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1. Identifying latent disease factors differently expressed in patient subgroups using group factor analysis

Author

Ferreira, Fabio S., Ashburner, John, Bouzigues, Arabella, Suksasilp, Chatrin, Russell, Lucy L., Foster, Phoebe H., Ferry-Bolder, Eve, van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Galimberti, Daniela, Vandenberghe, Rik, de Mendonca, Alexandre, Tiraboschi, Pietro, Santana, Isabel, Gerhard, Alexander, Levin, Johannes, Sorbi, Sandro, Otto, Markus, Pasquier, Florence, Ducharme, Simon, Butler, Chris R., Ber, Isabelle Le, Finger, Elizabeth, Tartaglia, Maria C., Masellis, Mario, Rowe, James B., Synofzik, Matthis, Moreno, Fermin, Borroni, Barbara, Kaski, Samuel, Rohrer, Jonathan D., and Mourao-Miranda, Janaina

Subjects
Statistics - Machine Learning, Computer Science - Machine Learning
Abstract

In this study, we propose a novel approach to uncover subgroup-specific and subgroup-common latent factors addressing the challenges posed by the heterogeneity of neurological and mental disorders, which hinder disease understanding, treatment development, and outcome prediction. The proposed approach, sparse Group Factor Analysis (GFA) with regularised horseshoe priors, was implemented with probabilistic programming and can uncover associations (or latent factors) among multiple data modalities differentially expressed in sample subgroups. Synthetic data experiments showed the robustness of our sparse GFA by correctly inferring latent factors and model parameters. When applied to the Genetic Frontotemporal Dementia Initiative (GENFI) dataset, which comprises patients with frontotemporal dementia (FTD) with genetically defined subgroups, the sparse GFA identified latent disease factors differentially expressed across the subgroups, distinguishing between "subgroup-specific" latent factors within homogeneous groups and "subgroup common" latent factors shared across subgroups. The latent disease factors captured associations between brain structure and non-imaging variables (i.e., questionnaires assessing behaviour and disease severity) across the different genetic subgroups, offering insights into disease profiles. Importantly, two latent factors were more pronounced in the two more homogeneous FTD patient subgroups (progranulin (GRN) and microtubule-associated protein tau (MAPT) mutation), showcasing the method's ability to reveal subgroup-specific characteristics. These findings underscore the potential of sparse GFA for integrating multiple data modalities and identifying interpretable latent disease factors that can improve the characterization and stratification of patients with neurological and mental health disorders., Comment: 38 pages, 14 figures

Published
2024

2. Fixed point indices of iterates of orientation-reversing homeomorphisms

Author

Graff, Grzegorz and Topór, Patryk

Subjects
Mathematics - Dynamical Systems, Primary 37B30, 55M20, Secondary 37E30
Abstract

We show that any sequence of integers satisfying necessary Dold's congruences is realized as the sequence of fixed point indices of the iterates of an orientation-reversing homeomorphism of $\mathbb{R}^{m}$ for $m\geq 3$. As an element of the construction of the above homeomorphism, we consider the class of boundary-preserving homeomorphisms of $\mathbb{R}^{m}_{+}$ and give the answer to [Problem 10.2, Topol. Methods Nonlinear Anal. 50 (2017), 643 - 667] providing a complete description of the forms of fixed point indices for this class of maps., Comment: 23 pages, 13 figures

Published
2024

3. Characteristics Associated with Measles, Mumps, and Rubella Coverage and Exemptions after a School Immunization Law Change in Washington, 2019-2020

Author

Tyler Moore, Katherine Graff, and Teal R. Bell

Abstract

Background: We aimed to better understand the impact of statewide legislation removing personal belief exemptions (PBEs) for the measles, mumps, and rubella (MMR) school immunization requirement and factors associated with resulting health-seeking behaviors. Methods: We used chi-squared tests and logistic regression models to determine individual- and school-level characteristics associated with holding a MMR PBE and with post-law MMR immunization status among students linked to the Washington State Immunization Information System. Results: Of students with a MMR PBE pre-law change, 43.0% completed the MMR vaccine series and 40.4% sought another exemption type. Religious exemptions made up most new MMR exemptions signed (71.8%), followed by medical exemptions (18.5%), and religious membership exemptions (9.7%). Students were more likely to complete the vaccine series post-law change if they attended a school with a low school-level MMR exemption rate, a public school, or held a lower number of school-required immunization exemptions. Conclusions: This study confirms previous concerns that parents might replace their PBE with another exemption type; however, nearly half the students in the cohort completed the MMR vaccine series. Our findings suggest that targeted immunization policies can increase MMR coverage 1-year post-law change but must account for a replacement effect when exemption categories are eliminated.

Published
2024
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4. Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration.

Author

Vandebergh, Marijne, Ramos, Eliana, Corriveau-Lecavalier, Nick, Ramanan, Vijay, Kornak, John, Mester, Carly, Kolander, Tyler, Brushaber, Danielle, Staffaroni, Adam, Geschwind, Daniel, Wolf, Amy, Kantarci, Kejal, Gendron, Tania, Petrucelli, Leonard, Van den Broeck, Marleen, Wynants, Sarah, Baker, Matthew, Borrego-Écija, Sergi, Appleby, Brian, Barmada, Sami, Bozoki, Andrea, Clark, David, Darby, R, Dickerson, Bradford, Domoto-Reilly, Kimiko, Fields, Julie, Galasko, Douglas, Ghoshal, Nupur, Graff-Radford, Neill, Grant, Ian, Honig, Lawrence, Hsiung, Ging-Yuek, Huey, Edward, Irwin, David, Knopman, David, Kwan, Justin, Léger, Gabriel, Litvan, Irene, Masdeu, Joseph, Mendez, Mario, Onyike, Chiadi, Pascual, Belen, Pressman, Peter, Ritter, Aaron, Roberson, Erik, Snyder, Allison, Sullivan, Anna, Tartaglia, Maria, Wint, Dylan, Heuer, Hilary, Forsberg, Leah, Boxer, Adam, Rosen, Howard, Boeve, Bradley, and Rademakers, Rosa

Subjects
Humans, Female, Male, Membrane Proteins, Middle Aged, Frontotemporal Lobar Degeneration, Aged, Nerve Tissue Proteins, Brain, Polymorphism, Single Nucleotide, Gray Matter, Cognition, Organ Size, Cross-Sectional Studies, Longitudinal Studies, Magnetic Resonance Imaging
Abstract

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106Bs effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Published
2024

5. Slack and Economic Development

Author

Walker, Michael, Shah, Nachiket, Miguel, Edward, Egger, Dennis, Soliman, Felix S, and Graff, Tilman

Subjects
slack, general equilibrium, cash transfers, Kenya, macroeconomics, production
Abstract

Slack – the underutilization of factors of production – varies systematically with economic development. Using novel and detailed measures of the utilization of labor and capital from a large representative sample of firms in rural and urban Kenya, we show that utilization is increasing in firm size, market access, and economic activity. We present a model of firm capacity choice where indivisibility in at least one input is a key driver of slack. We embed the model in spatial general equilibrium, with features characteristic of low-income settings – including many small firms and high transport costs – and show that it rationalizes both the endogenous emergence of slack in steady-state and elastic aggregate supply curves. We empirically validate model predictions using reduced-form estimates of the general equilibrium effects of cash transfers from a large-scale RCT in Kenya. The parsimonious model replicates much of the experimental evidence, predicting a large real multiplier of 1.5, driven by expansion in low-utilization sectors and firms, and limited average price inflation. Counterfactual analyses indicate that multipliers are likely to be meaningfully smaller in lower slack settings, such as urban areas. We use the model to revisit the estimation of spatial spillovers in clustered RCTs and uncover non-trivial ’missing intercept’ effects on income and inflation. Additionally, we innovate methodologically by pre registering key elements of model estimation and validation. The findings suggest that input indivisibilities and slack are key features of developing country settings, and are quantitatively important for macroeconomic dynamics and policies.

Published
2024

6. Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Author

Manzoni, Claudia, Kia, Demis, Ferrari, Raffaele, Leonenko, Ganna, Costa, Beatrice, Saba, Valentina, Jabbari, Edwin, Tan, Manuela, Albani, Diego, Alvarez, Victoria, Alvarez, Ignacio, Andreassen, Ole, Angiolillo, Antonella, Arighi, Andrea, Baker, Matt, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Blackburn, Daniel, Boada, Merce, Boeve, Bradley, Borrego-Ecija, Sergi, Borroni, Barbara, Bråthen, Geir, Brooks, William, Bruni, Amalia, Caroppo, Paola, Bandres-Ciga, Sara, Clarimon, Jordi, Colao, Rosanna, Cruchaga, Carlos, Danek, Adrian, de Boer, Sterre, de Rojas, Itziar, di Costanzo, Alfonso, Dickson, Dennis, Diehl-Schmid, Janine, Dobson-Stone, Carol, Dols-Icardo, Oriol, Donizetti, Aldo, Dopper, Elise, Durante, Elisabetta, Ferrari, Camilla, Forloni, Gianluigi, Frangipane, Francesca, Fratiglioni, Laura, Kramberger, Milica, Galimberti, Daniela, Gallucci, Maurizio, García-González, Pablo, Ghidoni, Roberta, Giaccone, Giorgio, Graff, Caroline, Graff-Radford, Neill, Grafman, Jordan, Halliday, Glenda, Hernandez, Dena, Hjermind, Lena, Hodges, John, Holloway, Guy, Huey, Edward, Illán-Gala, Ignacio, Josephs, Keith, Knopman, David, Kristiansen, Mark, Kwok, John, Leber, Isabelle, Leonard, Hampton, Libri, Ilenia, Lleo, Alberto, Mackenzie, Ian, Madhan, Gaganjit, Maletta, Raffaele, Marquié, Marta, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Morris, Christopher, Morris, Huw, Nacmias, Benedetta, Newton, Judith, Nielsen, Jørgen, Nilsson, Christer, Novelli, Valeria, Padovani, Alessandro, Pal, Suvankar, Pasquier, Florence, Pastor, Pau, Perneczky, Robert, Peterlin, Borut, Petersen, Ronald, Piguet, Olivier, Pijnenburg, Yolande, Puca, Annibale, Rademakers, Rosa, Rainero, Innocenzo, Reus, Lianne, Richardson, Anna, and Riemenschneider, Matthias

Subjects
Humans, Frontotemporal Dementia, tau Proteins, Genome-Wide Association Study, Apolipoproteins E, Male, Female, Genetic Predisposition to Disease, Aged, Polymorphism, Single Nucleotide, Genetic Loci, Middle Aged, Case-Control Studies, Myelin Proteins
Abstract

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Published
2024

7. Every finite set of natural numbers is realizable as algebraic periods of a Morse$\unicode{x2013}$Smale diffeomorphism

Author

Graff, Grzegorz, Marzantowicz, Wacław, Michalak, Łukasz Patryk, and Myszkowski, Adrian

Subjects
Mathematics - Dynamical Systems, Primary: 37C25 37E30, 57K20, Secondary: 55M20, 37D15
Abstract

A given self-map $f\colon M\to M$ of a compact manifold determines the sequence $\{L(f^n)\}_{n=1}^\infty$, of the Lefschetz numbers of its iterations. We consider its dual sequence $\{a_n(f)\}_{n=1}^\infty$ given by the M\"obius inversion formula. The set ${\mathcal AP}(f)=\{ n\in \mathbb N\ \colon\ a_n(f)\neq 0\}$ is called the set of algebraic periods. We solve an open problem existing in literature by showing that for every finite subset ${\mathcal A}$ of natural numbers there exist an orientable surface $S_{\rm g}$, as well as a non-orientable surface $N_{\rm g}$, of genus ${\rm g}$, and a Morse$\unicode{x2013}$Smale diffeomorphism $f$ of this surface such that $\mathcal{AP}(f)=\mathcal{A}$. For such a map it implies the existence of points of a minimal period $n$ for each odd $n \in \mathcal{A}$. For the orientation-reversing Morse$\unicode{x2013}$Smale diffeomorphisms of $S_{\rm g}$ we identify strong restrictions on ${\mathcal AP}(f)$. Our method also provides an estimate of the number of homotopy classes of Morse$\unicode{x2013}$Smale diffeomorphisms, which is exponential in ${\rm g}$.

Published
2024

8. Integrating Annotations into the Design Process for Sonifications and Physicalizations

Author

Sorenson-Graff, Rhys, Bae, S. Sandra, and Wirfs-Brock, Jordan

Subjects
Computer Science - Human-Computer Interaction
Abstract

Annotations are a critical component of visualizations, helping viewers interpret the visual representation and highlighting critical data insights. Despite their significant role, we lack an understanding of how annotations can be incorporated into other data representations, such as physicalizations and sonifications. Given the emergent nature of these representations, sonifications, and physicalizations lack formalized conventions (e.g., design space, vocabulary) that can introduce challenges for audiences to interpret the intended data encoding. To address this challenge, this work focuses on how annotations can be more tightly integrated into the design process of creating sonifications and physicalizations. In an exploratory study with 13 designers, we explore how visualization annotation techniques can be adapted to sonic and physical modalities. Our work highlights how annotations for sonification and physicalizations are inseparable from their data encodings., Comment: 4 pages, 3 figures, to be published in Proceedings of IEEE VIS 2024

Published
2024

9. OFDM-Based Positioning with Unknown Data Payloads: Bounds and Applications to LEO PNT

Author

Graff, Andrew M. and Humphreys, Todd E.

Subjects
Electrical Engineering and Systems Science - Signal Processing
Abstract

This paper presents bounds, estimators, and signal design strategies for exploiting both known pilot resources and unknown data payload resources in time-of-arrival (TOA)-based positioning systems with orthogonal frequency-division multiplexing (OFDM) signals. It is the first to derive the Ziv-Zakai bound (ZZB) on TOA estimation for OFDM signals containing both known pilot and unknown data resources. In comparison to the Cramer-Rao bounds (CRBs) derived in prior work, this ZZB captures the low-signal-to-noise ratio (SNR) thresholding effects in TOA estimation and accounts for an unknown carrier phase. The derived ZZB is evaluated against CRBs and empirical TOA error variances. It is then evaluated on signals with resource allocations optimized for pilot-only TOA estimation, quantifying the performance gain over the best-case pilot-only signal designs. Finally, the positioning accuracy of maximum-likelihood and decision-directed estimators is evaluated on simulated low-Earth-orbit non-terrestrial-network channels and compared against their respective ZZBs.

Published
2024

10. Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.

Author

Chen, Dorothy, Dong, Ruocheng, Kachuri, Linda, Hoffmann, Thomas, Jiang, Yu, Berndt, Sonja, Shelley, John, Schaffer, Kerry, Machiela, Mitchell, Freedman, Neal, Huang, Wen-Yi, Li, Shengchao, Lilja, Hans, Justice, Amy, Madduri, Ravi, Rodriguez, Alex, Van Den Eeden, Stephen, Chanock, Stephen, Haiman, Christopher, Conti, David, Klein, Robert, Mosley, Jonathan, Witte, John, and Graff, Rebecca

Subjects
gene expression, genetics, prostate cancer, prostate-specific antigen, screening, transcriptome-wide association study, Humans, Male, Prostate-Specific Antigen, Genome-Wide Association Study, Prostatic Neoplasms, Genetic Predisposition to Disease, Transcriptome, Gene Expression Profiling, Polymorphism, Single Nucleotide
Abstract

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Published
2024

11. Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Author

Wu, Lesley Yue, Real, Raquel, Martinez-Carrasco, Alejandro, Chia, Ruth, Lawton, Michael A, Shoai, Maryam, Bresner, Catherine, Blauwendraat, Cornelis, Singleton, Andrew B, Ryten, Mina, Abramzon, Yevgeniya, Ahmed, Sarah, Alba, Camille, Albert, Marilyn S, Bacikova, Dagmar, Barrett, Matthew J, Beach, Thomas G, Bennett, David A, Besser, Lilah M, Bigio, Eileen H, Boeve, Bradley F, Bohannan, Ryan C, Caraway, Chad A, Palma, Jose-Alberto, Dalgard, Clifton L, Dickson, Dennis, Ding, Jinhui, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David, Graff-Radford, Neill R, Hu, Heng-Chen, Hupalo, Daniel, Kaiser, Scott M, Kaufmann, Horacio, Kim, Ronald C, Klein, Gregory, Kukull, Walter, Kuzma, Amanda, Leverenz, James, Lopez, Grisel, Mao, Qinwen, Martinez-McGrath, Elisa, Masliah, Eliezer, Monuki, Ed, Newell, Kathy L, Norcliffe-Kaufmann, Lucy, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Ross, Owen A, Sabir, Marya S, Scherzer, Clemens R, Scholz, Sonja W, Serrano, Geidy, Shakkotai, Vikram, Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Traynor, Bryan J, Troncoso, Juan C, Viollet, Coralie, Walton, Ronald L, Woltjer, Randy, Wszolek, Zbigniew K, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Ferrari, Raffaele, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Reynolds, Regina H, Thomas, Alan J, Tilley, Bension S, Troakes, Claire, Brett, Francesca, Brice, Alexis, and Duyckaerts, Charles

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Prevention, Aging, Lewy Body Dementia, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, Human Genome, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, International Lewy Body Dementia Genomics Consortium, APOE, Lewy body diseases, dementia, genome-wide association studies, Clinical sciences, Biological psychology
Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Published
2024

12. Ambient air pollution and urological cancer risk: A systematic review and meta-analysis of epidemiological evidence.

Author

Li, Jinhui, Deng, Zhengyi, Soerensen, Simon, Kachuri, Linda, Cardenas, Andres, Graff, Rebecca, Leppert, John, Langston, Marvin, and Chung, Benjamin

Subjects
Humans, Air Pollution, Urologic Neoplasms, Particulate Matter, Male, Air Pollutants, Environmental Exposure, Risk Factors, Urinary Bladder Neoplasms, Kidney Neoplasms, Prostatic Neoplasms, Female
Abstract

Exposure to ambient air pollution has significant adverse health effects; however, whether air pollution is associated with urological cancer is largely unknown. We conduct a systematic review and meta-analysis with epidemiological studies, showing that a 5 μg/m3 increase in PM2.5 exposure is associated with a 6%, 7%, and 9%, increased risk of overall urological, bladder, and kidney cancer, respectively; and a 10 μg/m3 increase in NO2 is linked to a 3%, 4%, and 4% higher risk of overall urological, bladder, and prostate cancer, respectively. Were these associations to reflect causal relationships, lowering PM2.5 levels to 5.8 μg/m3 could reduce the age-standardized rate of urological cancer by 1.5 ~ 27/100,000 across the 15 countries with the highest PM2.5 level from the top 30 countries with the highest urological cancer burden. Implementing global health policies that can improve air quality could potentially reduce the risk of urologic cancer and alleviate its burden.

Published
2024

13. Homotopy braid groups are torsion-free

Author

Graff, Emmanuel

Subjects
Mathematics - Geometric Topology
Abstract

We show that, for any number of components, the group of braids up to link-homotopy is torsion-free. This generalizes a result of Humphries up to six components, and provides an explicit solution to a question posed by Lin and addressed by Linell and Schick regarding the existence of non-abelian torsion-free quotients of the braid group. The proof relies on the diagrammatic theory of welded braids and uses the Artin representation. As a corollary, we obtain yet another proof that braid groups themselves are torsion-free.

Published
2024

14. Coalescing sets preserving cospectrality of graphs arising from block similarity matrices

Author

Mahamud, Sajid Bin, Butler, Steve, Graff, Hannah, Layman, Nick, Luck, Taylor, Jin, Jiah, Owen, Noah, and Yuan, Angela

Subjects
Mathematics - Combinatorics
Abstract

Coalescing involves gluing one or more rooted graphs onto another graph. Under specific conditions, it is possible to start with cospectral graphs that are coalesced in similar ways that will result in new cospectral graphs. We present a sufficient condition for this based on the block structure of similarity matrices, possibly with additional constraints depending on which type of matrix is being considered. The matrices considered in this paper include the adjacency, Laplacian, signless Laplacian, distance, and generalized distance matrix.

Published
2024

15. Ziv-Zakai-Optimal OFDM Resource Allocation for Time-of-Arrival Estimation

Author

Graff, Andrew M. and Humphreys, Todd E.

Subjects
Electrical Engineering and Systems Science - Signal Processing
Abstract

This paper presents methods of optimizing the placement and power allocations of pilots in an orthogonal frequency-division multiplexing (OFDM) signal to minimize time-of-arrival (TOA) estimation errors under power and resource allocation constraints. TOA errors in this optimization are quantified through the Ziv-Zakai bound (ZZB), which captures error thresholding effects caused by sidelobes in the signal's autocorrelation function (ACF) which are not captured by the Cramer-Rao lower bound. This paper is the first to solve for these ZZB-optimal allocations in the context of OFDM signals, under integer resource allocation constraints, and under both coherent and noncoherent reception. Under convex constraints, the optimization of the ZZB is proven to be convex; under integer constraints, the optimization is lower bounded by a convex relaxation and a branch-and-bound algorithm is proposed for efficiently allocating pilot resources. These allocations are evaluated by their ZZBs and ACFs, compared against a typical uniform allocation, and deployed on a software-defined radio TOA measurement platform to demonstrate their applicability in real-world systems.

Published
2024

16. Analysis of Systems' Performance in Natural Language Processing Competitions

Author

Nava-Muñoz, Sergio, Graff, Mario, and Escalante, Hugo Jair

Subjects
Computer Science - Machine Learning
Abstract

Collaborative competitions have gained popularity in the scientific and technological fields. These competitions involve defining tasks, selecting evaluation scores, and devising result verification methods. In the standard scenario, participants receive a training set and are expected to provide a solution for a held-out dataset kept by organizers. An essential challenge for organizers arises when comparing algorithms' performance, assessing multiple participants, and ranking them. Statistical tools are often used for this purpose; however, traditional statistical methods often fail to capture decisive differences between systems' performance. This manuscript describes an evaluation methodology for statistically analyzing competition results and competition. The methodology is designed to be universally applicable; however, it is illustrated using eight natural language competitions as case studies involving classification and regression problems. The proposed methodology offers several advantages, including off-the-shell comparisons with correction mechanisms and the inclusion of confidence intervals. Furthermore, we introduce metrics that allow organizers to assess the difficulty of competitions. Our analysis shows the potential usefulness of our methodology for effectively evaluating competition results.

Published
2024
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17. Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits

Author

Wang, Ciyang, Yang, Chengran, Western, Daniel, Ali, Muhammad, Wang, Yueyao, Phuah, Chia-Ling, Budde, John, Wang, Lihua, Gorijala, Priyanka, Timsina, Jigyasha, Ruiz, Agustin, Pastor, Pau, Fernandez, Maria Victoria, Panyard, Daniel J., Engelman, Corinne D., Deming, Yuetiva, Boada, Merce, Cano, Amanda, Garcia-Gonzalez, Pablo, Graff-Radford, Neill R., Mori, Hiroshi, Lee, Jae-Hong, Perrin, Richard J., Ibanez, Laura, Sung, Yun Ju, and Cruchaga, Carlos

Published
2024
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20. Diagnosis of Alzheimer’s disease using plasma biomarkers adjusted to clinical probability

Author

Therriault, Joseph, Janelidze, Shorena, Benedet, Andréa Lessa, Ashton, Nicholas J., Arranz Martínez, Javier, Gonzalez-Escalante, Armand, Bellaver, Bruna, Alcolea, Daniel, Vrillon, Agathe, Karim, Helmet, Mielke, Michelle M., Hyung Hong, Chang, Roh, Hyun Woong, Contador, José, Puig Pijoan, Albert, Algeciras-Schimnich, Alicia, Vemuri, Prashanthi, Graff-Radford, Jonathan, Lowe, Val J., Karikari, Thomas K., Jonaitis, Erin, Brum, Wagner, Tissot, Cécile, Servaes, Stijn, Rahmouni, Nesrine, Macedo, Arthur C., Stevenson, Jenna, Fernandez-Arias, Jaime, Wang, Yi-Ting, Woo, Marcel S., Friese, Manuel A., Jia, Wan Lu, Dumurgier, Julien, Hourregue, Claire, Cognat, Emmanuel, Ferreira, Pamela Lukasewicz, Vitali, Paolo, Johnson, Sterling, Pascoal, Tharick A., Gauthier, Serge, Lleó, Alberto, Paquet, Claire, Petersen, Ronald C., Salmon, David, Mattsson-Carlgren, Niklas, Palmqvist, Sebastian, Stomrud, Erik, Galasko, Douglas, Son, Sang Joon, Zetterberg, Henrik, Fortea, Juan, Suárez-Calvet, Marc, Jack, Jr, Clifford R., Blennow, Kaj, Hansson, Oskar, and Rosa-Neto, Pedro

Published
2024
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21. AIntibody: an experimentally validated in silico antibody discovery design challenge

Author

Erasmus, M. Frank, Spector, Laura, Ferrara, Fortunato, DiNiro, Roberto, Pohl, Thomas J., Perea-Schmittle, Katheryn, Wang, Wei, Tessier, Peter M., Richardson, Crystal, Turner, Laure, Kumar, Sumit, Bedinger, Daniel, Sormanni, Pietro, Fernández-Quintero, Monica L., Ward, Andrew B., Loeffler, Johannes R., Swanson, Olivia M., Deane, Charlotte M., Raybould, Matthew I. J., Evers, Andreas, Sellmann, Carolin, Bachas, Sharrol, Ruffolo, Jeff, Nastri, Horacio G., Ramesh, Karthik, Sørensen, Jesper, Croasdale-Wood, Rebecca, Hijano, Oliver, Leal-Lopes, Camila, Shahsavarian, Melody, Qiu, Yu, Marcatili, Paolo, Vernet, Erik, Akbar, Rahmad, Friedensohn, Simon, Wagner, Rick, Kurella, Vinodh babu, Malhotra, Shipra, Kumar, Satyendra, Kidger, Patrick, Almagro, Juan C., Furfine, Eric, Stanton, Marty, Graff, Christilyn P., Villalba, Santiago David, Tomszak, Florian, Teixeira, Andre A. R., Hopkins, Elizabeth, Dovner, Molly, D’Angelo, Sara, and Bradbury, Andrew R. M.

Published
2024
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27. Genomic and transcriptomic landscape of HER2-low breast cancer

Author

Bansal, Rani, Adeyelu, Tolulope, Elliott, Andrew, Walker, Phillip, Bustos, Matias A., Rodriguez, Estelamari, Accordino, Melissa K., Meisel, Jane, Gatti-Mays, Margaret E., Hsu, Emily, Lathrop, Kate, Kaklamani, Virginia, Oberley, Matthew, Sledge, George, Sammons, Sarah L., and Graff, Stephanie L.

Published
2024
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29. Developmental characteristics and accuracy of autism screening among two-year-old toddlers in the ECHO program

Author

Shuster, Coral L., Brennan, Patricia A., Carter, Brian S., Check, Jennifer, D’Sa, Viren, Graff, Joyce C., Helderman, Jennifer, Hofheimer, Julie A., Joseph, Robert M., Murphy, Laura E., O’Connor, Thomas G., O’Shea, T. Michael, Pievsky, Michelle, Sheinkopf, Stephen J., Shuffrey, Lauren C., Smith, Lynne M., Wu, Pei-Chi, and Lester, Barry M.

Published
2024
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30. Differentiating patients with obstructive sleep apnea from healthy controls based on heart rate - blood pressure coupling quantified by entropy-based indices

Author

Pilarczyk, Paweł, Graff, Grzegorz, Amigó, José M., Tessmer, Katarzyna, Narkiewicz, Krzysztof, and Graff, Beata

Subjects
Physics - Medical Physics, Computer Science - Machine Learning
Abstract

We introduce an entropy-based classification method for pairs of sequences (ECPS) for quantifying mutual dependencies in heart rate and beat-to-beat blood pressure recordings. The purpose of the method is to build a classifier for data in which each item consists of the two intertwined data series taken for each subject. The method is based on ordinal patterns, and uses entropy-like indices. Machine learning is used to select a subset of indices most suitable for our classification problem in order to build an optimal yet simple model for distinguishing between patients suffering from obstructive sleep apnea and a control group., Comment: 7 figures

Published
2023
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31. An absorbing set for the Chialvo map

Author

Pilarczyk, Paweł and Graff, Grzegorz

Subjects
Mathematics - Dynamical Systems, 37N25 (Primary) 37M05, 37M22 (Secondary)
Abstract

The classical Chialvo model, introduced in 1995, is one of the most important models that describe single neuron dynamics. In order to conduct effective numerical analysis of this model, it is necessary to obtain a rigorous estimate for the maximal bounded invariant set. We discuss this problem, and we correct and improve the results obtained by Courbage and Nekorkin [Internat. J. Bifur. Chaos Appl. Sci. Engrg. 20 (2010), 1631-1651.] In particular, we provide an explicit formula for an absorbing set for the Chialvo neuron model. We also introduce the notion of a weakly absorbing set, outline the methodology for its construction, and show its advantage over an absorbing set by means of numerical computations., Comment: 24 pages, 4 figures. Authors' accepted manuscript (AAM)

Published
2024
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32. Protocol for combined N-of-1 trials to assess cerebellar neurostimulation for movement disorders in children and young adults with dyskinetic cerebral palsy.

Author

San Luciano, M, Oehrn, C, Wang, S, Tolmie, J, Wiltshire, A, Graff, R, Zhu, J, and Starr, P

Subjects
Cerebellum, Children, Deep brain stimulation, Dentate nucleus, Dyskinetic cerebral palsy, Electrophysiology, Young adults, Humans, Cerebral Palsy, Deep Brain Stimulation, Child, Adolescent, Young Adult, Movement Disorders, Cerebellum, Male, Female, Adult
Abstract

BACKGROUND: Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders. METHODS: Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS. DISCUSSION: Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT06122675, first registered November 7, 2023.

Published
2024

33. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Author

Suzuki, Ken, Hatzikotoulas, Konstantinos, Southam, Lorraine, Taylor, Henry, Yin, Xianyong, Lorenz, Kim, Mandla, Ravi, Huerta-Chagoya, Alicia, Melloni, Giorgio, Kanoni, Stavroula, Rayner, Nigel, Bocher, Ozvan, Arruda, Ana, Sonehara, Kyuto, Namba, Shinichi, Lee, Simon, Preuss, Michael, Petty, Lauren, Schroeder, Philip, Vanderwerff, Brett, Kals, Mart, Bragg, Fiona, Lin, Kuang, Guo, Xiuqing, Zhang, Weihua, Yao, Jie, Kim, Young, Graff, Mariaelisa, Takeuchi, Fumihiko, Nano, Jana, Lamri, Amel, Nakatochi, Masahiro, Moon, Sanghoon, Scott, Robert, Cook, James, Lee, Jung-Jin, Pan, Ian, Taliun, Daniel, Parra, Esteban, Chai, Jin-Fang, Bielak, Lawrence, Tabara, Yasuharu, Hai, Yang, Thorleifsson, Gudmar, Grarup, Niels, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloé, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Kwak, Soo-Heon, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-Min, Nongmaithem, Suraj, Noordam, Raymond, Lim, Victor, Tam, Claudia, Joo, Yoonjung, Chen, Chien-Hsiun, Raffield, Laura, Prins, Bram, Nicolas, Aude, Yanek, Lisa, Chen, Guanjie, Brody, Jennifer, Kabagambe, Edmond, An, Ping, Xiang, Anny, Choi, Hyeok, Cade, Brian, Tan, Jingyi, Broadaway, K, Williamson, Alice, Kamali, Zoha, Cui, Jinrui, Thangam, Manonanthini, Adair, Linda, Adeyemo, Adebowale, Aguilar-Salinas, Carlos, Ahluwalia, Tarunveer, Anand, Sonia, Bertoni, Alain, Bork-Jensen, Jette, Brandslund, Ivan, Buchanan, Thomas, Burant, Charles, Butterworth, Adam, Canouil, Mickaël, Chan, Juliana, Chang, Li-Ching, Chee, Miao-Li, Chen, Ji, Chen, Shyh-Huei, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, and Cushman, Mary

Subjects
Humans, Adipocytes, Chromatin, Coronary Artery Disease, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Disease Progression, Endothelial Cells, Enteroendocrine Cells, Epigenomics, Genetic Predisposition to Disease, Genome-Wide Association Study, Islets of Langerhans, Multifactorial Inheritance, Peripheral Arterial Disease, Single-Cell Analysis
Abstract

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

Published
2024

35. Teacher Spending Accounts: Supporting All Teachers. Sketching a New Conservative Education Agenda

Author

American Enterprise Institute (AEI) and Patrick Graff

Abstract

Browsing social media during back-to-school time, one frequently encounters pleas from teachers to help purchase classroom supplies through #clearthelist campaigns or to support their class' DonorsChoose projects. At a time of historically high levels of education spending, why do teachers require additional assistance to meet basic classroom needs? How is it that a fifth-grade teacher with 20 students--representing about $13,500 each in per-pupil funding--has so little control over how the more than a quarter million dollars those students represent enters the classroom? Education funding policies should put students' and teachers' needs first. An increasing number of students now have access to education savings accounts (ESAs), an increasingly popular policy reform that puts education funds directly in families' hands to use at the school or education provider of their choice. In this report, the author argues that teachers deserve similar support and flexibility through teacher spending accounts (TSAs).

Published
2023

41. Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers

Author

Muquith, Maishara, Espinoza, Magdalena, Elliott, Andrew, Xiu, Joanne, Seeber, Andreas, El-Deiry, Wafik, Antonarakis, Emmanuel S., Graff, Stephanie L., Hall, Michael J., Borghaei, Hossein, Hoon, Dave S. B., Liu, Stephen V., Ma, Patrick C., McKay, Rana R., Wise-Draper, Trisha, Marshall, John, Sledge, George W., Spetzler, David, Zhu, Hao, and Hsiehchen, David

Published
2024
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42. Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer: (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA)

Author

Vaz, Sofia C., Woll, John Patrick Pilkington, Cardoso, Fatima, Groheux, David, Cook, Gary J. R., Ulaner, Gary A., Jacene, Heather, Rubio, Isabel T., Schoones, Jan W., Peeters, Marie-Jeanne Vrancken, Poortmans, Philip, Mann, Ritse M., Graff, Stephanie L., Dibble, Elizabeth H., and de Geus-Oei, Lioe-Fee

Published
2024
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48. Neurophysiological and other features of working memory in older adults at risk for dementia

Author

Patterson, Rachel A., Brooks, Heather, Mirjalili, Mina, Rashidi-Ranjbar, Neda, Zomorrodi, Reza, Blumberger, Daniel M., Fischer, Corinne E., Flint, Alastair J., Graff-Guerrero, Ariel, Herrmann, Nathan, Kennedy, James L., Kumar, Sanjeev, Lanctôt, Krista L., Mah, Linda, Mulsant, Benoit H., Pollock, Bruce G., Voineskos, Aristotle N., Wang, Wei, and Rajji, Tarek K.

Published
2024
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50. Pareto Optimization to Accelerate Multi-Objective Virtual Screening

Author

Fromer, Jenna C., Graff, David E., and Coley, Connor W.

Subjects
Quantitative Biology - Quantitative Methods, Computer Science - Machine Learning
Abstract

The discovery of therapeutic molecules is fundamentally a multi-objective optimization problem. One formulation of the problem is to identify molecules that simultaneously exhibit strong binding affinity for a target protein, minimal off-target interactions, and suitable pharmacokinetic properties. Inspired by prior work that uses active learning to accelerate the identification of strong binders, we implement multi-objective Bayesian optimization to reduce the computational cost of multi-property virtual screening and apply it to the identification of ligands predicted to be selective based on docking scores to on- and off-targets. We demonstrate the superiority of Pareto optimization over scalarization across three case studies. Further, we use the developed optimization tool to search a virtual library of over 4M molecules for those predicted to be selective dual inhibitors of EGFR and IGF1R, acquiring 100% of the molecules that form the library's Pareto front after exploring only 8% of the library. This workflow and associated open source software can reduce the screening burden of molecular design projects and is complementary to research aiming to improve the accuracy of binding predictions and other molecular properties.

Published
2023

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