Biostatistics and Health Data Science Works
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Works authored by scholars from the Department of Biostatistics and Health Data Science, a dual department of the Richard M. Fairbanks School of Public Health and the IU School of Medicine.
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Item Impacts of Skeletal Anterior Open Bite Malocclusion on Speech(Sage, 2022) Keyser, Mary Morgan Bitler; Lathrop, Hillary; Jhingree, Samantha; Giduz, Natalie; Bocklage, Clare; Couldwell, Sandrine; Oliver, Steven; Moss, Kevin; Frazier-Bowers, Sylvia; Phillips, Ceib; Turvey, Timothy; Blakey, George; White, Ray; White, Raymond P., Jr.; McMichael, Dalton L.; Zajac, David; Mielke, Jeff; Jacox, Laura Anne; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthIntroduction: Articulation problems are seen in 80-90% of dentofacial deformity (DFD) subjects compared with 5% of the general population, impacting communication and quality of life, but the causal link is unclear. We hypothesize there are both qualitative (perceptual) and quantitative (spectral) differences in properties of stop (/t/ or /k/), fricative (/s/ or /∫/), and affricate (/t∫/) consonant sounds and that severity of anterior open bite (AOB) jaw disharmonies correlates with degree of speech abnormality. Methods: To test our hypotheses, surgical orthodontic records and audio recordings were collected from DFD patients (n=39 AOB, 62 controls). A speech pathologist evaluated subjects and recordings were analyzed using spectral moment analysis (SMA) to measure sound frequency distortions. Results: Perceptually, there is a higher prevalence of auditory and visual speech distortions in AOB DFD patients when compared to controls. Quantitatively, a significant (p<0.01) increase in the centroid frequency (M1) was seen in the /k/, /t/, /t∫/, and /s/ sounds of AOB subjects compared to the controls. Using linear regression, correlations between AOB skeletal severity and spectral distortion were found for /k/ and /t/ sounds. Conclusions: A higher prevalence of qualitative distortion and significant quantitative spectral distortions in consonant sounds were seen in AOB patients compared to controls. Additionally, severity of skeletal AOB is correlated with degree of distortion for consonant sounds. These findings provide insight into how the surgical and/or orthodontic treatment of AOB may impact speech.Item Orthognathic speech pathology: impacts of Class III malocclusion on speech(Oxford University Press, 2022) Lathrop-Marshall, Hillary; Keyser, Mary Morgan B.; Jhingree, Samantha; Giduz, Natalie; Bocklage, Clare; Couldwell, Sandrine; Edwards, Haley; Glesener, Tim; Moss, Kevin; Frazier-Bowers, Sylvia; Phillips, Ceib; Turvey, Timothy; Blakey, George; White, Ray; Mielke, Jeff; Zajac, David; Jacox, Laura A.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthIntroduction: Patients with dentofacial disharmonies (DFDs) seek orthodontic care and orthognathic surgery to address issues with mastication, esthetics, and speech. Speech distortions are seen 18 times more frequently in Class III DFD patients than the general population, with unclear causality. We hypothesize there are significant differences in spectral properties of stop (/t/ or /k/), fricative (/s/ or /ʃ/), and affricate (/tʃ/) consonants and that severity of Class III disharmony correlates with the degree of speech abnormality. Methods: To understand how jaw disharmonies influence speech, orthodontic records and audio recordings were collected from Class III surgical candidates and reference subjects (n = 102 Class III, 62 controls). A speech pathologist evaluated subjects and recordings were quantitatively analysed by Spectral Moment Analysis for frequency distortions. Results: A majority of Class III subjects exhibit speech distortions. A significant increase in the centroid frequency (M1) and spectral spread (M2) was seen in several consonants of Class III subjects compared to controls. Using regression analysis, correlations between Class III skeletal severity (assessed by cephalometric measures) and spectral distortion were found for /t/ and /k/ phones. Conclusions: Class III DFD patients have a higher prevalence of articulation errors and significant spectral distortions in consonants relative to controls. This is the first demonstration that severity of malocclusion is quantitatively correlated with the degree of speech distortion for consonants, suggesting causation. These findings offer insight into the complex relationship between craniofacial structures and speech distortions.Item Improved Adverse Drug Event Prediction Through Information Component Guided Pharmacological Network Model (IC-PNM)(IEEE, 2021) Ji, Xiangmin; Wang, Lei; Hua, Liyan; Wang, Xueying; Zhang, Pengyue; Shendre, Aditi; Feng, Weixing; Li, Jin; Li, Lang; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthImproving adverse drug event (ADE) prediction is highly critical in pharmacovigilance research. We propose a novel information component guided pharmacological network model (IC-PNM) to predict drug-ADE signals. This new method combines the pharmacological network model and information component, a Bayes statistics method. We use 33,947 drug-ADE pairs from the FDA Adverse Event Reporting System (FAERS) 2010 data as the training data, and the new 21,065 drug-ADE pairs from FAERS 2011-2015 as the validations samples. The IC-PNM data analysis suggests that both large and small sample size drug-ADE pairs are needed in training the predictive model for its prediction performance to reach an area under the receiver operating characteristic curve (\textAUROC)= 0.82(AUROC)=0.82. On the other hand, the IC-PNM prediction performance improved to \textAUROC= 0.91AUROC=0.91 if we removed the small sample size drug-ADE pairs from the prediction model during validation.Item Anti-cytomegalovirus antibody levels stratify human immune profiles across the lifespan(Springer, 2024) Watanabe, Makiko; Davidson, Lisa; Smith, Patricia; Castellucio, Peter F.; Jergovic, Mladen; Uhrlaub, Jennifer L.; Smithey, Megan J.; Fantry, Lori E.; Dechambre, Brett; Wilson, Rachel C.; Knox, Kenneth C.; Stowe, Raymond P.; Weinstock, George; Twigg, Homer, III; Nikolich, Janko Ž.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthHuman cytomegalovirus (hCMV) is a ubiquitous latent persistent herpesvirus infecting 60-90% of the population worldwide. hCMV carriage in immunocompetent people is asymptomatic; thus, hCMV can be considered a component of normative aging. However, hCMV powerfully modulates many features of the immune, and likely other, systems and organs. Questions remain as to how hCMV carriage affects the human host. We used anti-CMV antibody titers as a stratifying criterion to examine the impact of "intensity" of hCMV infection as a potential biomarker of aging, inflammation, and immune homeostasis in a cohort of 247 participants stratified into younger (21-40 years) and older (> 65 years of age) groups. We showed that anti-CMV antibody titers increased with age and directly correlated to increased levels of soluble tumor necrosis factor (sTNFR) I in younger but not older participants. CD8 + cell numbers were reduced in the older group due to the loss in CD8 + T naïve (Tn) cells. In CMV carriers and, in particular, in anti-CMV Ab-high participants, this loss was mitigated or reversed by an increase in the numbers of CD8 + T effector memory (Tem) and T effector memory reexpressing CD45RA (Temra) cells. Analysis of CD38, HLA-DR, and CD57 expression revealed subset (CD4 or CD8)-specific changes that correlated with anti-CMV Ab levels. In addition, anti-CMV Ab levels predicted anti-CMV CD8 T cell responsiveness to different CMV open reading frames (ORFs) selectively in older participants, which correlated to the transcriptional order of expression of specific CMV ORFs. Implications of these results for the potential predictive value of anti-CMV Ab titers during aging are discussed.Item Pro-survival signaling regulates lipophagy essential for multiple myeloma resistance to stress-induced death(Elsevier, 2024) Peng, Peng; Chavel, Colin; Liu, Wensheng; Carlson, Louise M.; Cao, Sha; Utley, Adam; Olejniczak, Scott H.; Lee, Kelvin P.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthPro-survival metabolic adaptations to stress in tumorigenesis remain less well defined. We find that multiple myeloma (MM) is unexpectedly dependent on beta-oxidation of long-chain fatty acids (FAs) for survival under both basal and stress conditions. However, under stress conditions, a second pro-survival signal is required to sustain FA oxidation (FAO). We previously found that CD28 is expressed on MM cells and transduces a significant pro-survival/chemotherapy resistance signal. We now find that CD28 signaling regulates autophagy/lipophagy that involves activation of the Ca2+→AMPK→ULK1 axis and regulates the translation of ATG5 through HuR, resulting in sustained lipophagy, increased FAO, and enhanced MM survival. Conversely, blocking autophagy/lipophagy sensitizes MM to chemotherapy in vivo. Our findings link a pro-survival signal to FA availability needed to sustain the FAO required for cancer cell survival under stress conditions and identify lipophagy as a therapeutic target to overcome treatment resistance in MM.Item Skin sympathetic nerve activity and nocturnal blood pressure non-dipping in patients with postural orthostatic tachycardia syndrome(Wolters Kluwer, 2023) Liu, Xiao; Rosenberg, Carine; Reaso, Jewel N.; Lee, Andrew M.; Ricafrente, Joselyn; Ebinger, Joseph E.; Chen, Lan S.; Li, Xiaochun; Merz, C. Noel Bairey; Rader, Florian; Chen, Peng-Sheng; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthObjective: Postural orthostatic tachycardia syndrome (POTS) is associated with abnormal blood pressure (BP) regulation and increased prevalence of nocturnal nondipping. We hypothesized that nocturnal nondipping of BP is associated with elevated skin sympathetic nerve activity (SKNA) in POTS. Method: We used an ambulatory monitor to record SKNA and electrocardiogram from 79 participants with POTS (36 ± 11 years, 72 women), including 67 with simultaneous 24-h ambulatory BP monitoring. Results: Nocturnal nondipping of BP was present in 19 of 67 (28%) participants. The nondipping group had a higher average SKNA (aSKNA) from midnight of day 1 to 0100 h on day 2 than the dipping group ( P = 0.016, P = 0.030, respectively). The differences (Δ) of aSKNA and mean BP between daytime and night-time were more significant in the dipping group compared with the nondipping group (ΔaSKNA 0.160 ± 0.103 vs. 0.095 ± 0.099 μV, P = 0.021, and Δmean BP 15.0 ± 5.2 vs. 4.9 ± 4.2 mmHg, P < 0.001, respectively). There were positive correlations between ΔaSKNA and standing norepinephrine (NE) (r = 0.421, P = 0.013) and the differences between standing and supine NE levels ( r = 0.411, P = 0.016). There were 53 (79%) patients with SBP less than 90 mmHg and 61 patients (91%) with DBP less than 60 mmHg. These hypotensive episodes were associated with aSKNA of 0.936 ± 0.081 and 0.936 ± 0.080 μV, respectively, which were both significantly lower than the nonhypotensive aSKNA (1.034 ± 0.087 μV, P < 0.001 for both) in the same patient. Conclusion: POTS patients with nocturnal nondipping have elevated nocturnal sympathetic tone and blunted reduction of SKNA between day and night. Hypotensive episodes were associated with reduced aSKNA.Item Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry(Wiley, 2024) Ray, Nicholas R.; Kunkle, Brian W.; Hamilton-Nelson, Kara; Kurup, Jiji T.; Rajabli, Farid; Qiao, Min; Vardarajan, Badri N.; Cosacak, Mehmet I.; Kizil, Caghan; Jean-Francois, Melissa; Cuccaro, Michael; Reyes-Dumeyer, Dolly; Cantwell, Laura; Kuzma, Amanda; Vance, Jeffery M.; Gao, Sujuan; Hendrie, Hugh C.; Baiyewu, Olusegun; Ogunniyi, Adesola; Akinyemi, Rufus O.; Alzheimer’s Disease Genetics Consortium; Lee, Wan-Ping; Martin, Eden R.; Wang, Li-San; Beecham, Gary W.; Bush, William S.; Xu, Wanying; Jin, Fulai; Wang, Liyong; Farrer, Lindsay A.; Haines, Jonathan L.; Byrd, Goldie S.; Schellenberg, Gerard D.; Mayeux, Richard; Pericak-Vance, Margaret A.; Reitz, Christiane; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthIntroduction: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. Methods: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. Results: A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, p = 3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. Discussion: These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. Highlights: Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at p < 9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.Item Association between Cognitive Function and Physical Function, Frailty, and Quality of Life in Older Breast Cancer Survivors(MDPI, 2024-07-31) Von Ah, Diane; Rio, Carielle Joy; Carter, Allie; Perkins, Susan M.; Stevens, Erin; Rosko, Ashley; Davenport, Ashley; Kalady, Mathew; Noonan, Anne M.; Crouch, Adele; Storey, Susan; Overcash, Janine; Han, Claire J.; Yang, Yesol; Li, Haiying; Saligan, Leorey N.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: Older cancer survivors in general are at greater risk for cancer-related cognitive impairment (CRCI), yet few studies have explored its association with health outcomes. This study examined the association between subjective and objective measures of cognitive function and physical function, frailty, and quality of life (QoL) among older breast cancer survivors. Materials and methods: Older breast cancer survivors who reported cognitive concerns completed surveys on patient-reported cognitive function, physical function, frailty, and QoL as well as objective tests of visuospatial working memory and sustained attention. Data were analyzed using descriptive statistics and separate linear regression models. Results: A total of 219 female breast cancer survivors completed the study. Perceived cognitive abilities were associated with better physical function, frailty, and QoL (p ≤ 0.001) while cognitive concerns were negatively related with these metrics (p ≤ 0.001). Poorer visuospatial working memory and sustained attention were linked to increased frailty (p ≤ 0.001-0.01), whereas poorer sustained attention was associated with poorer physical function (p < 0.01). Conclusions: Older breast cancer survivors with perceived cognitive impairment and poorer cognitive performance reported poorer physical functioning, increased frailty, and poorer QoL. These findings underscore the importance of assessing cognitive concerns and their associated outcomes in older breast cancer survivors.Item xSiGra: explainable model for single-cell spatial data elucidation(Oxford University Press, 2024) Budhkar, Aishwarya; Tang, Ziyang; Liu, Xiang; Zhang, Xuhong; Su, Jing; Song, Qianqian; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthRecent advancements in spatial imaging technologies have revolutionized the acquisition of high-resolution multichannel images, gene expressions, and spatial locations at the single-cell level. Our study introduces xSiGra, an interpretable graph-based AI model, designed to elucidate interpretable features of identified spatial cell types, by harnessing multimodal features from spatial imaging technologies. By constructing a spatial cellular graph with immunohistology images and gene expression as node attributes, xSiGra employs hybrid graph transformer models to delineate spatial cell types. Additionally, xSiGra integrates a novel variant of gradient-weighted class activation mapping component to uncover interpretable features, including pivotal genes and cells for various cell types, thereby facilitating deeper biological insights from spatial data. Through rigorous benchmarking against existing methods, xSiGra demonstrates superior performance across diverse spatial imaging datasets. Application of xSiGra on a lung tumor slice unveils the importance score of cells, illustrating that cellular activity is not solely determined by itself but also impacted by neighboring cells. Moreover, leveraging the identified interpretable genes, xSiGra reveals endothelial cell subset interacting with tumor cells, indicating its heterogeneous underlying mechanisms within complex cellular interactions.Item Social alignment matters: Following pandemic guidelines is associated with better wellbeing(Springer Nature, 2022-05-03) Tunçgenç, Bahar; Newson, Martha; Sulik, Justin; Zhao, Yi; Dezecache, Guillaume; Deroy, Ophelia; El Zein, Marwa; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: In response to the Covid-19 pandemic, most countries implemented physical distancing measures. Many mental health experts warned that through increasing social isolation and anxiety, these measures could negatively affect psychosocial wellbeing. However, socially aligning with others by adhering to these measures may also be beneficial for wellbeing. Methods: We examined these two contrasting hypotheses using cross-national survey data (N = 6675) collected fortnightly from participants in 115 countries over 3 months at the beginning of the pandemic. Participants reported their wellbeing, perceptions of how vulnerable they were to Covid-19 (i.e., high risk of infection) and how much they, and others in their social circle and country, were adhering to the distancing measures. Results: Linear mixed-effects models showed that being a woman, having lower educational attainment, living alone and perceived high vulnerability to Covid-19 were risk factors for poorer wellbeing. Being young (18-25) was associated with lower wellbeing, but longitudinal analyses showed that young people's wellbeing improved over 3 months. In contrast to widespread views that physical distancing measures negatively affect wellbeing, results showed that following the guidelines was positively associated with wellbeing even for people in high-risk groups. Conclusions: These findings provide an important counterpart to the idea that pandemic containment measures such as physical distancing negatively impacted wellbeing unequivocally. Despite the overall burden of the pandemic on psychosocial wellbeing, social alignment with others can still contribute to positive wellbeing. The pandemic has manifested our propensity to adapt to challenges, particularly highlighting how social alignment can forge resilience.