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Publications of Marc D. Ryser    :chronological  combined listing:

%% Papers Published   
   Author = {Murgas, KA and Ma, Y and Shahidi, LK and Mukherjee, S and Allen, AS and Shibata, D and Ryser, MD},
   Title = {A Bayesian Hierarchical Model to Estimate DNA Methylation
             Conservation in Colorectal Tumors.},
   Journal = {Bioinformatics (Oxford, England)},
   Pages = {btab637},
   Year = {2021},
   Month = {September},
   url = {},
   Abstract = {<h4>Motivation</h4>Conservation is broadly used to identify
             biologically important (epi)genomic regions. In the case of
             tumor growth, preferential conservation of DNA methylation
             can be used to identify areas of particular functional
             importance to the tumor. However, reliable assessment of
             methylation conservation based on multiple tissue samples
             per patient requires the decomposition of methylation
             variation at multiple levels.<h4>Results</h4>We developed a
             Bayesian hierarchical model that allows for variance
             decomposition of methylation on three levels:
             between-patient normal tissue variation, between-patient
             tumor-effect variation, and within-patient tumor variation.
             We then defined a model-based conservation score to identify
             loci of reduced within-tumor methylation variation relative
             to between-patient variation. We fit the model to
             multi-sample methylation array data from 21 colorectal
             cancer (CRC) patients using a Monte Carlo Markov Chain
             algorithm (Stan). Sets of genes implicated in CRC
             tumorigenesis exhibited preferential conservation,
             demonstrating the model's ability to identify functionally
             relevant genes based on methylation conservation. A pathway
             analysis of preferentially conserved genes implicated
             several CRC relevant pathways and pathways related to
             neoantigen presentation and immune evasion.<h4>Conclusions</h4>Our
             findings suggest that preferential methylation conservation
             may be used to identify novel gene targets that are not
             consistently mutated in CRC. The flexible structure makes
             the model amenable to the analysis of more complex
             multi-sample data structures.<h4>Availability</h4>The data
             underlying this article are available in the NCBI GEO
             Database, under accession code GSE166212. The R analysis
             code is available at<h4>Supplementary
             information</h4>Supplementary data are available at
             Bioinformatics online.},
   Doi = {10.1093/bioinformatics/btab637},
   Key = {fds359358}

   Author = {Fridman, I and Chan, L and Thomas, J and Fish, LJ and Falkovic, M and Brioux, J and Hunter, N and Ryser, DH and Hwang, ES and Pollak, KI and Weinfurt, KP and Ryser, MD},
   Title = {A web-based personalized decision support tool for patients
             diagnosed with ductal carcinoma in situ: development,
             content evaluation, and usability testing.},
   Journal = {Breast Cancer Res Treat},
   Volume = {192},
   Number = {3},
   Pages = {517-527},
   Year = {2022},
   Month = {April},
   url = {},
   Abstract = {PURPOSE: Patients diagnosed with ductal carcinoma in situ
             (DCIS) face trade-offs when deciding among different
             treatments, including surgery, radiation, and endocrine
             therapy. A less chosen option is active monitoring. While
             evidence from clinical trials is not yet available,
             observational studies show comparable results for active
             monitoring and immediate treatment on cancer outcomes in
             select subgroups of patients. We developed and tested a
             web-based decision support tool (DST) to help patients
             explore current knowledge about DCIS and make an informed
             choice. METHODS: The DST, an interactive web application,
             was informed by literature reviews and formative work with
             patients, breast surgeons, and health communication experts.
             We conducted iterative interviews to evaluate the DST
             content among women with and without a history of breast
             cancer, as well as breast cancer experts. For usability
             testing, we conducted an online survey among women with and
             without a history of breast cancer. RESULTS: For content
             evaluation, 5 women with and 10 women without a history of
             DCIS were interviewed. The sample included 11 White and 4
             non-White women, with a mean age of 64 years. The expert
             sample consisted of 5 attendings and a physician assistant.
             The feedback was used to add, clarify, or reorganize
             information in the DST. For usability testing, 22
             participants with a mean age of 61 years were recruited
             including 15 White and 7 Black women and 6 women with a
             history of DCIS. The mean usability score was 3.7 out of 5.
             Most participants (86%) found that the DST provided unbiased
             information about treatments. To improve usability, we
             reduced the per-page content and added navigation cues.
             CONCLUSION: Content and usability evaluation showed that the
             DST helps patients explore trade-offs of active monitoring
             and immediate treatment. By adopting a personalized
             approach, the tool will enable informed decisions aligned
             with patients' values and expectations.},
   Doi = {10.1007/s10549-022-06512-8},
   Key = {fds357630}

   Author = {Schmitz, RSJM and van den Belt-Dusebout, SW and Cresta, C and Liu,
             Y-H and Schaapveld, M and Clements, K and Timbres, J and Byng, DT and Ryser, MD and Ren, Y and Lynch, T and Hyslop, T and Menegaz, B and Collyar,
             D and Hwang, S and Thompson, A and Sawyer, E and Wesseling, J and Lips, EH and Schmidt, MK},
   Title = {Abstract P1-22-02: Subsequent risk of ipsilateral breast
             events in a multinational DCIS cohort of 48.619 patients: A
             meta-analysis within the PRECISION consortium},
   Journal = {Cancer Research},
   Volume = {82},
   Number = {4_Supplement},
   Publisher = {American Association for Cancer Research
   Year = {2022},
   Month = {February},
   url = {},
   Abstract = {<jats:title>Abstract</jats:title> <jats:p>Background: The
             PRECISION (PREvent ductal Carcinoma In Situ Invasive
             Overtreatment Now) CRUK Grand Challenge project focusses on
             discriminating hazardous from indolent ductal carcinoma in
             situ (DCIS). Aim of these analyses is to identify factors
             associated with a lower or higher risk of developing
             invasive breast cancer after an initial DCIS diagnosis.
             Knowledge of these factors is crucial in our quest to
             reducing overtreatment for women with DCIS. Many
             clinicopathological features are hypothesized to be
             important factors affecting the risk of a subsequent breast
             lesion. Most studies performed so far are from trial or
             single country studies, we now present an integrated
             analysis of four different cohorts from three
             countries.Methods: Four cohorts from the three countries
             participating in PRECISION were identified. A population
             based cohort from the Netherlands cancer registry (Dutch
             cohort); a population based, prospective, screening cohort
             from the United Kingdom (Sloane cohort); a single center
             cohort from MD Anderson Cancer Center (MDACC) and a subset
             of DCIS patients abstracted from a population based National
             Cancer Database Special Study cohort (NCDB subset) in the
             United States. Patient-level data from these cohorts were
             combined for this analysis. Subsequent ipsilateral invasive
             breast cancer (iIBC) and subsequent ipsilateral DCIS (iDCIS)
             were assessed at five and ten years by Kaplan Meier
             analysis. The cumulative incidence of iIBC was assessed in
             three treatment groups: breast conserving surgery only
             (BCS), breast conserving surgery with radiotherapy (BCS+RT)
             and mastectomy (MST). Cumulative incidence of iDCIS was
             assessed in patients receiving BCS or BCS+RT. Additionally,
             cumulative incidences were calculated for iIBC and IDCIS in
             patients who received endocrine treatment (ET) after BCS or
             BCS+RT versus patients who did not receive ET. All
             cumulative incidences were calculated with death as
             competing risk. Results: The joint PRECISION cohort
             consisted of 48,619 patients, diagnosed between 1999 and
             2017. Median follow-up was 7.4 years (0.6-17.9). In
             preliminary analyses, Kaplan Meier curves showed broadly
             similar risks in iIBC and iDCIS between the four different
             cohorts. The cumulative incidence of iIBC was 1.6% at five
             years and 3.5% at 10 years. Five-year cumulative incidence
             of iIBC was highest in patients receiving BCS (3.4%)
             compared with patients receiving BCS+RT or MST (1.3%). The
             cumulative incidence of iDCIS was 1.7% at 5 years and 2.4%
             at 10 years. Five-year cumulative incidence of iDCIS was
             higher in patients receiving BCS (3.5%) compared to patients
             receiving BCS+RT (1.9%). In univariate analyses, the effect
             of ET on cumulative incidence of both iIBC and iDCIS was
             modest, especially with respect to radiotherapy. Conclusion:
             Overall, 5- and 10-year incidence of an ipsilateral in situ
             or invasive breast lesion was low and similar between the
             four different cohorts. The incidence of iIBC and iDCIS was
             higher in patients receiving BCS, compared to women
             receiving BCS+RT or MST.</jats:p> <jats:p>Table 1.Cohort and
             patient characteristicsDutch Cohort Sloane MDACCNCDB
             subsetTotal CohortN=18,995N=8,425N=1,820N=19,379N=48,619Cohort
             descriptionProspectiveNoYesNoNoPopulation basedYesYesNo,
             single centerYesScreening and non-screeningYesScreening
             onlyYesYesMean (min - max)Mean (min - max)Mean (min -
             max)Mean (min-max)Mean (min-max)Age diagnosis DCIS58.3
             (21-94)59.8 (46-88)55.6 (20-90)59.7 (20-98)59.0 (20-98)Year
             of diagnosis (range)1999-20152003-20121999-20172007-20151999-2017Follow-up
             in years10.4 (0.5-21.1)5.3 (0.5-9.7)8.7 (0.25-17.8)5.8
             (0.5-10.7)7.6 (0.25-2.1)N (%)N (%)N (%)N (%)N (%)GradeGrade
             12,844 (15.0)784 (9.3)141 (7.8)3,158 (16.3)6,927 (14.3)Grade
             25,952 (31.3)2,328 (27.6)737 (40.5)6,844 (35.3)15,861
             (32.6)Grade 38,944 (47.1)5,305 (62.9)933 (51.3)7,848
             (40.5)23,030 (47.3)Unknown grade1,255 (6.6)8 (0.1)9
             (0.5)1,529 (7.9)2,801 (5.8)Type of surgeryBreast conserving
             surgery (BCS)11,790 (62.1)5,830 (69.2)1,031 (56.7)14,504
             (74.8)33,155 (68.2)Mastectomy (MST)7,205 (37.9)2,595
             (30.8)789 (43.4)4,875 (25.2)15,464 (31.8)Adjuvant
             treatmentRadiotherapy (RT)9,650 (50.8)3,418 (40.6)762
             (41.9)10,620 (54.8)24,450 (50.3)Endocrine treatmentNA1,151
             (13.6)999 (54.9)8,849 (45.7)10,999 (37.0)5 years Cumulative
             statusAlive16,472 (86.7)8,147 (96.7)1,668 (91.7)18,161
             (93.7)44,448 (91.4)Deceased2,523 (13.3)278 (3.3)152
             (8.4)1,218 (6.3)4,171 (8.6)This work was supported by Cancer
             Research UK and by KWF Dutch Cancer Society
             (ref.C38317/A24043)</jats:p> <jats:p>Citation Format: Renée
             SJM Schmitz, Sandra W van den Belt-Dusebout, Chiara Cresta,
             Yat-Hee Liu, Michael Schaapveld, Karen Clements, Jasmine
             Timbres, Danalyn T Byng, Marc D Ryser, Yi Ren, Thomas Lynch,
             Terry Hyslop, Brian Menegaz, Deborah Collyar, Shelley Hwang,
             Alastair Thompson, Elinor Sawyer, Jelle Wesseling, Esther H
             Lips, Marjanka K Schmidt, Grand Challenge PRECISION
             consortium. Subsequent risk of ipsilateral breast events in
             a multinational DCIS cohort of 48.619 patients: A
             meta-analysis within the PRECISION consortium [abstract].
             In: Proceedings of the 2021 San Antonio Breast Cancer
             Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia
             (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr
   Doi = {10.1158/1538-7445.sabcs21-p1-22-02},
   Key = {fds367149}

   Author = {Epplein, M and Le Marchand and L and Cover, TL and Song, M and Blot, WJ and Peek, RM and Teras, LR and Visvanathan, K and Chen, Y and Sesso, HD and Zeleniuch-Jacquotte, A and Berndt, SI and Potter, JD and Ryser, MD and Haiman, CA and Wassertheil-Smoller, S and Tinker, LF and Waterboer,
             T and Butt, J},
   Title = {Association of Combined Sero-Positivity to Helicobacter
             pylori and Streptococcus gallolyticus with Risk of
             Colorectal Cancer.},
   Journal = {Microorganisms},
   Volume = {8},
   Number = {11},
   Year = {2020},
   Month = {October},
   url = {},
   Abstract = {Previously, we found that risk of colorectal cancer (CRC) is
             increased in individuals with serum antibody response to
             both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA)
             toxin or Streptococcus gallolyticus (SGG) pilus protein
             Gallo2178. In the present analysis, we tested the hypothesis
             that combined seropositivity to both antigens is a better
             indicator of CRC risk than seropositivity to single
             antigens. We used multiplex serologic assays to analyze
             pre-diagnostic serum for antibody responses from 4063
             incident CRC cases and 4063 matched controls from 10 US
             cohorts. To examine whether combined SGG Gallo2178 and HP
             VacA sero-status was associated with CRC risk, we used
             conditional logistic regression models to estimate odds
             ratios (ORs) and 95% confidence intervals (CIs). Compared to
             dual sero-negative individuals, there was no increased risk
             for individuals sero-positive to SGG Gallo2178 only (OR:
             0.93; 95% CI: 0.66-1.31) or to HP VacA only (OR: 1.08; 95%
             CI: 0.98-1.19). However, dual sero-positive individuals had
             a >50% increased odds of developing CRC (OR: 1.54; 95% CI:
             1.16-2.04), suggesting an interaction between antibody
             responses to these two pathogens and CRC risk (pinteraction
             = 0.06). In conclusion, this study suggests that dual
             sero-positivity to HP VacA and SGG Gallo2178 is an indicator
             of increased risk of CRC.},
   Doi = {10.3390/microorganisms8111698},
   Key = {fds354107}

   Author = {Butt, J and Blot, WJ and Visvanathan, K and Le Marchand and L and Wilkens,
             LR and Chen, Y and Sesso, HD and Teras, L and Ryser, MD and Hyslop, T and Wassertheil-Smoller, S and Tinker, LF and Potter, JD and Song, M and Berndt, SI and Waterboer, T and Pawlita, M and Epplein,
   Title = {Auto-antibodies to p53 and the Subsequent Development of
             Colorectal Cancer in a U.S. Prospective Cohort
   Journal = {Cancer Epidemiol Biomarkers Prev},
   Volume = {29},
   Number = {12},
   Pages = {2729-2734},
   Year = {2020},
   Month = {December},
   url = {},
   Abstract = {BACKGROUND: Auto-antibodies to tumor suppressor p53 are
             found in a subset of patients with colorectal cancer. A
             recent prospective study in the United States has reported a
             significant 1.8-fold increased odds for colorectal cancer
             development with prediagnostic seropositivity to p53. In
             this study, we sought to examine this association in a U.S.
             colorectal cancer cohort consortium to evaluate the
             potential utility of p53 auto-antibodies as an early
             biomarker for colorectal cancer. METHODS: Auto-antibodies to
             p53 were measured in prediagnostic blood samples of 3,702
             incident colorectal cancer cases and 3,702 controls, matched
             by age, race, and sex, from 9 U.S. prospective cohorts. The
             association of seropositivity to p53 with colorectal cancer
             risk, overall and by time between blood draw and diagnosis,
             was determined by conditional logistic regression. RESULTS:
             Overall, 5% of controls and 7% of cases were seropositive to
             p53, resulting in a statistically significant 33% increased
             colorectal cancer risk [odds ratio (OR), 1.33; 95%
             confidence interval (CI), 1.09-1.61]. By follow-up time, the
             association was only significant with colorectal cancer
             diagnoses within 4 years after blood draw (OR, 2.27; 95% CI,
             1.62-3.19), but not thereafter (OR, 0.97; 95% CI,
             0.76-1.24). CONCLUSIONS: In this large consortium of
             prospective cohorts, we found that prediagnostic
             seropositivity to tumor suppressor p53 was significantly
             associated with an over 2-fold increased odds of developing
             colorectal cancer within 4 years after blood draw. IMPACT:
             Our finding suggests that p53 seropositivity may not be a
             useful predictor of long-term colorectal cancer risk;
             however, it might be considered as a marker to aid in the
             early diagnosis of colorectal cancer.},
   Doi = {10.1158/1055-9965.EPI-20-0780},
   Key = {fds352569}

   Author = {Ryser, MD and Murgas, KA},
   Title = {Bone remodeling as a spatial evolutionary
   Journal = {J Theor Biol},
   Volume = {418},
   Pages = {16-26},
   Year = {2017},
   Month = {April},
   url = {},
   Abstract = {Bone remodeling is a complex process involving cell-cell
             interactions, biochemical signaling and mechanical stimuli.
             Early models of the biological aspects of remodeling were
             non-spatial and focused on the local dynamics at a fixed
             location in the bone. Several spatial extensions of these
             models have been proposed, but they generally suffer from
             two limitations: first, they are not amenable to analysis
             and are computationally expensive, and second, they neglect
             the role played by bone-embedded osteocytes. To address
             these issues, we developed a novel model of spatial
             remodeling based on the principles of evolutionary game
             theory. The analytically tractable framework describes the
             spatial interactions between zones of bone resorption, bone
             formation and quiescent bone, and explicitly accounts for
             regulation of remodeling by bone-embedded,
             mechanotransducing osteocytes. Using tools from the theory
             of interacting particle systems we systematically classified
             the different dynamic regimes of the spatial model and
             identified regions of parameter space that allow for global
             coexistence of resorption, formation and quiescence, as
             observed in physiological remodeling. In coexistence
             scenarios, three-dimensional simulations revealed the
             emergence of sponge-like bone clusters. Comparison between
             spatial and non-spatial dynamics revealed substantial
             differences and suggested a stabilizing role of space. Our
             findings emphasize the importance of accounting for spatial
             structure and bone-embedded osteocytes when modeling the
             process of bone remodeling. Thanks to the lattice-based
             framework, the proposed model can easily be coupled to a
             mechanical model of bone loading.},
   Doi = {10.1016/j.jtbi.2017.01.021},
   Key = {fds354109}

   Author = {Ryser, MD and Weaver, DL and Zhao, F and Worni, M and Grimm, LJ and Gulati,
             R and Etzioni, R and Hyslop, T and Lee, SJ and Hwang,
   Title = {Cancer Outcomes in DCIS Patients Without Locoregional
   Journal = {J Natl Cancer Inst},
   Volume = {111},
   Number = {9},
   Pages = {952-960},
   Year = {2019},
   Month = {September},
   url = {},
   Abstract = {BACKGROUND: The vast majority of women diagnosed with ductal
             carcinoma in situ (DCIS) undergo treatment. Therefore, the
             risks of invasive progression and competing death in the
             absence of locoregional therapy are uncertain. METHODS: We
             performed survival analyses of patient-level data from DCIS
             patients who did not receive definitive surgery or radiation
             therapy as recorded in the US National Cancer Institute's
             Surveillance, Epidemiology, and End Results program
             (1992-2014). Kaplan-Meier curves were used to estimate the
             net risk of subsequent ipsilateral invasive cancer. The
             cumulative incidences of ipsilateral invasive cancer,
             contralateral breast cancer, and death were estimated using
             competing risk methods. RESULTS: A total of 1286 DCIS
             patients who did not undergo locoregional therapy were
             identified. Median age at diagnosis was 60 years
             (inter-quartile range = 51-74 years), with median follow-up
             of 5.5 years (inter-quartile range = 2.3-10.6 years).
             Among patients with tumor grade I/II (n = 547), the
             10-year net risk of ipsilateral invasive breast cancer was
             12.2% (95% confidence interval [CI] = 8.6% to 17.1%)
             compared with 17.6% (95% CI = 12.1% to 25.2%) among patients
             with tumor grade III (n = 244) and 10.1% (95% CI = 7.4%
             to 13.8%) among patients with unknown grade (n = 495).
             Among all patients, the 10-year cumulative incidences of
             ipsilateral invasive cancer, contralateral breast cancer,
             and all-cause mortality were 10.5% (95% CI = 8.5% to 12.4%),
             3.9% (95% CI = 2.6% to 5.2%), and 24.1% (95% CI = 21.2% to
             26.9%), respectively. CONCLUSION: Despite limited data, our
             findings suggest that DCIS patients without locoregional
             treatment have a limited risk of invasive progression.
             Although the cohort is not representative of the general
             population of patients diagnosed with DCIS, the findings
             suggest that there may be overtreatment, especially among
             older patients and patients with elevated
   Doi = {10.1093/jnci/djy220},
   Key = {fds342717}

   Author = {Cao, Y and Ryser, MD and Payne, S and Li, B and Rao, CV and You,
   Title = {Collective Space-Sensing Coordinates Pattern Scaling in
             Engineered Bacteria.},
   Journal = {Cell},
   Volume = {165},
   Number = {3},
   Pages = {620-630},
   Year = {2016},
   Month = {April},
   url = {},
   Abstract = {Scale invariance refers to the maintenance of a constant
             ratio of developing organ size to body size. Although
             common, its underlying mechanisms remain poorly understood.
             Here, we examined scaling in engineered Escherichia coli
             that can form self-organized core-ring patterns in colonies.
             We found that the ring width exhibits perfect scale
             invariance to the colony size. Our analysis revealed a
             collective space-sensing mechanism, which entails sequential
             actions of an integral feedback loop and an incoherent
             feedforward loop. The integral feedback is implemented by
             the accumulation of a diffusive chemical produced by a
             colony. This accumulation, combined with nutrient
             consumption, sets the timing for ring initiation. The
             incoherent feedforward is implemented by the opposing
             effects of the domain size on the rate and duration of ring
             maturation. This mechanism emphasizes a role of timing
             control in achieving robust pattern scaling and provides a
             new perspective in examining the phenomenon in natural
   Doi = {10.1016/j.cell.2016.03.006},
   Key = {fds339505}

   Author = {Byng, D and Retel, VP and van Harten, W and Rushing, CN and Thomas, SM and Lynch, T and McCarthy, A and Francescatti, AB and Frank, ES and Partridge, AH and Thompson, AM and Grimm, L and Hyslop, T and Hwang,
             E-SS and Ryser, MD},
   Title = {Disparities in surveillance imaging after breast conserving
             surgery for primary DCIS.},
   Journal = {Journal of Clinical Oncology : Official Journal of the
             American Society of Clinical Oncology},
   Volume = {39},
   Number = {15_suppl},
   Pages = {6516-6516},
   Publisher = {American Society of Clinical Oncology (ASCO)},
   Year = {2021},
   Month = {May},
   url = {},
   Abstract = {<jats:p> 6516 </jats:p><jats:p> Background: Due to the
             elevated risk of ipsilateral invasive breast cancer (iIBC)
             after diagnosis with primary ductal carcinoma in situ
             (DCIS), professional guidelines recommend surveillance
             screening within 6-12 months (mo) after completion of
             initial local treatment and annually thereafter. To
             characterize adherence to these guidelines, we explored
             longitudinal patterns of utilization and factors associated
             with the use of surveillance imaging (mammography, MRI,
             ultrasound) for women with primary DCIS treated with breast
             conserving surgery (BCS) ± radiotherapy (RT) within 6 mo of
             diagnosis. Methods: A treatment-stratified random sample of
             patients diagnosed with screen-detected and biopsy-confirmed
             DCIS in 2008-15 was selected from 1,330 Commission on
             Cancer-accredited facilities (up to 20/site) in the US. All
             imaging exams coded as asymptomatic were collected from 6 mo
             up to 10 years (yr) post-diagnosis. Time was defined
             according to 12-mo long surveillance periods. To be included
             in a given surveillance period, women had to be alive and
             free of a new breast cancer diagnosis through the end of the
             period. Women were classified as “consistent” screeners
             if they had at least one surveillance screen during each
             period, for the first 5 yr post-treatment or until
             censoring, whichever occurred first. Repeated measures
             multivariable logistic regression with generalized
             estimating equations was used to model receipt of
             surveillance breast imaging over time. The model included
             clinical and socioeconomic features. Results: The final
             analytic cohort contained 12,559 women; 8,989 (71.6%)
             received RT after BCS. Median age was 60 yr (interquartile
             range: 52-69) and median follow-up was 5.6 yr (95%
             confidence interval [CI] 5.6-5.7). Among women who received
             BCS (instead of BCS+RT), 62.5% (79.7%) underwent
             surveillance imaging within 6-18 mo after diagnosis. 38.7%
             (54.0%) were categorized as “consistent” screeners.
             Compared to white women, Black women were less likely to
             receive surveillance screening after treatment for primary
             DCIS (odds ratio [OR] 0.85, 95% CI 0.77-0.94). Hispanic
             ethnicity had a similar association (OR 0.86, 95% CI
             0.74-0.99) compared to non-Hispanic ethnicity. Women with
             private insurance, compared to government insurance, were
             more likely to receive screening (OR 1.20, 95% CI
             1.11-1.30). Prognostic tumor features indicative of a higher
             risk of subsequent iIBC, including higher grade, presence of
             comedonecrosis, and hormone receptor-negative DCIS, were not
             associated with screening uptake. Conclusions: Despite
             guidelines recommending annual surveillance imaging, many
             women with primary DCIS do not undergo regular imaging after
             BCS. The findings from this US-based study suggest that
             disparities in screening uptake are associated with
             race/ethnicity and insurance status rather than prognostic
             tumor features. </jats:p>},
   Doi = {10.1200/jco.2021.39.15_suppl.6516},
   Key = {fds367151}

   Author = {Grimm, LJ and Rahbar, H and Abdelmalak, M and Hall, AH and Ryser,
   Title = {Ductal Carcinoma in Situ: State-of-the-Art
   Journal = {Radiology},
   Volume = {302},
   Number = {2},
   Pages = {246-255},
   Year = {2022},
   Month = {February},
   url = {},
   Abstract = {Ductal carcinoma in situ (DCIS) is a nonobligate precursor
             of invasive cancer, and its detection, diagnosis, and
             management are controversial. DCIS incidence grew with the
             expansion of screening mammography programs in the 1980s and
             1990s, and DCIS is viewed as a major driver of overdiagnosis
             and overtreatment. For pathologists, the diagnosis and
             classification of DCIS is challenging due to undersampling
             and interobserver variability. Understanding the progression
             from normal breast tissue to DCIS and, ultimately, to
             invasive cancer is limited by a paucity of natural history
             data with multiple proposed evolutionary models of DCIS
             initiation and progression. Although radiologists are
             familiar with the classic presentation of DCIS as
             asymptomatic calcifications at mammography, the expanded
             pool of modalities, advanced imaging techniques, and image
             analytics have identified multiple potential biomarkers of
             histopathologic characteristics and prognosis. Finally,
             there is growing interest in the nonsurgical management of
             DCIS, including active surveillance, to reduce overtreatment
             and provide patients with more personalized management
             options. However, current biomarkers are not adept at
             enabling identification of occult invasive disease at biopsy
             or accurately predicting the risk of progression to invasive
             disease. Several active surveillance trials are ongoing and
             are expected to better identify women with low-risk DCIS who
             may avoid surgery.},
   Doi = {10.1148/radiol.211839},
   Key = {fds367150}

   Author = {Ryser, MD and Yu, M and Grady, W and Siegmund, K and Shibata,
   Title = {Epigenetic Heterogeneity in Human Colorectal Tumors Reveals
             Preferential Conservation And Evidence of Immune
   Journal = {Scientific Reports},
   Volume = {8},
   Number = {1},
   Pages = {17292},
   Year = {2018},
   Month = {November},
   url = {},
   Abstract = {Genomic intratumoral heterogeneity (ITH) is common in
             cancers, but the extent of phenotypic ITH is uncertain
             because most subclonal mutations are passengers. Since tumor
             phenotypes are largely driven by epigenetics, methylomic
             analyses can provide insights into phenotypic ITH. Following
             this principle, we determined the extent of epigenetic ITH
             in 16 human colorectal tumors by comparing the methylomes
             from spatially separated regions in each tumor. Methylomes
             from opposite tumor sides were similar (Pearson correlation
             >0.95) with little evidence of ITH or stepwise selection
             during growth, suggesting that the epigenome of a sampled
             tumor largely reflects that of its founder cell. Epigenetic
             conservation was functional, with higher conservation at
             promoters and expressed genes compared to non-coding
             regions. Despite epigenomic conservation, RNA expression
             varied between individual tumor glands, indicating continued
             adaption during growth. Because many promoters and enhancers
             were unmethylated, continued adaptation may be due to
             phenotypic plasticity. Gene enrichment analyses identified
             that interferon signaling and antigen-processing and
             presenting pathways were strongly conserved during tumor
             growth, suggesting a mechanism for immune evasion. In
             summary, our findings suggest that epigenomes are
             preferentially conserved during tumor growth and that early
             tumor cells are poised for rapid growth, phenotypic
             adaptation, and immune evasion.},
   Doi = {10.1038/s41598-018-35621-y},
   Key = {fds339945}

   Author = {Shen, Y and Dong, W and Gulati, R and Ryser, MD and Etzioni,
   Title = {Estimating the frequency of indolent breast cancer in
             screening trials.},
   Journal = {Stat Methods Med Res},
   Volume = {28},
   Number = {4},
   Pages = {1261-1271},
   Year = {2019},
   Month = {April},
   url = {},
   Abstract = {Cancer screening can detect cancer that would not have been
             detected in a patient's lifetime without screening. Standard
             methods for analyzing screening data do not explicitly
             account for the possibility that a fraction of tumors may
             remain latent indefinitely. We extend these methods by
             representing cancers as a mixture of those that progress to
             symptoms (progressive) and those that remain latent
             (indolent). Given sensitivity of the screening test, we
             derive likelihood expressions to simultaneously estimate (1)
             the rate of onset of preclinical cancer, (2) the average
             preclinical duration of progressive cancers, and (3) the
             fraction of preclinical cancers that are indolent.
             Simulations demonstrate satisfactory performance of the
             estimation approach to identify model parameters subject to
             precise specifications of input parameters and adequate
             numbers of interval cancers. In application to four breast
             cancer screening trials, the estimated indolent fraction
             among preclinical cancers varies between 2% and 35% when
             assuming 80% test sensitivity and varying specifications for
             the earliest time that participants could plausibly have
             developed cancer. We conclude that standard methods for
             analyzing screening data can be extended to allow some
             indolent cancers, but accurate estimation depends on
             correctly specifying key inputs that may be difficult to
             determine precisely in practice.},
   Doi = {10.1177/0962280217754232},
   Key = {fds339498}

   Author = {Ryser, MD and Lange, J and Inoue, LYT and O'Meara, ES and Gard, C and Miglioretti, DL and Bulliard, J-L and Brouwer, AF and Hwang, ES and Etzioni, RB},
   Title = {Estimation of Breast Cancer Overdiagnosis in a U.S. Breast
             Screening Cohort.},
   Journal = {Ann Intern Med},
   Volume = {175},
   Number = {4},
   Pages = {471-478},
   Year = {2022},
   Month = {April},
   url = {},
   Abstract = {BACKGROUND: Mammography screening can lead to
             overdiagnosis-that is, screen-detected breast cancer that
             would not have caused symptoms or signs in the remaining
             lifetime. There is no consensus about the frequency of
             breast cancer overdiagnosis. OBJECTIVE: To estimate the rate
             of breast cancer overdiagnosis in contemporary mammography
             practice accounting for the detection of nonprogressive
             cancer. DESIGN: Bayesian inference of the natural history of
             breast cancer using individual screening and diagnosis
             records, allowing for nonprogressive preclinical cancer.
             Combination of fitted natural history model with life-table
             data to predict the rate of overdiagnosis among
             screen-detected cancer under biennial screening. SETTING:
             Breast Cancer Surveillance Consortium (BCSC) facilities.
             PARTICIPANTS: Women aged 50 to 74 years at first mammography
             screen between 2000 and 2018. MEASUREMENTS: Screening
             mammograms and screen-detected or interval breast cancer.
             RESULTS: The cohort included 35 986 women, 82 677
             mammograms, and 718 breast cancer diagnoses. Among all
             preclinical cancer cases, 4.5% (95% uncertainty interval
             [UI], 0.1% to 14.8%) were estimated to be nonprogressive. In
             a program of biennial screening from age 50 to 74 years,
             15.4% (UI, 9.4% to 26.5%) of screen-detected cancer cases
             were estimated to be overdiagnosed, with 6.1% (UI, 0.2% to
             20.1%) due to detecting indolent preclinical cancer and 9.3%
             (UI, 5.5% to 13.5%) due to detecting progressive preclinical
             cancer in women who would have died of an unrelated cause
             before clinical diagnosis. LIMITATIONS: Exclusion of women
             with first mammography screen outside BCSC. CONCLUSION: On
             the basis of an authoritative U.S. population data set, the
             analysis projected that among biennially screened women aged
             50 to 74 years, about 1 in 7 cases of screen-detected cancer
             is overdiagnosed. This information clarifies the risk for
             breast cancer overdiagnosis in contemporary screening
             practice and should facilitate shared and informed decision
             making about mammography screening. PRIMARY FUNDING SOURCE:
             National Cancer Institute.},
   Doi = {10.7326/M21-3577},
   Key = {fds363082}

   Author = {Grimm, LJ and Miller, MM and Thomas, SM and Liu, Y and Lo, JY and Hwang,
             ES and Hyslop, T and Ryser, MD},
   Title = {Growth Dynamics of Mammographic Calcifications:
             Differentiating Ductal Carcinoma in Situ from Benign Breast
   Journal = {Radiology},
   Volume = {292},
   Number = {1},
   Pages = {77-83},
   Year = {2019},
   Month = {July},
   url = {},
   Abstract = {Background Most ductal carcinoma in situ (DCIS) lesions are
             first detected on screening mammograms as calcifications.
             However, false-positive biopsy rates for calcifications
             range from 30% to 87%. Improved methods to differentiate
             benign from malignant calcifications are thus needed.
             Purpose To quantify the growth rates of DCIS and benign
             breast disease that manifest as mammographic calcifications.
             Materials and Methods All calcifications (n = 2359) for
             which a stereotactic biopsy was performed from 2008 through
             2015 at Duke University Medical Center were retrospectively
             identified. Mammograms from all cases of DCIS (n = 404) were
             reviewed for calcifications that were visible on mammograms
             taken at least 6 months before biopsy. Women with at least
             one prior mammogram with visible calcifications were age-
             and race-matched 1:2 to women with a benign breast biopsy
             and calcifications visible on prior mammograms. The long
             axis of the calcifications was measured on all mammograms.
             Multivariable adjusted linear mixed-effects models estimated
             the association of calcification growth rates with patholo
             findings. Hierarchical clustering accounted for matching
             benign and DCIS groups. Results A total of 74 DCIS
             calcifications and 148 benign calcifications were included
             for final analysis. The median patient age was 62 years
             (interquartile range, 51-71 years). No significant
             difference in breast density (P > .05) or number of
             available mammograms (P > .05) was detected between groups.
             Calcifications associated with DCIS were larger than those
             associated with benign breast disease at biopsy (median, 10
             mm vs 6 mm, respectively; P < .001). After adjustment, the
             relative annual increase in the long-axis length of DCIS
             calcifications was greater than that of benign breast
             calcifications (96% [95% confidence interval: 72%, 224%] vs
             68% [95% confidence interval: 56%, 80%] per year,
             respectively; P < .001). Conclusion Ductal carcinoma in situ
             calcifications are more extensive at diagnosis and grow
             faster in extent than those associated with benign breast
             disease. The rate of calcification change may help to
             discriminate benign from malignant calcifications. © RSNA,
             2019 Online supplemental material is available for this
   Doi = {10.1148/radiol.2019182599},
   Key = {fds343483}

   Author = {Ryser, MD and Horton, JK and Hwang, ES},
   Title = {How Low Can We Go-and Should We? Risk Reduction for
             Minimal-Volume DCIS.},
   Journal = {Annals of Surgical Oncology},
   Volume = {25},
   Number = {2},
   Pages = {354-355},
   Year = {2018},
   Month = {February},
   url = {},
   Doi = {10.1245/s10434-017-6128-4},
   Key = {fds339496}

   Author = {Ryser, MD and Myers, ER and Durrett, R},
   Title = {HPV clearance and the neglected role of stochasticity.},
   Journal = {Plos Computational Biology},
   Volume = {11},
   Number = {3},
   Pages = {e1004113},
   Year = {2015},
   Month = {March},
   url = {},
   Abstract = {Clearance of anogenital and oropharyngeal HPV infections is
             attributed primarily to a successful adaptive immune
             response. To date, little attention has been paid to the
             potential role of stochastic cell dynamics in the time it
             takes to clear an HPV infection. In this study, we combine
             mechanistic mathematical models at the cellular level with
             epidemiological data at the population level to disentangle
             the respective roles of immune capacity and cell dynamics in
             the clearing mechanism. Our results suggest that chance-in
             form of the stochastic dynamics of basal stem cells-plays a
             critical role in the elimination of HPV-infected cell
             clones. In particular, we find that in immunocompetent
             adolescents with cervical HPV infections, the immune
             response may contribute less than 20% to virus clearance-the
             rest is taken care of by the stochastic proliferation
             dynamics in the basal layer. In HIV-negative individuals,
             the contribution of the immune response may be
   Doi = {10.1371/journal.pcbi.1004113},
   Key = {fds339507}

   Author = {Ryser, MD and Gulati, R and Eisenberg, MC and Shen, Y and Hwang, ES and Etzioni, RB},
   Title = {Identification of the Fraction of Indolent Tumors and
             Associated Overdiagnosis in Breast Cancer Screening
   Journal = {American Journal of Epidemiology},
   Volume = {188},
   Number = {1},
   Pages = {197-205},
   Year = {2019},
   Month = {January},
   url = {},
   Abstract = {It is generally accepted that some screen-detected breast
             cancers are overdiagnosed and would not progress to
             symptomatic cancer if left untreated. However, precise
             estimates of the fraction of nonprogressive cancers remain
             elusive. In recognition of the weaknesses of overdiagnosis
             estimation methods based on excess incidence, there is a
             need for model-based approaches that accommodate
             nonprogressive lesions. Here, we present an in-depth
             analysis of a generalized model of breast cancer natural
             history that allows for a mixture of progressive and
             indolent lesions. We provide a formal proof of global
             structural identifiability of the model and use simulation
             to identify conditions that allow for parameter estimates
             that are sufficiently precise and practically actionable. We
             show that clinical follow-up after the last screening can
             play a critical role in ensuring adequately precise
             identification of the fraction of indolent cancers in a
             stop-screen trial design, and we demonstrate that model
             misspecification can lead to substantially biased estimates
             of mean sojourn time. Finally, we illustrate our findings
             using the example of Canadian National Breast Screening
             Study 2 (1980-1985) and show that the fraction of indolent
             cancers is not precisely identifiable. Our findings provide
             the foundation for extended models that account for both in
             situ and invasive lesions.},
   Doi = {10.1093/aje/kwy214},
   Key = {fds339494}

   Author = {Ryser, MD and McGoff, K and Herzog, DP and Sivakoff, DJ and Myers,
   Title = {Impact of coverage-dependent marginal costs on optimal HPV
             vaccination strategies.},
   Journal = {Epidemics},
   Volume = {11},
   Pages = {32-47},
   Year = {2015},
   Month = {June},
   ISSN = {1755-4365},
   url = { Duke open
   Abstract = {The effectiveness of vaccinating males against the human
             papillomavirus (HPV) remains a controversial subject. Many
             existing studies conclude that increasing female coverage is
             more effective than diverting resources into male
             vaccination. Recently, several empirical studies on HPV
             immunization have been published, providing evidence of the
             fact that marginal vaccination costs increase with coverage.
             In this study, we use a stochastic agent-based modeling
             framework to revisit the male vaccination debate in light of
             these new findings. Within this framework, we assess the
             impact of coverage-dependent marginal costs of vaccine
             distribution on optimal immunization strategies against HPV.
             Focusing on the two scenarios of ongoing and new vaccination
             programs, we analyze different resource allocation policies
             and their effects on overall disease burden. Our results
             suggest that if the costs associated with vaccinating males
             are relatively close to those associated with vaccinating
             females, then coverage-dependent, increasing marginal costs
             may favor vaccination strategies that entail immunization of
             both genders. In particular, this study emphasizes the
             necessity for further empirical research on the nature of
             coverage-dependent vaccination costs.},
   Doi = {10.1016/j.epidem.2015.01.003},
   Key = {fds244097}

   Author = {Ryser, MD and Hendrix, LH and Worni, M and Liu, Y and Hyslop, T and Hwang,
   Title = {Incidence of Ductal Carcinoma In Situ in the United States,
   Journal = {Cancer Epidemiol Biomarkers Prev},
   Volume = {28},
   Number = {8},
   Pages = {1316-1323},
   Year = {2019},
   Month = {August},
   url = {},
   Abstract = {BACKGROUND: In absence of definitive molecular risk markers,
             clinical management of patients diagnosed with ductal
             carcinoma in situ (DCIS) remains largely guided by patient
             and tumor characteristics. In this study, we analyzed recent
             trends in DCIS incidence and compared them against trends in
             mammography use. METHODS: The Surveillance, Epidemiology,
             and End Results registry was queried for patients diagnosed
             with DCIS from 2000 to 2014 (18 registries). Joinpoint
             regression analyses were used to compute age- and
             race-stratified trends in age-adjusted incidence of DCIS.
             The patterns of DCIS incidence were compared against
             mammography utilization data from the National Health
             Interview Survey. RESULTS: Between 2000 and 2014, overall
             DCIS incidence in the U.S. population was stable (P = 0.24).
             Among age groups 20 to 44 years and 45 to 55 years, DCIS
             incidence increased by 1.3% (P = 0.001) and 0.6% (P = 0.02)
             per year, respectively. Although stable among white women,
             DCIS incidence increased among black women and women of
             other races by 1.6% (P < 0.001) and 1.0% (P = 0.002) per
             year, respectively. Mammography uptake correlated well with
             DCIS incidence, with the exception of women ages 40 to 49
             years and black women who experienced an increase in DCIS
             incidence despite stagnating and decreasing mammography
             uptake, respectively. CONCLUSIONS: Overall DCIS incidence
             rates have remained stable between 2000 and 2014. However,
             subgroup analyses revealed an increase in incidence among
             both younger women and black women. IMPACT: DCIS incidence
             trends did not correlate with the mammography uptake
             patterns, suggesting that etiologic factors other than
             screening may be leading to an increased DCIS incidence in
             these groups.},
   Doi = {10.1158/1055-9965.EPI-18-1262},
   Key = {fds345487}

   Author = {Ryser, MD and Sorribes, IC and Greenwald, M and Wu, E and Hall, A and Mallo, D and King, LM and Hardman, T and Simpson, L and Maley, CC and Marks, JR and Shibata, D and Hwang, ES},
   Title = {Inferring the evolutionary dynamics of ductal carcinoma in
             situ through multi-regional sequencing and mathematical
   Journal = {Cancer Research},
   Volume = {80},
   Number = {21},
   Year = {2020},
   Key = {fds354106}

   Author = {Fridman, I and Kumaresan, V and Vijendra, P and Seshadri, P and Garland,
             S and Kim, G and Fagerlin, A and Ubel, PA and Ryser,
   Journal = {Medical Decision Making : an International Journal of the
             Society for Medical Decision Making},
   Volume = {40},
   Number = {1},
   Pages = {E183-E184},
   Year = {2020},
   Month = {January},
   Key = {fds349462}

   Author = {Lehning, M and Loewe, H and Ryser, MD and Raderschall,
   Title = {Inhomogeneous precipitation distribution and snow transport
             in steep terrain},
   Journal = {Water Resour. Res.},
   Year = {2008},
   url = {},
   Key = {fds244100}

   Author = {Ryser, MD and Hendrix, L and Thomas, SM and Lynch, T and McCarthy, A and Mohammed, Z and Francescatti, AB and Frank, ES and Partridge, AH and Thompson, AM and Hyslop, T and Hwang, E-SS},
   Title = {Ipsilateral invasive cancer risk after diagnosis with ductal
             carcinoma in situ (DCIS): Comparison of patients with and
             without index surgery.},
   Journal = {Journal of Clinical Oncology : Official Journal of the
             American Society of Clinical Oncology},
   Volume = {38},
   Number = {15},
   Year = {2020},
   Key = {fds354108}

   Author = {Ryser, MD and Rushing, CN and Thomas, SM and Lynch, T and McCarthy, A and Mohammed, ZA and Francescatti, AB and Frank, ES and Partridge, AH and Thompson, AM and Hyslop, T and Hwang, ES},
   Title = {Ipsilateral invasive cancer risk after diagnosis with ductal
             carcinoma in situ in patients with and without index
             surgery: The effects of endocrine therapy and radiation
   Journal = {Cancer Research},
   Volume = {81},
   Number = {4},
   Year = {2021},
   Key = {fds366619}

   Author = {van Seijen, M and Lips, EH and Fu, L and Giardiello, D and van
             Duijnhoven, F and de Munck, L and Elshof, LE and Thompson, A and Sawyer,
             E and Ryser, MD and Hwang, ES and Schmidt, MK and Elkhuizen, PHM and Grand
             Challenge PRECISION Consortium, and Wesseling, J and Schaapveld,
   Title = {Long-term risk of subsequent ipsilateral lesions after
             surgery with or without radiotherapy for ductal carcinoma in
             situ of the breast.},
   Journal = {Br J Cancer},
   Volume = {125},
   Number = {10},
   Pages = {1443-1449},
   Year = {2021},
   Month = {November},
   url = {},
   Abstract = {BACKGROUND: Radiotherapy (RT) following breast-conserving
             surgery (BCS) for ductal carcinoma in situ (DCIS) reduces
             ipsilateral breast event rates in clinical trials. This
             study assessed the impact of DCIS treatment on a 20-year
             risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive
             breast cancer (iIBC) in a population-based cohort. METHODS:
             The cohort comprised all women diagnosed with DCIS in the
             Netherlands during 1989-2004 with follow-up until 2017.
             Cumulative incidence of iDCIS and iIBC following BCS and
             BCS + RT were assessed. Associations of DCIS treatment
             with iDCIS and iIBC risk were estimated in multivariable Cox
             models. RESULTS: The 20-year cumulative incidence of any
             ipsilateral breast event was 30.6% (95% confidence interval
             (CI): 28.9-32.6) after BCS compared to 18.2% (95% CI
             16.3-20.3) following BCS  +  RT. Women treated with
             BCS compared to BCS + RT had higher risk of developing
             iDCIS and iIBC within 5 years after DCIS diagnosis (for
             iDCIS: hazard ratio (HR)age < 50 3.2 (95% CI 1.6-6.6);
             HRage ≥ 50 3.6 (95% CI 2.6-4.8) and for iIBC: HRage<50
             2.1 (95% CI 1.4-3.2); HRage ≥ 50 4.3 (95% CI
             3.0-6.0)). After 10 years, the risk of iDCIS and iIBC no
             longer differed for BCS versus BCS + RT (for iDCIS:
             HRage < 50 0.7 (95% CI 0.3-1.5); HRage ≥ 50 0.7
             (95% CI 0.4-1.3) and for iIBC: HRage < 50 0.6 (95% CI
             0.4-0.9); HRage ≥ 50 1.2 (95% CI 0.9-1.6)).
             CONCLUSION: RT is associated with lower iDCIS and iIBC risk
             up to 10 years after BCS, but this effect wanes
   Doi = {10.1038/s41416-021-01496-6},
   Key = {fds358880}

   Author = {Ryser, MD and Komarova, SV},
   Title = {Mathematical Modeling of Cancer Metastases},
   Pages = {211-230},
   Booktitle = {Computational Bioengineering},
   Publisher = {CRC},
   Year = {2015},
   Month = {January},
   ISBN = {9781466517561},
   url = {},
   Abstract = {Most cancer types develop the ability to leave their site of
             origin and spread to distant organs to form metastases, also
             called secondary cancers. Metastases are the most common
             cause of death among cancer patients, and hence there is an
             immense clinical interest to understand the underlying
             biological mechanisms and to develop preventive and
             therapeutic measures. Over the past decades, an increasing
             number of applied mathematicians and biomedical engineers
             have taken on the challenge to design models and devise in
             silico tools for the study of cancer and cancer metastases.
             The goals of this chapter are to introduce to the reader the
             important challenges in the field of metastases and to give
             an overview of the existing modeling tools. Guided by
             pertinent biological questions, we review a number of
             deterministic and stochastic approaches and discuss their
             potential and limitations.},
   Doi = {10.1201/b18320-13},
   Key = {fds367152}

   Author = {Ryser, MD and Nigam, N and Komarova, SV},
   Title = {Mathematical modeling of spatio-temporal dynamics of a
             single bone multicellular unit.},
   Journal = {J Bone Miner Res},
   Volume = {24},
   Number = {5},
   Pages = {860-870},
   Year = {2009},
   Month = {May},
   url = {},
   Abstract = {During bone remodeling, bone-resorbing osteoclasts and
             bone-forming osteoblasts are organized in bone multicellular
             units (BMUs), which travel at a rate of 20-40 mum/d for 6-12
             mo, maintaining a cylindrical structure. However, the
             interplay of local BMU geometry with biochemical regulation
             is poorly understood. We developed a mathematical model of
             BMU describing changes in time and space of the
             concentrations of proresorptive cytokine RANKL and its
             inhibitor osteoprotegerin (OPG), in osteoclast and
             osteoblast numbers, and in bone mass. We assumed that
             osteocytes surrounding a microfracture produce RANKL, which
             attracted osteoclasts. OPG and RANKL were produced by
             osteoblasts and diffused through bone, RANKL was eliminated
             by binding to OPG and RANK. Osteoblasts were coupled to
             osteoclasts through paracrine factors. The evolution of the
             BMU arising from this model was studied using numerical
             simulations. Our model recapitulated the spatio-temporal
             dynamics observed in vivo in a cross-section of bone. In
             response to a RANKL field, osteoclasts moved as a
             well-confined cutting cone. The coupling of osteoclasts to
             osteoblasts allowed for sufficient recruitment of
             osteoblasts to the resorbed surfaces. The RANKL field was
             the highest at the microfracture in front of the BMU,
             whereas the OPG field peaked at the back of the BMU,
             resulting in the formation of a RANKL/OPG gradient, which
             strongly affected the rate of BMU progression and its size.
             Thus, the spatial organization of a BMU provides important
             constraints on the roles of RANKL and OPG as well as
             possibly other regulators in determining the outcome of
             remodeling in the BMU.},
   Doi = {10.1359/jbmr.081229},
   Key = {fds244101}

   Author = {Ryser, MD and Gravitt, PE and Myers, ER},
   Title = {Mechanistic mathematical models: An underused platform for
             HPV research.},
   Journal = {Papillomavirus Research (Amsterdam, Netherlands)},
   Volume = {3},
   Pages = {46-49},
   Year = {2017},
   Month = {June},
   url = {},
   Abstract = {Health economic modeling has become an invaluable
             methodology for the design and evaluation of clinical and
             public health interventions against the human papillomavirus
             (HPV) and associated diseases. At the same time, relatively
             little attention has been paid to a different yet
             complementary class of models, namely that of mechanistic
             mathematical models. The primary focus of mechanistic
             mathematical models is to better understand the intricate
             biologic mechanisms and dynamics of disease. Inspired by a
             long and successful history of mechanistic modeling in other
             biomedical fields, we highlight several areas of HPV
             research where mechanistic models have the potential to
             advance the field. We argue that by building quantitative
             bridges between biologic mechanism and population level
             data, mechanistic mathematical models provide a unique
             platform to enable collaborations between experimentalists
             who collect data at different physical scales of the HPV
             infection process. Through such collaborations, mechanistic
             mathematical models can accelerate and enhance the
             investigation of HPV and related diseases.},
   Doi = {10.1016/j.pvr.2017.01.004},
   Key = {fds339502}

   Author = {Ryser, MD and Mallo, D and Hall, A and Hardman, T and King, LM and Tatishchev, S and Sorribes, IC and Maley, CC and Marks, JR and Hwang,
             ES and Shibata, D},
   Title = {Minimal barriers to invasion during human colorectal tumor
   Journal = {Nature Communications},
   Volume = {11},
   Number = {1},
   Pages = {1280},
   Year = {2020},
   Month = {March},
   url = {},
   Abstract = {Intra-tumoral heterogeneity (ITH) could represent clonal
             evolution where subclones with greater fitness confer more
             malignant phenotypes and invasion constitutes an
             evolutionary bottleneck. Alternatively, ITH could represent
             branching evolution with invasion of multiple subclones. The
             two models respectively predict a hierarchy of subclones
             arranged by phenotype, or multiple subclones with shared
             phenotypes. We delineate these modes of invasion by merging
             ancestral, topographic, and phenotypic information from 12
             human colorectal tumors (11 carcinomas, 1 adenoma) obtained
             through saturation microdissection of 325 small tumor
             regions. The majority of subclones (29/46, 60%) share
             superficial and invasive phenotypes. Of 11 carcinomas, 9
             show evidence of multiclonal invasion, and invasive and
             metastatic subclones arise early along the ancestral trees.
             Early multiclonal invasion in the majority of these tumors
             indicates the expansion of co-evolving subclones with
             similar malignant potential in absence of late bottlenecks
             and suggests that barriers to invasion are minimal during
             colorectal cancer growth.},
   Doi = {10.1038/s41467-020-14908-7},
   Key = {fds348805}

   Author = {Schapiro, D and Yapp, C and Sokolov, A and Reynolds, SM and Chen, Y-A and Sudar, D and Xie, Y and Muhlich, J and Arias-Camison, R and Arena, S and Taylor, AJ and Nikolov, M and Tyler, M and Lin, J-R and Burlingame, EA and Human Tumor Atlas Network, and Chang, YH and Farhi, SL and Thorsson,
             V and Venkatamohan, N and Drewes, JL and Pe'er, D and Gutman, DA and Herrmann, MD and Gehlenborg, N and Bankhead, P and Roland, JT and Herndon, JM and Snyder, MP and Angelo, M and Nolan, G and Swedlow, JR and Schultz, N and Merrick, DT and Mazzili, SA and Cerami, E and Rodig, SJ and Santagata, S and Sorger, PK},
   Title = {MITI minimum information guidelines for highly multiplexed
             tissue images.},
   Journal = {Nat Methods},
   Volume = {19},
   Number = {3},
   Pages = {262-267},
   Year = {2022},
   Month = {March},
   url = {},
   Abstract = {The imminent release of tissue atlases combining
             multi-channel microscopy with single cell sequencing and
             other omics data from normal and diseased specimens creates
             an urgent need for data and metadata standards that guide
             data deposition, curation and release. We describe a Minimum
             Information about highly multiplexed Tissue Imaging (MITI)
             standard that applies best practices developed for genomics
             and other microscopy data to highly multiplexed tissue
             images and traditional histology.},
   Doi = {10.1038/s41592-022-01415-4},
   Key = {fds367148}

   Author = {Ryser, MD and Rositch, A and Gravitt, PE},
   Title = {Modeling of US Human Papillomavirus (HPV) Seroprevalence by
             Age and Sexual Behavior Indicates an Increasing Trend of HPV
             Infection Following the Sexual Revolution.},
   Journal = {J Infect Dis},
   Volume = {216},
   Number = {5},
   Pages = {604-611},
   Year = {2017},
   Month = {September},
   url = {},
   Abstract = {BACKGROUND: The United States has experienced an increase in
             the incidence of human papillomavirus (HPV)-related cancers
             that are not screen-detectable. It has been hypothesized,
             but not directly demonstrated, that this is due to
             increasing HPV prevalence in the unvaccinated population.
             METHODS: Female self-reported numbers of lifetime sex
             partners and HPV serology from the National Health and
             Nutrition Examination Survey (NHANES) were used to develop
             mathematical models of sexual partner acquisition and
             antibody dynamics. Modeled trends in sexual behaviors were
             compared to incidence data for cervical adenocarcinoma,
             oropharyngeal cancer, and anal cancer. RESULTS: The
             age-specific HPV seroprevalence data were best explained by
             a partner acquisition model that explicitly accounted for
             cohort-dependent changes in sexual behavior. Estimates of
             the mean time to loss of natural antibodies varied by model,
             ranging from 49 to 145 years. Inferred trends in sexual
             behavior over the past decades paralleled the increasing
             incidence of HPV-related cancers in the United States.
             CONCLUSIONS: The findings suggest that lower HPV
             seroprevalence in older US women primarily reflects
             cohort-specific differences in sexual behaviors, and is only
             marginally attributable to immune waning with age. Our
             results emphasize the importance of continuing surveillance
             of sexual behaviors, alongside vaccine status, to predict
             future disease burden.},
   Doi = {10.1093/infdis/jix333},
   Key = {fds339501}

   Author = {Chootipongchaivat, S and van Ravesteyn, NT and Li, X and Huang, H and Weedon-Fekjær, H and Ryser, MD and Weaver, DL and Burnside, ES and Heckman-Stoddard, BM and de Koning, HJ and Lee,
   Title = {Modeling the natural history of ductal carcinoma in situ
             based on population data.},
   Journal = {Breast Cancer Res},
   Volume = {22},
   Number = {1},
   Pages = {53},
   Year = {2020},
   Month = {May},
   url = {},
   Abstract = {BACKGROUND: The incidence of ductal carcinoma in situ (DCIS)
             has increased substantially since the introduction of
             mammography screening. Nevertheless, little is known about
             the natural history of preclinical DCIS in the absence of
             biopsy or complete excision. METHODS: Two well-established
             population models evaluated six possible DCIS natural
             history submodels. The submodels assumed 30%, 50%, or 80% of
             breast lesions progress from undetectable DCIS to
             preclinical screen-detectable DCIS; each model additionally
             allowed or prohibited DCIS regression. Preclinical
             screen-detectable DCIS could also progress to clinical DCIS
             or invasive breast cancer (IBC). Applying US population
             screening dissemination patterns, the models projected
             age-specific DCIS and IBC incidence that were compared to
             Surveillance, Epidemiology, and End Results data. Models
             estimated mean sojourn time (MST) in the preclinical
             screen-detectable DCIS state, overdiagnosis, and the risk of
             progression from preclinical screen-detectable DCIS.
             RESULTS: Without biopsy and surgical excision, the majority
             of DCIS (64-100%) in the preclinical screen-detectable state
             progressed to IBC in submodels assuming no DCIS regression
             (36-100% in submodels allowing for DCIS regression). DCIS
             overdiagnosis differed substantially between models and
             submodels, 3.1-65.8%. IBC overdiagnosis ranged 1.3-2.4%.
             Submodels assuming DCIS regression resulted in a higher DCIS
             overdiagnosis than submodels without DCIS regression. MST
             for progressive DCIS varied between 0.2 and 2.5 years.
             CONCLUSIONS: Our findings suggest that the majority of
             screen-detectable but unbiopsied preclinical DCIS lesions
             progress to IBC and that the MST is relatively short.
             Nevertheless, due to the heterogeneity of DCIS, more
             research is needed to understand the progression of DCIS by
             grades and molecular subtypes.},
   Doi = {10.1186/s13058-020-01287-6},
   Key = {fds350405}

   Author = {Foo, J and Leder, K and Ryser, MD},
   Title = {Multifocality and recurrence risk: a quantitative model of
             field cancerization.},
   Journal = {J Theor Biol},
   Volume = {355},
   Pages = {170-184},
   Year = {2014},
   Month = {August},
   url = {},
   Abstract = {Primary tumors often emerge within genetically altered
             fields of premalignant cells that appear histologically
             normal but have a high chance of progression to malignancy.
             Clinical observations have suggested that these premalignant
             fields pose high risks for emergence of recurrent tumors if
             left behind after surgical removal of the primary tumor. In
             this work, we develop a spatio-temporal stochastic model of
             epithelial carcinogenesis, combining cellular dynamics with
             a general framework for multi-stage genetic progression to
             cancer. Using the model, we investigate how various
             properties of the premalignant fields depend on microscopic
             cellular properties of the tissue. In particular, we provide
             analytic results for the size-distribution of the
             histologically undetectable premalignant fields at the time
             of diagnosis, and investigate how the extent and the
             geometry of these fields depend upon key groups of
             parameters associated with the tissue and genetic pathways.
             We also derive analytical results for the relative risks of
             local vs. distant secondary tumors for different parameter
             regimes, a critical aspect for the optimal choice of
             post-operative therapy in carcinoma patients. This study
             contributes to a growing literature seeking to obtain a
             quantitative understanding of the spatial dynamics in cancer
   Doi = {10.1016/j.jtbi.2014.02.042},
   Key = {fds339510}

   Author = {Ryser, MD and Nigam, N and Tupper, PF},
   Title = {On the well-posedness of the stochastic Allen-Cahn equation
             in two dimensions},
   Journal = {Journal of Computational Physics},
   Volume = {231},
   Number = {6},
   Pages = {2537-2550},
   Year = {2012},
   Month = {March},
   url = {},
   Abstract = {White noise-driven nonlinear stochastic partial differential
             equations (SPDEs) of parabolic type are frequently used to
             model physical systems in space dimensions d= 1, 2, 3.
             Whereas existence and uniqueness of weak solutions to these
             equations are well established in one dimension, the
             situation is different for d≥ 2. Despite their popularity
             in the applied sciences, higher dimensional versions of
             these SPDE models are generally assumed to be ill-posed by
             the mathematics community. We study this discrepancy on the
             specific example of the two dimensional Allen-Cahn equation
             driven by additive white noise. Since it is unclear how to
             define the notion of a weak solution to this equation, we
             regularize the noise and introduce a family of
             approximations. Based on heuristic arguments and numerical
             experiments, we conjecture that these approximations exhibit
             divergent behavior in the continuum limit. The results
             strongly suggest that shrinking the mesh size in simulations
             of the two-dimensional white noise-driven Allen-Cahn
             equation does not lead to the recovery of a physically
             meaningful limit. © 2011 .},
   Doi = {10.1016/},
   Key = {fds303560}

   Author = {Ryser, MD and Qu, Y and Komarova, SV},
   Title = {Osteoprotegerin in bone metastases: mathematical solution to
             the puzzle.},
   Journal = {Plos Computational Biology},
   Volume = {8},
   Number = {10},
   Pages = {e1002703},
   Year = {2012},
   url = {},
   Abstract = {Bone is a common site for cancer metastasis. To create space
             for their growth, cancer cells stimulate bone resorbing
             osteoclasts. Cytokine RANKL is a key osteoclast activator,
             while osteoprotegerin (OPG) is a RANKL decoy receptor and an
             inhibitor of osteoclastogenesis. Consistently, systemic
             application of OPG decreases metastatic tumor burden in
             bone. However, OPG produced locally by cancer cells was
             shown to enhance osteolysis and tumor growth. We propose
             that OPG produced by cancer cells causes a local reduction
             in RANKL levels, inducing a steeper RANKL gradient away from
             the tumor and towards the bone tissue, resulting in faster
             resorption and tumor expansion. We tested this hypothesis
             using a mathematical model of nonlinear partial differential
             equations describing the spatial dynamics of OPG, RANKL,
             PTHrP, osteoclasts, tumor and bone mass. We demonstrate that
             at lower expression rates, tumor-derived OPG enhances the
             chemotactic RANKL gradient and osteolysis, whereas at higher
             expression rates OPG broadly inhibits RANKL and decreases
             osteolysis and tumor burden. Moreover, tumor expression of a
             soluble mediator inducing RANKL in the host tissue, such as
             PTHrP, is important for correct orientation of the RANKL
             gradient. A meta-analysis of OPG, RANKL and PTHrP expression
             in normal prostate, carcinoma and metastatic tissues
             demonstrated an increase in expression of OPG, but not
             RANKL, in metastatic prostate cancer, and positive
             correlation between OPG and PTHrP in metastatic prostate
             cancer. The proposed mechanism highlights the importance of
             the spatial distribution of receptors, decoys and ligands,
             and can be applied to other systems involving regulation of
             spatially anisotropic processes.},
   Doi = {10.1371/journal.pcbi.1002703},
   Key = {fds244098}

   Author = {Ryser, MD and Worni, M and Turner, EL and Marks, JR and Durrett, R and Hwang, ES},
   Title = {Outcomes of Active Surveillance for Ductal Carcinoma in
             Situ: A Computational Risk Analysis.},
   Journal = {J Natl Cancer Inst},
   Volume = {108},
   Number = {5},
   Pages = {djv372},
   Year = {2016},
   Month = {May},
   url = {},
   Abstract = {BACKGROUND: Ductal carcinoma in situ (DCIS) is a noninvasive
             breast lesion with uncertain risk for invasive progression.
             Usual care (UC) for DCIS consists of treatment upon
             diagnosis, thus potentially overtreating patients with low
             propensity for progression. One strategy to reduce
             overtreatment is active surveillance (AS), whereby DCIS is
             treated only upon detection of invasive disease. Our goal
             was to perform a quantitative evaluation of outcomes
             following an AS strategy for DCIS. METHODS: Age-stratified,
             10-year disease-specific cumulative mortality (DSCM) for AS
             was calculated using a computational risk projection model
             based upon published estimates for natural history
             parameters, and Surveillance, Epidemiology, and End Results
             data for outcomes. AS projections were compared with the
             DSCM for patients who received UC. To quantify the
             propagation of parameter uncertainty, a 95% projection range
             (PR) was computed, and sensitivity analyses were performed.
             RESULTS: Under the assumption that AS cannot outperform UC,
             the projected median differences in 10-year DSCM between AS
             and UC when diagnosed at ages 40, 55, and 70 years were 2.6%
             (PR = 1.4%-5.1%), 1.5% (PR = 0.5%-3.5%), and 0.6% (PR =
             0.0%-2.4), respectively. Corresponding median numbers of
             patients needed to treat to avert one breast cancer death
             were 38.3 (PR = 19.7-69.9), 67.3 (PR = 28.7-211.4), and
             157.2 (PR = 41.1-3872.8), respectively. Sensitivity analyses
             showed that the parameter with greatest impact on DSCM was
             the probability of understaging invasive cancer at
             diagnosis. CONCLUSION: AS could be a viable management
             strategy for carefully selected DCIS patients, particularly
             among older age groups and those with substantial competing
             mortality risks. The effectiveness of AS could be markedly
             improved by reducing the rate of understaging.},
   Doi = {10.1093/jnci/djv372},
   Key = {fds339504}

   Author = {Cao, Y and Feng, Y and Ryser, MD and Zhu, K and Herschlag, G and Cao, C and Marusak, K and Zauscher, S and You, L},
   Title = {Programmable assembly of pressure sensors using
             pattern-forming bacteria.},
   Journal = {Nat Biotechnol},
   Volume = {35},
   Number = {11},
   Pages = {1087-1093},
   Year = {2017},
   Month = {November},
   url = {},
   Abstract = {Biological systems can generate microstructured materials
             that combine organic and inorganic components and possess
             diverse physical and chemical properties. However, these
             natural processes in materials fabrication are not readily
             programmable. Here, we use a synthetic-biology approach to
             assemble patterned materials. We demonstrate programmable
             fabrication of three-dimensional (3D) materials by printing
             engineered self-patterning bacteria on permeable membranes
             that serve as a structural scaffold. Application of gold
             nanoparticles to the colonies creates hybrid
             organic-inorganic dome structures. The dynamics of the dome
             structures' response to pressure is determined by their
             geometry (colony size, dome height, and pattern), which is
             easily modified by varying the properties of the membrane
             (e.g., pore size and hydrophobicity). We generate resettable
             pressure sensors that process signals in response to varying
             pressure intensity and duration.},
   Doi = {10.1038/nbt.3978},
   Key = {fds339500}

   Author = {Ryser, MD and Lee, WT and Ready, NE and Leder, KZ and Foo,
   Title = {Quantifying the Dynamics of Field Cancerization in
             Tobacco-Related Head and Neck Cancer: A Multiscale Modeling
   Journal = {Cancer Res},
   Volume = {76},
   Number = {24},
   Pages = {7078-7088},
   Year = {2016},
   Month = {December},
   url = {},
   Abstract = {High rates of local recurrence in tobacco-related head and
             neck squamous cell carcinoma (HNSCC) are commonly attributed
             to unresected fields of precancerous tissue. Because they
             are not easily detectable at the time of surgery without
             additional biopsies, there is a need for noninvasive methods
             to predict the extent and dynamics of these fields. Here, we
             developed a spatial stochastic model of tobacco-related
             HNSCC at the tissue level and calibrated the model using a
             Bayesian framework and population-level incidence data from
             the Surveillance, Epidemiology, and End Results (SEER)
             registry. Probabilistic model analyses were performed to
             predict the field geometry at time of diagnosis, and model
             predictions of age-specific recurrence risks were tested
             against outcome data from SEER. The calibrated models
             predicted a strong dependence of the local field size on age
             at diagnosis, with a doubling of the expected field diameter
             between ages at diagnosis of 50 and 90 years, respectively.
             Similarly, the probability of harboring multiple, clonally
             unrelated fields at the time of diagnosis was found to
             increase substantially with patient age. On the basis of
             these findings, we hypothesized a higher recurrence risk in
             older than in younger patients when treated by surgery
             alone; we successfully tested this hypothesis using
             age-stratified outcome data. Further clinical studies are
             needed to validate the model predictions in a
             patient-specific setting. This work highlights the
             importance of spatial structure in models of epithelial
             carcinogenesis and suggests that patient age at diagnosis
             may be a critical predictor of the size and multiplicity of
             precancerous lesions. Cancer Res; 76(24); 7078-88. ©2016
   Doi = {10.1158/0008-5472.CAN-16-1054},
   Key = {fds354110}

   Author = {Rodriguez-Homs, LG and Hammill, BG and Ryser, MD and Phillips, HR and Mosca, PJ},
   Title = {Relationship Between HCAHPS Scores and Survey Response Rate
             Is Linked to Hospital Size.},
   Journal = {J Patient Exp},
   Volume = {7},
   Number = {6},
   Pages = {1543-1548},
   Year = {2020},
   Month = {December},
   url = {},
   Abstract = {Patient experience is an important dimension of health care
             quality and is assessed using the standard Hospital Consumer
             Assessment of Healthcare Providers and Systems (HCAHPS)
             survey for inpatients. The HCAHPS scores may vary based on
             survey response rate and hospital size. The objective of
             this study was to describe the association between survey
             response rate and HCAHPS scores and examine whether the
             relationship varies based on hospital size. Medicare's
             Hospital Compare publicly reported HCAHPS data were used.
             Pearson correlation, controlling for number of staffed beds,
             and linear regression models were used for the analysis.
             Hospitals were grouped into quartiles based on number of
             staffed beds to delineate the effect of increasing hospital
             size on the relationship between survey response rate and
             HCAHPS scores. A significant association between HCAHPS
             survey response rate and all examined HCAHPS domain scores
             was observed. The effect size across HCAHPS domains varied
             based on hospital size. The relationship between HCAHPS
             score and survey response rate differed significantly
             between hospitals in the smallest and largest size quartiles
             for discharge information, nurse communication, and hospital
             quietness. While a causal relationship cannot be inferred
             from this study, the response rate could be a direct and/or
             indirect driver of HCAHPS scores. Future research should be
             aimed to further explore the basis of this relationship and
             to determine how it may inform the interpretation of HCAHPS
   Doi = {10.1177/2374373520932458},
   Key = {fds355730}

   Author = {Ryser, MD and Hwang, ES},
   Title = {Response to Habel and Buist.},
   Journal = {J Natl Cancer Inst},
   Volume = {112},
   Number = {2},
   Pages = {216-217},
   Year = {2020},
   Month = {February},
   url = {},
   Doi = {10.1093/jnci/djz120},
   Key = {fds349461}

   Author = {Shehata, MN and Rahbar, H and Flanagan, MR and Kilgore, MR and Lee, CI and Ryser, MD and Lowry, KP},
   Title = {Risk for Upgrade to Malignancy After Breast Core Needle
             Biopsy Diagnosis of Lobular Neoplasia: A Systematic Review
             and Meta-Analysis.},
   Journal = {Journal of the American College of Radiology :
   Volume = {17},
   Number = {10},
   Pages = {1207-1219},
   Year = {2020},
   Month = {October},
   url = {},
   Abstract = {PURPOSE: Lobular neoplasia (LN) detected on breast core
             needle biopsy is frequently managed with surgical excision
             because of concern for undersampled malignancy. The authors
             performed a systematic review and meta-analysis to estimate
             the risk for upgrade to malignancy in the setting of
             imaging-concordant classic LN diagnosed on core biopsy.
             METHODS: PubMed and Embase were searched for original
             articles published from 1998 to 2020 that reported rates of
             upgrade to malignancy for classic LN, including atypical
             lobular hyperplasia (ALH) and classic lobular carcinoma in
             situ (LCIS). Two reviewers extracted study data and assessed
             the following quality criteria: exclusion of variant LCIS,
             exclusion of imaging-discordant lesions, and outcome
             reporting for ≥70% of lesions. For studies meeting all
             criteria, pooled risks for upgrade to any malignancy
             (invasive carcinoma or ductal carcinoma in situ) and
             invasive malignancy for all LN, ALH, and LCIS were estimated
             using random-effects models. RESULTS: For 65 full-text
             articles included in the review, the risk for upgrade to any
             malignancy ranged from 0% to 45%. Among the 16 studies that
             met all quality criteria for the meta-analysis, pooled
             risks for upgrade to any malignancy were 3.1% (95%
             confidence interval [CI], 1.8%-5.2%) for all LN, 2.5% (95%
             CI, 1.6%-3.9%) for ALH, and 5.8% (95% CI, 2.9%-11.3%) for
             LCIS. Risks for upgrade to invasive malignancy were 1.3%
             (95% CI, 0.7%-2.4%) for all LN, 0.4% (95% CI, 0.0%-4.2%) for
             ALH, and 3.5% (95% CI, 2.0%-5.9%) for LCIS. CONCLUSIONS: The
             risk for upgrade to malignancy for LN found on breast biopsy
             is low. Imaging surveillance can likely be offered as an
             alternative to surgical management for LN, particularly for
   Doi = {10.1016/j.jacr.2020.07.036},
   Key = {fds352571}

   Author = {Grimm, LJ and Ryser, MD and Hyslop, T},
   Title = {Role of Preoperative Variables in Reducing the Rate of
             Occult Invasive Disease for Women Considering Active
             Surveillance for Ductal Carcinoma In Situ.},
   Journal = {Jama Surg},
   Volume = {153},
   Number = {3},
   Pages = {290-291},
   Year = {2018},
   Month = {March},
   url = {},
   Doi = {10.1001/jamasurg.2017.5566},
   Key = {fds339495}

   Author = {Storey, K and Ryser, MD and Leder, K and Foo, J},
   Title = {Spatial Measures of Genetic Heterogeneity During
   Journal = {Bull Math Biol},
   Volume = {79},
   Number = {2},
   Pages = {237-276},
   Year = {2017},
   Month = {February},
   url = {},
   Abstract = {In this work we explore the temporal dynamics of spatial
             heterogeneity during the process of tumorigenesis from
             healthy tissue. We utilize a spatial stochastic model of
             mutation accumulation and clonal expansion in a structured
             tissue to describe this process. Under a two-step
             tumorigenesis model, we first derive estimates of a
             non-spatial measure of diversity: Simpson's Index, which is
             the probability that two individuals sampled at random from
             the population are identical, in the premalignant
             population. We next analyze two new measures of spatial
             population heterogeneity. In particular we study the typical
             length scale of genetic heterogeneity during the
             carcinogenesis process and estimate the extent of a
             surrounding premalignant clone given a clinical observation
             of a premalignant point biopsy. This evolutionary framework
             contributes to a growing literature focused on developing a
             better understanding of the spatial population dynamics of
             cancer initiation and progression.},
   Doi = {10.1007/s11538-016-0234-5},
   Key = {fds339503}

   Author = {Ryser, MD and Min, B-H and Siegmund, KD and Shibata,
   Title = {Spatial mutation patterns as markers of early colorectal
             tumor cell mobility.},
   Journal = {Proc Natl Acad Sci U S A},
   Volume = {115},
   Number = {22},
   Pages = {5774-5779},
   Year = {2018},
   Month = {May},
   url = {},
   Abstract = {A growing body of evidence suggests that a subset of human
             cancers grows as single clonal expansions. In such a nearly
             neutral evolution scenario, it is possible to infer the
             early ancestral tree of a full-grown tumor. We hypothesized
             that early tree reconstruction can provide insights into the
             mobility phenotypes of tumor cells during their first few
             cell divisions. We explored this hypothesis by means of a
             computational multiscale model of tumor expansion
             incorporating the glandular structure of colorectal tumors.
             After calibrating the model to multiregional and single
             gland data from 19 human colorectal tumors using approximate
             Bayesian computation, we examined the role of early tumor
             cell mobility in shaping the private mutation patterns of
             the final tumor. The simulations showed that early cell
             mixing in the first tumor gland can result in
             side-variegated patterns where the same private mutations
             could be detected on opposite tumor sides. In contrast,
             absence of early mixing led to nonvariegated, sectional
             mutation patterns. These results suggest that the patterns
             of detectable private mutations in colorectal tumors may be
             a marker of early cell movement and hence the invasive and
             metastatic potential of the tumor at the start of the
             growth. In alignment with our hypothesis, we found evidence
             of early abnormal cell movement in 9 of 15 invasive
             colorectal carcinomas ("born to be bad"), but in none of 4
             benign adenomas. If validated with a larger dataset, the
             private mutation patterns may be used for outcome prediction
             among screen-detected lesions with unknown invasive
   Doi = {10.1073/pnas.1716552115},
   Key = {fds338377}

   Author = {Williamson, T and Ryser, MD and Abdelgadir, J and Lemmon, M and Barks,
             MC and Zakare, R and Ubel, PA},
   Title = {Surgical decision making in the setting of severe traumatic
             brain injury: A survey of neurosurgeons.},
   Journal = {Plos One},
   Volume = {15},
   Number = {3},
   Pages = {e0228947},
   Year = {2020},
   url = {},
   Abstract = {BACKGROUND: Surgical decision-making in severe traumatic
             brain injury (TBI) is complex. Neurosurgeons weigh risks and
             benefits of interventions that have the potential to both
             maximize the chance of recovery and prolong suffering.
             Inaccurate prognostication can lead to over- or
             under-estimation of outcomes and influence treatment
             recommendations. OBJECTIVE: To evaluate the impact of
             evidence-based risk estimates on neurosurgeon treatment
             recommendations and prognostic beliefs in severe TBI.
             METHODS: In a survey-based randomized experiment, a total of
             139 neurosurgeons were presented with two hypothetical
             patient with severe TBI and subdural hematoma; the
             intervention group received additional evidence-based risk
             estimates for each patient. The main outcome was
             neurosurgeon treatment recommendation of non-surgical
             management. Secondary outcomes included prediction of
             functional recovery at six months. RESULTS: In the first
             patient scenario, 22% of neurosurgeons recommended
             non-surgical management and provision of evidence-based risk
             estimates increased the propensity to recommend non-surgical
             treatment (odds ratio [OR]: 2.81, 95% CI: 1.21-6.98; p =
             0.02). Neurosurgeon prognostic beliefs of 6-month functional
             recovery were variable in both control (median 20%, IQR:
             10%-40%) and intervention (30% IQR: 10%-50%) groups and
             neurosurgeons were less likely to recommend non-surgical
             management when they believed prognosis was favorable (odds
             ratio [OR] per percentage point increase in 6-month
             functional recovery: 0.97, 95% confidence interval [CI]:
             0.95-0.99). The results for the second patient scenario were
             qualitatively similar. CONCLUSIONS: Our findings show that
             the provision of evidence-based risk predictions can
             influence neurosurgeon treatment recommendations and
             prognostication, but the effect is modest and there remains
             large variability in neurosurgeon prognostication.},
   Doi = {10.1371/journal.pone.0228947},
   Key = {fds349463}

   Author = {Grimm, LJ and Ryser, MD and Partridge, AH and Thompson, AM and Thomas,
             JS and Wesseling, J and Hwang, ES},
   Title = {Surgical Upstaging Rates for Vacuum Assisted Biopsy Proven
             DCIS: Implications for Active Surveillance
   Journal = {Annals of Surgical Oncology},
   Volume = {24},
   Number = {12},
   Pages = {3534-3540},
   Year = {2017},
   Month = {November},
   url = {},
   Abstract = {PURPOSE: This study was designed to determine invasive
             cancer upstaging rates at surgical excision following
             vacuum-assisted biopsy of ductal carcinoma in situ (DCIS)
             among women meeting eligibility for active surveillance
             trials. METHODS: Patients with vacuum-assisted,
             biopsy-proven DCIS at a single center from 2008 to 2015 were
             retrospectively reviewed. Imaging and pathology reports were
             interrogated for the imaging appearance, tumor grade,
             hormone receptor status, and presence of comedonecrosis.
             Subsequent surgical reports were reviewed for upstaging to
             invasive disease. Cases were classified by eligibility
             criteria for the COMET, LORIS, and LORD DCIS active
             surveillance trials. RESULTS: Of 307 DCIS diagnoses, 15 (5%)
             were low, 95 (31%) intermediate, and 197 (64%) high nuclear
             grade. The overall upstage rate to invasive disease was 17%
             (53/307). Eighty-one patients were eligible for the COMET
             Trial, 74 for the LORIS trial, and 10 for the LORD Trial,
             although LORIS trial eligibility also included real-time,
             multiple central pathology review, including elements not
             routinely reported. The upstaging rates to invasive disease
             were 6% (5/81), 7% (5/74), and 10% (1/10) for the COMET,
             LORIS, and LORD trials, respectively. Among upstaged cancers
             (n = 5), four tumors were Stage IA invasive ductal
             carcinoma and one was Stage IIA invasive lobular carcinoma;
             all were node-negative. CONCLUSIONS: DCIS upstaging rates in
             women eligible for active surveillance trials are low
             (6-10%), and in this series, all those with invasive disease
             were early-stage, node-negative. The careful patient
             selection for DCIS active surveillance trials has a low risk
             of missing occult invasive cancer and additional studies
             will determine clinical outcomes.},
   Doi = {10.1245/s10434-017-6018-9},
   Key = {fds339499}

   Author = {Payne, S and Li, B and Cao, Y and Schaeffer, D and Ryser, MD and You,
   Title = {Temporal control of self-organized pattern formation without
             morphogen gradients in bacteria.},
   Journal = {Molecular Systems Biology},
   Volume = {9},
   Number = {697},
   Pages = {697},
   Year = {2013},
   Month = {October},
   url = {},
   Abstract = {Diverse mechanisms have been proposed to explain biological
             pattern formation. Regardless of their specific molecular
             interactions, the majority of these mechanisms require
             morphogen gradients as the spatial cue, which are either
             predefined or generated as a part of the patterning process.
             However, using Escherichia coli programmed by a synthetic
             gene circuit, we demonstrate here the generation of robust,
             self-organized ring patterns of gene expression in the
             absence of an apparent morphogen gradient. Instead of being
             a spatial cue, the morphogen serves as a timing cue to
             trigger the formation and maintenance of the ring patterns.
             The timing mechanism enables the system to sense the domain
             size of the environment and generate patterns that scale
             accordingly. Our work defines a novel mechanism of pattern
             formation that has implications for understanding natural
             developmental processes.},
   Doi = {10.1038/msb.2013.55},
   Key = {fds339511}

   Author = {Ryser, MD and Komarova, SV and Nigam, N},
   Title = {The cellular dynamics of bone remodeling: A mathematical
   Journal = {Siam Journal on Applied Mathematics},
   Volume = {70},
   Number = {6},
   Pages = {1899-1921},
   Year = {2010},
   Month = {April},
   url = {},
   Abstract = {The mechanical properties of vertebrate bone are largely
             determined by a process which involves the complex interplay
             of three different cell types. This process is called bone
             remodeling and occurs asynchronously at multiple sites in
             the mature skeleton. The cells involved are bone resorbing
             osteoclasts, bone matrix producing osteoblasts, and
             mechanosensing osteocytes. These cells communicate with each
             other by means of autocrine and paracrine signaling factors
             and operate in complex entities, the so-called bone
             multicellular units (BMUs). To investigate the BMU dynamics
             in silico, we develop a novel mathematical model resulting
             in a system of nonlinear partial differential equations
             (PDEs) with time delays. The model describes the osteoblast
             and osteoclast populations together with the dynamics of the
             key messenger molecule RANKL and its decoy receptor OPG.
             Scaling theory is used to address parameter sensitivity and
             predict the emergence of pathological remodeling regimes.
             The model is studied numerically in one and two space
             dimensions using finite difference schemes in space and
             explicit delay equation solvers in time. The computational
             results are in agreement with in vivo observations and
             provide new insights into the role of the RANKL/OPG pathway
             in the spatial regulation of bone remodeling. © 2010
             Society for Industrial and Applied Mathematics.},
   Doi = {10.1137/090746094},
   Key = {fds303559}

   Author = {Rozenblatt-Rosen, O and Regev, A and Oberdoerffer, P and Nawy, T and Hupalowska, A and Rood, JE and Ashenberg, O and Cerami, E and Coffey,
             RJ and Demir, E and Ding, L and Esplin, ED and Ford, JM and Goecks, J and Ghosh, S and Gray, JW and Guinney, J and Hanlon, SE and Hughes, SK and Hwang, ES and Iacobuzio-Donahue, CA and Jané-Valbuena, J and Johnson, BE and Lau, KS and Lively, T and Mazzilli, SA and Pe'er, D and Santagata, S and Shalek, AK and Schapiro, D and Snyder, MP and Sorger,
             PK and Spira, AE and Srivastava, S and Tan, K and West, RB and Williams,
             EH and Human Tumor Atlas Network},
   Title = {The Human Tumor Atlas Network: Charting Tumor Transitions
             across Space and Time at Single-Cell Resolution.},
   Journal = {Cell},
   Volume = {181},
   Number = {2},
   Pages = {236-249},
   Year = {2020},
   Month = {April},
   url = {},
   Abstract = {Crucial transitions in cancer-including tumor initiation,
             local expansion, metastasis, and therapeutic
             resistance-involve complex interactions between cells within
             the dynamic tumor ecosystem. Transformative single-cell
             genomics technologies and spatial multiplex in situ methods
             now provide an opportunity to interrogate this complexity at
             unprecedented resolution. The Human Tumor Atlas Network
             (HTAN), part of the National Cancer Institute (NCI) Cancer
             Moonshot Initiative, will establish a clinical,
             experimental, computational, and organizational framework to
             generate informative and accessible three-dimensional
             atlases of cancer transitions for a diverse set of tumor
             types. This effort complements both ongoing efforts to map
             healthy organs and previous large-scale cancer genomics
             approaches focused on bulk sequencing at a single point in
             time. Generating single-cell, multiparametric, longitudinal
             atlases and integrating them with clinical outcomes should
             help identify novel predictive biomarkers and features as
             well as therapeutically relevant cell types, cell states,
             and cellular interactions across transitions. The resulting
             tumor atlases should have a profound impact on our
             understanding of cancer biology and have the potential to
             improve cancer detection, prevention, and therapeutic
             discovery for better precision-medicine treatments of cancer
             patients and those at risk for cancer.},
   Doi = {10.1016/j.cell.2020.03.053},
   Key = {fds349460}

   Author = {Buenzli, PR and Martin, PA and Ryser, MD},
   Title = {Thermal quantum electrodynamics of nonrelativistic charged
   Journal = {Physical Review. E, Statistical, Nonlinear, and Soft Matter
   Volume = {75},
   Number = {4 Pt 1},
   Pages = {041125},
   Year = {2007},
   Month = {April},
   ISSN = {1539-3755},
   url = {},
   Abstract = {The theory relevant to the study of matter in equilibrium
             with the radiation field is thermal quantum electrodynamics
             (TQED). We present a formulation of the theory, suitable for
             nonrelativistic fluids, based on a joint functional integral
             representation of matter and field variables. In this
             formalism cluster expansion techniques of classical
             statistical mechanics become operative. They provide an
             alternative to the usual Feynman diagrammatics in many-body
             problems, which is not perturbative with respect to the
             coupling constant. As an application we show that the
             effective Coulomb interaction between quantum charges is
             partially screened by thermalized photons at large
             distances. More precisely one observes an exact cancellation
             of the dipolar electric part of the interaction, so that the
             asymptotic particle density correlation is now determined by
             relativistic effects. It still has the r(-6) decay typical
             for quantum charges, but with an amplitude strongly reduced
             by a relativistic factor.},
   Doi = {10.1103/PhysRevE.75.041125},
   Key = {fds244099}

   Author = {Brouwer, AF and He, K and Chinn, SB and Mondul, AM and Chapman, CH and Ryser, MD and Banerjee, M and Eisenberg, MC and Meza, R and Taylor,
   Title = {Time-varying survival effects for squamous cell carcinomas
             at oropharyngeal and nonoropharyngeal head and neck sites in
             the United States, 1973-2015.},
   Journal = {Cancer},
   Volume = {126},
   Number = {23},
   Pages = {5137-5146},
   Year = {2020},
   Month = {December},
   url = {},
   Abstract = {BACKGROUND: Anatomical site is strongly associated with head
             and neck cancer etiology, and etiology and patient
             sociodemographic characteristics are prognostic factors for
             survival. It is not known whether the effects of these
             predictors persist over the postdiagnosis period or are
             strongest proximal to the time of diagnosis. METHODS: Using
             survival times and causes of death for 180,434 patients with
             head and neck cancer in the Surveillance, Epidemiology, and
             End Results cancer registry (1973-2015), the empirical
             cumulative incidences of cancer-specific death and
             other-cause death were calculated with a competing risks
             framework, and the time-dependent effects (hazard ratios) of
             anatomical tumor site (oropharynx, oral cavity, or
             hypopharynx/larynx), age, sex, race, and year of diagnosis
             on cancer-specific death and other-cause death, stratified
             by tumor stage, were estimated. RESULTS: All effects were
             significantly time-varying (P < .001). Patients with
             nonoropharyngeal cancer had a higher hazard of
             cancer-specific death but a similar cumulative fraction of
             deaths because of a higher rate of death from other causes.
             Cancer-specific survival has not changed for patients with
             nonoropharyngeal cancer over the past decades but has
             improved since 2000 for patients with oropharyngeal cancer.
             The effects of age and sex on cancer survival were strongest
             proximal to the diagnosis, whereas the effect of race
             persisted over time. CONCLUSIONS: Recent improvements in
             survival for patients with oropharyngeal cancer may be due
             more to an increasing fraction of cancers attributable to
             human papillomavirus than to increasing treatment
             effectiveness. The prognostic strength of anatomical site
             and other predictors changes over the postdiagnosis period.
             LAY SUMMARY: It is generally assumed that the effects of
             tumor and personal characteristics on the survival of
             patients with head and neck cancer are fixed over time, but
             this study shows that many factors are most important only
             in the first few years after diagnosis. Also, recent
             improvements in the survival of patients with head and neck
             cancer appear to benefit only patients with cancers of the
             oropharynx. The improvements may be due more to an
             increasing fraction of cancers caused by human
             papillomavirus (which generally have better outcomes) than
             to advances in head and neck cancer treatment
   Doi = {10.1002/cncr.33174},
   Key = {fds352570}

   Author = {Worni, M and Akushevich, I and Greenup, R and Sarma, D and Ryser, MD and Myers, ER and Hwang, ES},
   Title = {Trends in Treatment Patterns and Outcomes for Ductal
             Carcinoma In Situ.},
   Journal = {J Natl Cancer Inst},
   Volume = {107},
   Number = {12},
   Pages = {djv263},
   Year = {2015},
   Month = {December},
   url = {},
   Abstract = {BACKGROUND: Impact of contemporary treatment of pre-invasive
             breast cancer (ductal carcinoma in situ [DCIS]) on long-term
             outcomes remains poorly defined. We aimed to evaluate
             national treatment trends for DCIS and to determine their
             impact on disease-specific (DSS) and overall survival (OS).
             METHODS: The Surveillance, Epidemiology, and End Results
             (SEER) registry was queried for patients diagnosed with DCIS
             from 1991 to 2010. Treatment pattern trends were analyzed
             using Cochran-Armitage trend test. Survival analyses were
             performed using inverse probability weights (IPW)-adjusted
             competing risk analyses for DSS and Cox proportional hazard
             regression for OS. All tests performed were two-sided.
             RESULTS: One hundred twenty-one thousand and eighty DCIS
             patients were identified. The greatest proportion of
             patients was treated with lumpectomy and radiation therapy
             (43.0%), followed by lumpectomy alone (26.5%) and unilateral
             (23.8%) or bilateral mastectomy (4.5%) with significant
             shifts over time. The rate of sentinel lymph node biopsy
             increased from 9.7% to 67.1% for mastectomy and from 1.4% to
             17.8% for lumpectomy. Compared with mastectomy, OS was
             higher for lumpectomy with radiation (hazard ratio [HR] =
             0.79, 95% confidence interval [CI] = 0.76 to 0.83, P < .001)
             and lower for lumpectomy alone (HR = 1.17, 95% CI = 1.13 to
             1.23, P < .001). IPW-adjusted ten-year DSS was highest in
             lumpectomy with XRT (98.9%), followed by mastectomy (98.5%),
             and lumpectomy alone (98.4%). CONCLUSIONS: We identified
             substantial shifts in treatment patterns for DCIS from 1991
             to 2010. When outcomes between locoregional treatment
             options were compared, we observed greater differences in OS
             than DSS, likely reflecting both a prevailing patient
             selection bias as well as clinically negligible differences
             in breast cancer outcomes between groups.},
   Doi = {10.1093/jnci/djv263},
   Key = {fds339506}

   Author = {Hairer, M and Ryser, M and Weber, H},
   Title = {Triviality of the 2D stochastic Allen-Cahn
   Journal = {Electronic Journal of Probability},
   Volume = {17},
   Number = {none},
   Publisher = {Institute of Mathematical Statistics},
   Year = {2012},
   Month = {January},
   url = {},
   Abstract = {We consider the stochastic Allen-Cahn equation driven by
             mollified space-time white noise. We show that, as the
             mollifier is removed, the solutions converge weakly to 0,
             independently of the initial condition. If the intensity of
             the noise simultaneously converges to 0 at a sufficiently
             fast rate, then the solutions converge to those of the
             deterministic equation. At the critical rate, the limiting
             solution is still deterministic, but it exhibits an
             additional damping term.},
   Doi = {10.1214/ejp.v17-1731},
   Key = {fds303558}

   Author = {Chan, L and Fridman, I and Grant, J and Hwang, ES and Weinfurt, K and Ryser, MD},
   Journal = {Medical Decision Making : an International Journal of the
             Society for Medical Decision Making},
   Volume = {41},
   Number = {4},
   Pages = {E284-E286},
   Year = {2021},
   Key = {fds357629}

   Author = {Williamson, T and Ryser, MD and Ubel, PA and Abdelgadir, J and Spears,
             CA and Liu, B and Komisarow, J and Lemmon, ME and Elsamadicy, A and Lad,
   Title = {Withdrawal of Life-supporting Treatment in Severe Traumatic
             Brain Injury.},
   Journal = {Jama Surg},
   Volume = {155},
   Number = {8},
   Pages = {723-731},
   Year = {2020},
   Month = {August},
   url = {},
   Abstract = {IMPORTANCE: There are limited data on which factors affect
             the critical and complex decision to withdraw
             life-supporting treatment (LST) in patients with severe
             traumatic brain injury (sTBI). OBJECTIVE: To determine
             demographic and clinical factors associated with the
             decision to withdraw LST in patients with sTBI. DESIGN,
             SETTING, AND PARTICIPANTS: This retrospective analysis of
             inpatient data from more than 825 trauma centers across the
             US in the American College of Surgeons Trauma Quality
             Improvement Program database from January 2013 to December
             2015 included adult patients with sTBI and documentation of
             a decision regarding withdrawal of LST (WLST). Data analysis
             was conducted in September 2019. MAIN OUTCOMES AND MEASURES:
             Factors associated with WLST in sTBI. RESULTS: A total of
             37931 patients (9817 women [25.9%]) were included in the
             multivariable analysis; 7864 (20.7%) had WLST. Black
             patients (4806 [13.2%]; odds ratio [OR], 0.66; 95% CI,
             0.59-0.72; P < .001) and patients of other race (4798
             [13.2%]; OR, 0.83; 95% CI, 0.76-0.91; P < .001) were
             less likely than white patients (26 864 [73.7%]) to have
             WLST. Patients from hospitals in the Midwest (OR, 1.12; 95%
             CI, 1.04-1.20; P = .002) or Northeast (OR, 1.23; 95% CI,
             1.13-1.34; P < .001) were more likely to have WLST than
             patients from hospitals in the South. Patients with Medicare
             (OR, 1.55; 95% CI, 1.43-1.69; P < .001) and self-pay
             patients (OR, 1.36; 95% CI, 1.25-1.47; P < .001) were
             more likely to have WLST than patients with private
             insurance. Older patients and those with lower Glasgow Coma
             Scale scores, higher Injury Severity Scores, or craniotomy
             were generally more likely to have WLST. Withdrawal of LST
             was more likely for patients with functionally dependent
             health status (OR, 1.30; 95% CI, 1.08-1.58; P = .01),
             hematoma (OR, 1.19; 95% CI, 1.12-1.27; P < .001),
             dementia (OR, 1.29; 95% CI, 1.08-1.53; P = .004), and
             disseminated cancer (OR, 2.82; 95% CI, 2.07-3.82;
             P < .001) than for patients without these conditions.
             CONCLUSIONS AND RELEVANCE: Withdrawal of LST is common in
             sTBI and socioeconomic factors are associated with the
             decision to withdraw LST. These results highlight the many
             factors that contribute to decision-making in sTBI and
             demonstrate that in a complex and variable disease process,
             variation based on race, payment, and region presents as a
             potential challenge.},
   Doi = {10.1001/jamasurg.2020.1790},
   Key = {fds350404}
ph: 919.660.2800
fax: 919.660.2821

Mathematics Department
Duke University, Box 90320
Durham, NC 27708-0320