ILI activity across geographical areas for CDC ILINet and athenahealth data. ILI activity for FNY displayed little variation across geographical areas, whereas differences in ILI activity for HealthTweets.org were associated with the total number of tweets within a geographical area. The percentage of FNY participants who sought health care for ILI symptoms differed slightly across geographical areas, and these percentages were positively correlated with CDC ILINet and athenahealth baselines. CONCLUSIONS: Our findings suggest that differences in ILI activity across geographical areas as reported by a given surveillance system may not accurately reflect true differences in the prevalence of ILI. Instead, these differences may reflect systematic collection and aggregation biases that are particular to each system and consistent across influenza seasons. These findings are potentially relevant in the real-time analysis of the influenza season and in the definition of unbiased forecast models.

Results from the second year of a collaborative effort to forecast influenza seasons in the United States.

Accurate forecasts could enable more informed public health decisions. Since 2013, CDC has worked with external researchers to improve influenza forecasts by coordinating seasonal challenges for the United States and the 10 Health and Human Service Regions. Forecasted targets for the 2014-15 challenge were the onset week, peak week, and peak intensity of the season and the weekly percent of outpatient visits due to influenza-like illness (ILI) 1-4 weeks in advance. We used a logarithmic scoring rule to score the weekly forecasts, averaged the scores over an evaluation period, and then exponentiated the resulting logarithmic score. Poor forecasts had a score near 0, and perfect forecasts a score of 1. Five teams submitted forecasts from seven different models. At the national level, the team scores for onset week ranged from <0.01 to 0.41, peak week ranged from 0.08 to 0.49, and peak intensity ranged from <0.01 to 0.17. The scores for predictions of ILI 1-4 weeks in advance ranged from 0.02-0.38 and was highest 1 week ahead. Forecast skill varied by HHS region. Forecasts can predict epidemic characteristics that inform public health actions. CDC, state and local health officials, and researchers are working together to improve forecasts.

Identifying cycling genes by combining sequence homology and expression data.

MOTIVATION: The expression of genes during the cell division process has now been studied in many different species. An important goal of these studies is to identify the set of cycling genes. To date, this was done independently for each of the species studied. Due to noise and other data analysis problems, accurately deriving a set of cycling genes from expression data is a hard problem. This is especially true for some of the multicellular organisms, including humans. RESULTS: Here we present the first algorithm that combines microarray expression data from multiple species for identifying cycling genes. Our algorithm represents genes from multiple species as nodes in a graph. Edges between genes represent sequence similarity. Starting with the measured expression values for each species we use Belief Propagation to determine a posterior score for genes. This posterior is used to determine a new set of cycling genes for each species. We applied our algorithm to improve the identification of the set of cell cycle genes in budding yeast and humans. As we show, by incorporating sequence similarity information we were able to obtain a more accurate set of genes compared to methods that rely on expression data alone. Our method was especially successful for the human dataset indicating that it can use a high quality dataset from one species to overcome noise problems in another. AVAILABILITY: C implementation is available from the supporting website: http://www.cs.cmu.edu/~lyongu/pub/cellcycle/.