Laura Symul

All Publications

• Assessment of menstrual health status and evolution through mobile apps for fertility awareness. NPJ digital medicine Symul, L., Wac, K., Hillard, P., Salathe, M. 2019; 2: 64

  Abstract

  For most women of reproductive age, assessing menstrual health and fertility typically involves regular visits to a gynecologist or another clinician. While these evaluations provide critical information on an individual's reproductive health status, they typically rely on memory-based self-reports, and the results are rarely, if ever, assessed at the population level. In recent years, mobile apps for menstrual tracking have become very popular, allowing us to evaluate the reliability and tracking frequency of millions of self-observations, thereby providing an unparalleled view, both in detail and scale, on menstrual health and its evolution for large populations. In particular, the primary aim of this study was to describe the tracking behavior of the app users and their overall observation patterns in an effort to understand if they were consistent with previous small-scale medical studies. The secondary aim was to investigate whether their precision allowed the detection and estimation of ovulation timing, which is critical for reproductive and menstrual health. Retrospective self-observation data were acquired from two mobile apps dedicated to the application of the sympto-thermal fertility awareness method, resulting in a dataset of more than 30 million days of observations from over 2.7 million cycles for two hundred thousand users. The analysis of the data showed that up to 40% of the cycles in which users were seeking pregnancy had recordings every single day. With a modeling approach using Hidden Markov Models to describe the collected data and estimate ovulation timing, it was found that follicular phases average duration and range were larger than previously reported, with only 24% of ovulations occurring at cycle days 14 to 15, while the luteal phase duration and range were in line with previous reports, although short luteal phases (10 days or less) were more frequently observed (in up to 20% of cycles). The digital epidemiology approach presented here can help to lead to a better understanding of menstrual health and its connection to women's health overall, which has historically been severely understudied.

  View details for DOI 10.1038/s41746-019-0139-4

  View details for PubMedID 31341953

• Predicting pregnancy using large-scale data from a women's health tracking mobile application Liu, B., Shi, S., Wu, Y., Thomas, D., Symul, L., Pierson, E., Leskovec, J., Assoc Comp Machinery ASSOC COMPUTING MACHINERY. 2019: 2999–3005

  Abstract

  Predicting pregnancy has been a fundamental problem in women's health for more than 50 years. Previous datasets have been collected via carefully curated medical studies, but the recent growth of women's health tracking mobile apps offers potential for reaching a much broader population. However, the feasibility of predicting pregnancy from mobile health tracking data is unclear. Here we develop four models - a logistic regression model, and 3 LSTM models - to predict a woman's probability of becoming pregnant using data from a women's health tracking app, Clue by BioWink GmbH. Evaluating our models on a dataset of 79 million logs from 65,276 women with ground truth pregnancy test data, we show that our predicted pregnancy probabilities meaningfully stratify women: women in the top 10% of predicted probabilities have a 89% chance of becoming pregnant over 6 menstrual cycles, as compared to a 27% chance for women in the bottom 10%. We develop a technique for extracting interpretable time trends from our deep learning models, and show these trends are consistent with previous fertility research. Our findings illustrate the potential that women's health tracking data offers for predicting pregnancy on a broader population; we conclude by discussing the steps needed to fulfill this potential.

  View details for DOI 10.1145/3308558.3313512

  View details for Web of Science ID 000483508403011

  View details for PubMedID 31538145

  View details for PubMedCentralID PMC6752881

• FoodRepo: An Open Food Repository of Barcoded Food Products FRONTIERS IN NUTRITION Lazzari, G., Jaquet, Y., Kebaili, D. J., Symul, L., Salathe, M. 2018; 5: 57

  View details for DOI 10.3389/fnut.2018.00057

  View details for Web of Science ID 000440538500001

  View details for PubMedID 30023359

  View details for PubMedCentralID PMC6040205

• Circadian clock-dependent and -independent posttranscriptional regulation underlies temporal mRNA accumulation in mouse liver. Proceedings of the National Academy of Sciences of the United States of America Wang, J. n., Symul, L. n., Yeung, J. n., Gobet, C. n., Sobel, J. n., Lück, S. n., Westermark, P. O., Molina, N. n., Naef, F. n. 2018; 115 (8): E1916–E1925

  Abstract

  The mammalian circadian clock coordinates physiology with environmental cycles through the regulation of daily oscillations of gene expression. Thousands of transcripts exhibit rhythmic accumulations across mouse tissues, as determined by the balance of their synthesis and degradation. While diurnally rhythmic transcription regulation is well studied and often thought to be the main factor generating rhythmic mRNA accumulation, the extent of rhythmic posttranscriptional regulation is debated, and the kinetic parameters (e.g., half-lives), as well as the underlying regulators (e.g., mRNA-binding proteins) are relatively unexplored. Here, we developed a quantitative model for cyclic accumulations of pre-mRNA and mRNA from total RNA-seq data, and applied it to mouse liver. This allowed us to identify that about 20% of mRNA rhythms were driven by rhythmic mRNA degradation, and another 15% of mRNAs regulated by both rhythmic transcription and mRNA degradation. The method could also estimate mRNA half-lives and processing times in intact mouse liver. We then showed that, depending on mRNA half-life, rhythmic mRNA degradation can either amplify or tune phases of mRNA rhythms. By comparing mRNA rhythms in wild-type and Bmal1-/- animals, we found that the rhythmic degradation of many transcripts did not depend on a functional BMAL1. Interestingly clock-dependent and -independent degradation rhythms peaked at distinct times of day. We further predicted mRNA-binding proteins (mRBPs) that were implicated in the posttranscriptional regulation of mRNAs, either through stabilizing or destabilizing activities. Together, our results demonstrate how posttranscriptional regulation temporally shapes rhythmic mRNA accumulation in mouse liver.

  View details for DOI 10.1073/pnas.1715225115

  View details for PubMedID 29432155

  View details for PubMedCentralID PMC5828596

• Non-Circadian Expression Masking Clock-Driven Weak Transcription Rhythms in U2OS Cells PLOS ONE Hoffmann, J., Symul, L., Shostak, A., Fischer, T., Naef, F., Brunner, M. 2014; 9 (7): e102238

  Abstract

  U2OS cells harbor a circadian clock but express only a few rhythmic genes in constant conditions. We identified 3040 binding sites of the circadian regulators BMAL1, CLOCK and CRY1 in the U2OS genome. Most binding sites even in promoters do not correlate with detectable rhythmic transcript levels. Luciferase fusions reveal that the circadian clock supports robust but low amplitude transcription rhythms of representative promoters. However, rhythmic transcription of these potentially clock-controlled genes is masked by non-circadian transcription that overwrites the weaker contribution of the clock in constant conditions. Our data suggest that U2OS cells harbor an intrinsically rather weak circadian oscillator. The oscillator has the potential to regulate a large number of genes. The contribution of circadian versus non-circadian transcription is dependent on the metabolic state of the cell and may determine the apparent complexity of the circadian transcriptome.

  View details for DOI 10.1371/journal.pone.0102238

  View details for Web of Science ID 000339040600108

  View details for PubMedID 25007071

  View details for PubMedCentralID PMC4090172

• The Circadian Clock Coordinates Ribosome Biogenesis PLOS BIOLOGY Jouffe, C., Cretenet, G., Symul, L., Martin, E., Atger, F., Naef, F., Gachon, F. 2013; 11 (1): e1001455

  Abstract

  Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis.

  View details for DOI 10.1371/journal.pbio.1001455

  View details for Web of Science ID 000314648700001

  View details for PubMedID 23300384

  View details for PubMedCentralID PMC3536797

• Genome-Wide RNA Polymerase II Profiles and RNA Accumulation Reveal Kinetics of Transcription and Associated Epigenetic Changes During Diurnal Cycles PLOS BIOLOGY Le Martelot, G., Canella, D., Symul, L., Migliavacca, E., Gilardi, F., Liechti, R., Martin, O., Harshman, K., Delorenzi, M., Desvergne, B., Herr, W., Deplancke, B., Schibler, U., Rougemont, J., Guex, N., Hernandez, N., Naef, F., CycliX Consortium 2012; 10 (11): e1001442

  Abstract

  Interactions of cell-autonomous circadian oscillators with diurnal cycles govern the temporal compartmentalization of cell physiology in mammals. To understand the transcriptional and epigenetic basis of diurnal rhythms in mouse liver genome-wide, we generated temporal DNA occupancy profiles by RNA polymerase II (Pol II) as well as profiles of the histone modifications H3K4me3 and H3K36me3. We used these data to quantify the relationships of phases and amplitudes between different marks. We found that rhythmic Pol II recruitment at promoters rather than rhythmic transition from paused to productive elongation underlies diurnal gene transcription, a conclusion further supported by modeling. Moreover, Pol II occupancy preceded mRNA accumulation by 3 hours, consistent with mRNA half-lives. Both methylation marks showed that the epigenetic landscape is highly dynamic and globally remodeled during the 24-hour cycle. While promoters of transcribed genes had tri-methylated H3K4 even at their trough activity times, tri-methylation levels reached their peak, on average, 1 hour after Pol II. Meanwhile, rhythms in tri-methylation of H3K36 lagged transcription by 3 hours. Finally, modeling profiles of Pol II occupancy and mRNA accumulation identified three classes of genes: one showing rhythmicity both in transcriptional and mRNA accumulation, a second class with rhythmic transcription but flat mRNA levels, and a third with constant transcription but rhythmic mRNAs. The latter class emphasizes widespread temporally gated posttranscriptional regulation in the mouse liver.

  View details for DOI 10.1371/journal.pbio.1001442

  View details for Web of Science ID 000311888300020

  View details for PubMedID 23209382

  View details for PubMedCentralID PMC3507959