Browsing by Subject "Probability"
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Item Open Access A Generalized Lyapunov Construction for Proving Stabilization by Noise(2012) Kolba, Tiffany NicoleNoise-induced stabilization occurs when an unstable deterministic system is stabilized by the addition of white noise. Proving that this phenomenon occurs for a particular system is often manifested through the construction of a global Lyapunov function. However, the procedure for constructing a Lyapunov function is often quite ad hoc, involving much time and tedium. In this thesis, a systematic algorithm for the construction of a global Lyapunov function for planar systems is presented. The general methodology is to construct a sequence of local Lyapunov functions in different regions of the plane, where the regions are delineated by different behaviors of the deterministic dynamics. A priming region, where the deterministic drift is directed inward, is first identified where there is an obvious choice for a local Lyapunov function. This priming Lyapunov function is then propagated to the other regions through a series of Poisson equations. The local Lyapunov functions are lastly patched together to form one smooth global Lyapunov function.
The algorithm is applied to a model problem which displays finite time blow up in the deterministic setting in order to prove that the system exhibits noise-induced stabilization. Moreover, the Lyapunov function constructed is in fact what we define to be a super Lyapunov function. We prove that the existence of a super Lyapunov function, along with a minorization condition, implies that the corresponding system converges to a unique invariant probability measure at an exponential rate that is independent of the initial condition.
Item Open Access A quantitative formulation of biology's first law.(Evolution; international journal of organic evolution, 2019-06) McShea, Daniel W; Wang, Steve C; Brandon, Robert NThe zero-force evolutionary law (ZFEL) states that in evolutionary systems, in the absence of forces or constraints, diversity and complexity tend to increase. The reason is that diversity and complexity are both variance measures, and variances tend to increase spontaneously as random events accumulate. Here, we use random-walk models to quantify the ZFEL expectation, producing equations that give the probabilities of diversity or complexity increasing as a function of time, and that give the expected magnitude of the increase. We produce two sets of equations, one for the case in which variation occurs in discrete steps, the other for the case in which variation is continuous. The equations provide a way to decompose actual trajectories of diversity or complexity into two components, the portion due to the ZFEL and a remainder due to selection and constraint. Application of the equations is demonstrated using real and hypothetical data.Item Open Access A unifying framework for interpreting and predicting mutualistic systems.(Nature communications, 2019-01) Wu, Feilun; Lopatkin, Allison J; Needs, Daniel A; Lee, Charlotte T; Mukherjee, Sayan; You, LingchongCoarse-grained rules are widely used in chemistry, physics and engineering. In biology, however, such rules are less common and under-appreciated. This gap can be attributed to the difficulty in establishing general rules to encompass the immense diversity and complexity of biological systems. Furthermore, even when a rule is established, it is often challenging to map it to mechanistic details and to quantify these details. Here we report a framework that addresses these challenges for mutualistic systems. We first deduce a general rule that predicts the various outcomes of mutualistic systems, including coexistence and productivity. We further develop a standardized machine-learning-based calibration procedure to use the rule without the need to fully elucidate or characterize their mechanistic underpinnings. Our approach consistently provides explanatory and predictive power with various simulated and experimental mutualistic systems. Our strategy can pave the way for establishing and implementing other simple rules for biological systems.Item Restricted Application of Edwards' statistical mechanics to high-dimensional jammed sphere packings.(Phys Rev E Stat Nonlin Soft Matter Phys, 2010-11) Jin, Yuliang; Charbonneau, Patrick; Meyer, Sam; Song, Chaoming; Zamponi, FrancescoThe isostatic jamming limit of frictionless spherical particles from Edwards' statistical mechanics [Song et al., Nature (London) 453, 629 (2008)] is generalized to arbitrary dimension d using a liquid-state description. The asymptotic high-dimensional behavior of the self-consistent relation is obtained by saddle-point evaluation and checked numerically. The resulting random close packing density scaling ϕ∼d2(-d) is consistent with that of other approaches, such as replica theory and density-functional theory. The validity of various structural approximations is assessed by comparing with three- to six-dimensional isostatic packings obtained from simulations. These numerical results support a growing accuracy of the theoretical approach with dimension. The approach could thus serve as a starting point to obtain a geometrical understanding of the higher-order correlations present in jammed packings.Item Restricted Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.(PLoS One, 2010-04-08) Schildkraut, Joellen M; Iversen, Edwin S; Wilson, Melanie A; Clyde, Merlise A; Moorman, Patricia G; Palmieri, Rachel T; Whitaker, Regina; Bentley, Rex C; Marks, Jeffrey R; Berchuck, AndrewBACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.Item Open Access Effective spread and timecourse of neural inactivation caused by lidocaine injection in monkey cerebral cortex.(J Neurosci Methods, 1997-06-06) Tehovnik, EJ; Sommer, MAWe studied the effective spread of lidocaine to inactivate neural tissue in the frontal cortex of the rhesus monkey. Injections of 2% lidocaine at 4 microl/min were made while units were recorded 1 or 2 mm away. To inactivate units 1 mm away from the injection site 100% of the time, 7 microl of lidocaine had to be injected. To inactivate units 2 mm away from the injection site 100% of the time, 30 microl of lidocaine were required. Units were maximally inactivated around 8 min after the start of a lidocaine injection, and they gradually recovered, regaining most of their initial activity by around 30 min after the start of an injection. The volume of lidocaine required to inactivate neurons > 90% of the time could be estimated by the spherical volume equation, V = 4/3 pi (r)3. To prolong the inactivation, a slower infusion of lidocaine subsequent to an initial bolus was effective. Saline control injections had no effect. These results allow both a prediction of the timecourse of neural inactivation and an estimate of the spread of neural inactivation following injection of lidocaine into the monkey cerebral cortex.Item Open Access Effects of FOXO genotypes on longevity: a biodemographic analysis.(J Gerontol A Biol Sci Med Sci, 2010-12) Zeng, Y; Cheng, L; Chen, H; Cao, H; Hauser, ER; Liu, Y; Xiao, Z; Tan, Q; Tian, XL; Vaupel, JWBased on data from 760 centenarians and 1060 middle-age controls (all Han Chinese), this article contributes biodemographic insights and syntheses concerning the magnitude of effects of the FOXO genotypes on longevity. We also estimate independent and joint effects of the genotypes of FOXO1A and FOXO3A genes on long-term survival, considering carrying or not-carrying the minor allele of the single-nucleotide polymorphism of another relevant gene. We found substantial gender differences in the independent effects; positive effects of FOXO3A and negative effects of FOXO1A largely compensate each other if one carries both, although FOXO3A has a stronger impact. Ten-year follow-up cohort analysis shows that at very advanced ages 92-110, adjusted for various confounders, positive effects of FOXO3A on survival remain statistically significant, but no significant effects of FOXO1A alone; G × G interactions between FOXO1A-209 and FOXO3A-310 or FOXO3A-292 decrease survival likelihood by 32%-36% (p < .05); G × E interactions between FOXO1A-209 and regular exercise increase survival likelihood by 31%-32% (p < .05).Item Open Access Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure.(Hypertension, 2010-06) Smith, Patrick J; Blumenthal, James A; Babyak, Michael A; Craighead, Linda; Welsh-Bohmer, Kathleen A; Browndyke, Jeffrey N; Strauman, Timothy A; Sherwood, AndrewHigh blood pressure increases the risks of stroke, dementia, and neurocognitive dysfunction. Although aerobic exercise and dietary modifications have been shown to reduce blood pressure, no randomized trials have examined the effects of aerobic exercise combined with dietary modification on neurocognitive functioning in individuals with high blood pressure (ie, prehypertension and stage 1 hypertension). As part of a larger investigation, 124 participants with elevated blood pressure (systolic blood pressure 130 to 159 mm Hg or diastolic blood pressure 85 to 99 mm Hg) who were sedentary and overweight or obese (body mass index: 25 to 40 kg/m(2)) were randomized to the Dietary Approaches to Stop Hypertension (DASH) diet alone, DASH combined with a behavioral weight management program including exercise and caloric restriction, or a usual diet control group. Participants completed a battery of neurocognitive tests of executive function-memory-learning and psychomotor speed at baseline and again after the 4-month intervention. Participants on the DASH diet combined with a behavioral weight management program exhibited greater improvements in executive function-memory-learning (Cohen's D=0.562; P=0.008) and psychomotor speed (Cohen's D=0.480; P=0.023), and DASH diet alone participants exhibited better psychomotor speed (Cohen's D=0.440; P=0.036) compared with the usual diet control. Neurocognitive improvements appeared to be mediated by increased aerobic fitness and weight loss. Also, participants with greater intima-medial thickness and higher systolic blood pressure showed greater improvements in executive function-memory-learning in the group on the DASH diet combined with a behavioral weight management program. In conclusion, combining aerobic exercise with the DASH diet and caloric restriction improves neurocognitive function among sedentary and overweight/obese individuals with prehypertension and hypertension.Item Open Access Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States.(Proceedings of the National Academy of Sciences of the United States of America, 2022-04) Cramer, Estee Y; Ray, Evan L; Lopez, Velma K; Bracher, Johannes; Brennen, Andrea; Castro Rivadeneira, Alvaro J; Gerding, Aaron; Gneiting, Tilmann; House, Katie H; Huang, Yuxin; Jayawardena, Dasuni; Kanji, Abdul H; Khandelwal, Ayush; Le, Khoa; Mühlemann, Anja; Niemi, Jarad; Shah, Apurv; Stark, Ariane; Wang, Yijin; Wattanachit, Nutcha; Zorn, Martha W; Gu, Youyang; Jain, Sansiddh; Bannur, Nayana; Deva, Ayush; Kulkarni, Mihir; Merugu, Srujana; Raval, Alpan; Shingi, Siddhant; Tiwari, Avtansh; White, Jerome; Abernethy, Neil F; Woody, Spencer; Dahan, Maytal; Fox, Spencer; Gaither, Kelly; Lachmann, Michael; Meyers, Lauren Ancel; Scott, James G; Tec, Mauricio; Srivastava, Ajitesh; George, Glover E; Cegan, Jeffrey C; Dettwiller, Ian D; England, William P; Farthing, Matthew W; Hunter, Robert H; Lafferty, Brandon; Linkov, Igor; Mayo, Michael L; Parno, Matthew D; Rowland, Michael A; Trump, Benjamin D; Zhang-James, Yanli; Chen, Samuel; Faraone, Stephen V; Hess, Jonathan; Morley, Christopher P; Salekin, Asif; Wang, Dongliang; Corsetti, Sabrina M; Baer, Thomas M; Eisenberg, Marisa C; Falb, Karl; Huang, Yitao; Martin, Emily T; McCauley, Ella; Myers, Robert L; Schwarz, Tom; Sheldon, Daniel; Gibson, Graham Casey; Yu, Rose; Gao, Liyao; Ma, Yian; Wu, Dongxia; Yan, Xifeng; Jin, Xiaoyong; Wang, Yu-Xiang; Chen, YangQuan; Guo, Lihong; Zhao, Yanting; Gu, Quanquan; Chen, Jinghui; Wang, Lingxiao; Xu, Pan; Zhang, Weitong; Zou, Difan; Biegel, Hannah; Lega, Joceline; McConnell, Steve; Nagraj, VP; Guertin, Stephanie L; Hulme-Lowe, Christopher; Turner, Stephen D; Shi, Yunfeng; Ban, Xuegang; Walraven, Robert; Hong, Qi-Jun; Kong, Stanley; van de Walle, Axel; Turtle, James A; Ben-Nun, Michal; Riley, Steven; Riley, Pete; Koyluoglu, Ugur; DesRoches, David; Forli, Pedro; Hamory, Bruce; Kyriakides, Christina; Leis, Helen; Milliken, John; Moloney, Michael; Morgan, James; Nirgudkar, Ninad; Ozcan, Gokce; Piwonka, Noah; Ravi, Matt; Schrader, Chris; Shakhnovich, Elizabeth; Siegel, Daniel; Spatz, Ryan; Stiefeling, Chris; Wilkinson, Barrie; Wong, Alexander; Cavany, Sean; España, Guido; Moore, Sean; Oidtman, Rachel; Perkins, Alex; Kraus, David; Kraus, Andrea; Gao, Zhifeng; Bian, Jiang; Cao, Wei; Lavista Ferres, Juan; Li, Chaozhuo; Liu, Tie-Yan; Xie, Xing; Zhang, Shun; Zheng, Shun; Vespignani, Alessandro; Chinazzi, Matteo; Davis, Jessica T; Mu, Kunpeng; Pastore Y Piontti, Ana; Xiong, Xinyue; Zheng, Andrew; Baek, Jackie; Farias, Vivek; Georgescu, Andreea; Levi, Retsef; Sinha, Deeksha; Wilde, Joshua; Perakis, Georgia; Bennouna, Mohammed Amine; Nze-Ndong, David; Singhvi, Divya; Spantidakis, Ioannis; Thayaparan, Leann; Tsiourvas, Asterios; Sarker, Arnab; Jadbabaie, Ali; Shah, Devavrat; Della Penna, Nicolas; Celi, Leo A; Sundar, Saketh; Wolfinger, Russ; Osthus, Dave; Castro, Lauren; Fairchild, Geoffrey; Michaud, Isaac; Karlen, Dean; Kinsey, Matt; Mullany, Luke C; Rainwater-Lovett, Kaitlin; Shin, Lauren; Tallaksen, Katharine; Wilson, Shelby; Lee, Elizabeth C; Dent, Juan; Grantz, Kyra H; Hill, Alison L; Kaminsky, Joshua; Kaminsky, Kathryn; Keegan, Lindsay T; Lauer, Stephen A; Lemaitre, Joseph C; Lessler, Justin; Meredith, Hannah R; Perez-Saez, Javier; Shah, Sam; Smith, Claire P; Truelove, Shaun A; Wills, Josh; Marshall, Maximilian; Gardner, Lauren; Nixon, Kristen; Burant, John C; Wang, Lily; Gao, Lei; Gu, Zhiling; Kim, Myungjin; Li, Xinyi; Wang, Guannan; Wang, Yueying; Yu, Shan; Reiner, Robert C; Barber, Ryan; Gakidou, Emmanuela; Hay, Simon I; Lim, Steve; Murray, Chris; Pigott, David; Gurung, Heidi L; Baccam, Prasith; Stage, Steven A; Suchoski, Bradley T; Prakash, B Aditya; Adhikari, Bijaya; Cui, Jiaming; Rodríguez, Alexander; Tabassum, Anika; Xie, Jiajia; Keskinocak, Pinar; Asplund, John; Baxter, Arden; Oruc, Buse Eylul; Serban, Nicoleta; Arik, Sercan O; Dusenberry, Mike; Epshteyn, Arkady; Kanal, Elli; Le, Long T; Li, Chun-Liang; Pfister, Tomas; Sava, Dario; Sinha, Rajarishi; Tsai, Thomas; Yoder, Nate; Yoon, Jinsung; Zhang, Leyou; Abbott, Sam; Bosse, Nikos I; Funk, Sebastian; Hellewell, Joel; Meakin, Sophie R; Sherratt, Katharine; Zhou, Mingyuan; Kalantari, Rahi; Yamana, Teresa K; Pei, Sen; Shaman, Jeffrey; Li, Michael L; Bertsimas, Dimitris; Skali Lami, Omar; Soni, Saksham; Tazi Bouardi, Hamza; Ayer, Turgay; Adee, Madeline; Chhatwal, Jagpreet; Dalgic, Ozden O; Ladd, Mary A; Linas, Benjamin P; Mueller, Peter; Xiao, Jade; Wang, Yuanjia; Wang, Qinxia; Xie, Shanghong; Zeng, Donglin; Green, Alden; Bien, Jacob; Brooks, Logan; Hu, Addison J; Jahja, Maria; McDonald, Daniel; Narasimhan, Balasubramanian; Politsch, Collin; Rajanala, Samyak; Rumack, Aaron; Simon, Noah; Tibshirani, Ryan J; Tibshirani, Rob; Ventura, Valerie; Wasserman, Larry; O'Dea, Eamon B; Drake, John M; Pagano, Robert; Tran, Quoc T; Ho, Lam Si Tung; Huynh, Huong; Walker, Jo W; Slayton, Rachel B; Johansson, Michael A; Biggerstaff, Matthew; Reich, Nicholas GShort-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.Item Open Access From Spectral Theorem to Spectral Statistics of Large Random Matrices with Spatio-Temporal Dependencies(2023) Naeem, Muhammad AbdullahHigh dimensional random dynamical systems are ubiquitous, including-but not limited to- cyber-physical systems, daily return on different stocks of S\&P 1500 and velocity profile of interacting particle systems around McKeanVlasov limit. Mathematically speaking, observed time series data can be captured via a stable $n-$ dimensional linear transformation `$A$' and additive randomness. System identification aims at extracting useful information about underlying dynamical system, given a length $N$ trajectory from it (corresponds to an $n \times N$ dimensional data matrix). We use spectral theorem for non-Hermitian operators to show that spatio-temperal correlations are dictated by the \emph{discrepancy between algebraic andgeometric multiplicity of distinct eigenvalues} corresponding to state transition matrix. Small discrepancies imply that original trajectory essentially comprises of multiple \emph{lower dimensional random dynamical systems living on $A$ invariant subspaces and are statistically independent of each other}. In the process, we provide first quantitative handle on decay rate of finite powers of state transition matrix $\|A^{k}\|$ . It is shown that when a stable dynamical system has only one distinct eigenvalue and discrepancy of $n-1$: $\|A\|$ has a dependence on $n$, resulting dynamics are \emph{spatially inseparable} and consequently there exist at least one row with covariates of typical size $\Theta\big(\sqrt{N-n+1}$ $e^{n}\big)$ i.e., even under stability assumption, covariates can \emph{suffer from curse of dimensionality }.
In the light of these findings we set the stage for non-asymptotic error analysis in estimation of state transition matrix $A$ via least squares regression on observed trajectory by showing that element-wise error is essentially a variant of well-know Littlewood-Offord problem and(can be extremely sensitive to dimension of the state space and number of iterations). We also show that largest singular value of the data matrix can be cursed by dimensionality even when state-transition matrix is stable. Overarching theme of this thesis is new theoretical results on spectral theorem for non-Hermitian operators, non-asymptotic behavior of high dimensional dynamical systems , which we incorporate with the work of Talagrand on concentration of measure phenomenon to better understand behavior of the structured random matrices(data matrix) and subsequently the performance of different learning algorithms with dependent data. Besides, we also show that there exists stable linear Gaussians with process level Talagrands' inequality linear in dimension of the state space(previously an open problem), along with deterioration of mixing times with increase in discrepancy between algebraic and geometric multiplicity of $A$.
Item Open Access Gender and age interact to affect early outcome after intracerebral hemorrhage.(PLoS One, 2013) Umeano, Odera; Phillips-Bute, Barbara; Hailey, Claire E; Sun, Wei; Gray, Marisa C; Roulhac-Wilson, Briana; McDonagh, David L; Kranz, Peter G; Laskowitz, Daniel T; James, Michael LBACKGROUND: Intracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH. METHODS: Adult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. RESULTS: In this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death. CONCLUSION: While independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings.Item Open Access Hematopoietic cell transplantation with cord blood for cure of HIV infections.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2013-03) Petz, Lawrence D; Redei, Istvan; Bryson, Yvonne; Regan, Donna; Kurtzberg, Joanne; Shpall, Elizabeth; Gutman, Jonathan; Querol, Sergio; Clark, Pamela; Tonai, Richard; Santos, Sarah; Bravo, Aide; Spellman, Stephen; Gragert, Loren; Rossi, John; Li, Shirley; Li, Haitang; Senitzer, David; Zaia, John; Rosenthal, Joseph; Forman, Stephen; Chow, RobertHematopoietic cell transplantation (HCT) using CCR5-Δ32/Δ32 stem cells from an adult donor has resulted in the only known cure of human immunodeficiency virus (HIV) infection. However, it is not feasible to repeat this procedure except rarely because of the low incidence of the CCR5-Δ32 allele, the availability of only a small number of potential donors for most patients, and the need for a very close human leukocyte antigen (HLA) match between adult donors and recipients. In contrast, cord blood (CB) transplantations require significantly less stringent HLA matching. Therefore, our hypothesis is that cure of HIV infections by HCT can be accomplished much more readily using umbilical CB stem cells obtained from a modestly sized inventory of cryopreserved CCR5-Δ32/Δ32 CB units. To test this hypothesis, we developed a screening program for CB units and are developing an inventory of CCR5-Δ32/Δ32 cryopreserved units available for HCT. Three hundred such units are projected to provide for white pediatric patients a 73.6% probability of finding an adequately HLA matched unit with a cell dose of ≥2.5 × 10(7) total nucleated cells (TNCs)/kg and a 27.9% probability for white adults. With a cell dose of ≥1 × 10(7) TNCs/kg, the corresponding projected probabilities are 85.6% and 82.1%. The projected probabilities are lower for ethnic minorities. Impetus for using CB HCT was provided by a transplantation of an adult with acute myelogenous leukemia who was not HIV infected. The HCT was performed with a CCR5-Δ32/Δ32 CB unit, and posttransplantation in vitro studies indicated that the patient's peripheral blood mononuclear cells were resistant to HIV infection.Item Open Access Improvement and International Validation of the Predictive Probability of the Patient Demographics, Radiographic Index, and Surgical Invasiveness for Mechanical Failure (PRISM) Model for Preventive Procedures in Adult Spinal Deformity Surgery.(Spine, 2022-05) Yagi, Mitsuru; Hosogane, Naobumi; Ames, Christopher P; Smith, Justin S; Shaffrey, Christopher I; Schwab, Frank J; Lafage, Virginie; Bess, Shay; Suzuki, Satoshi; Satoshi, Nori; Takahashi, Yohei; Tsuji, Osahiko; Nagoshi, Narihito; Nakamura, Masaya; Matsumoto, Morio; Watanabe, Kota; International Spine Study Group (ISSG)Study design
This is an international multicenter retrospective review of 219 surgically treated consecutive adult spinal deformity (ASD) patients who had a minimum of five fused segments, completed a 2-year follow-up.Objective
The purpose of this study was to add the indices of preventive procedures to improve and to validate the predictive probability of the PRISM (patient demographics, radiographic index, and surgical invasiveness for mechanical failure) for mechanical failure (MF) following ASD surgery.Summary of background data
The PRISM was developed from the data of 321 ASD patients, which stratified the risk of MF from six types of risk.Methods
Data from 136 Japanese ASD patients (age 49 ± 21 yr, 88% female) were used to develop PRISM2, and data from 83 US ASD patients (age 58 ± 12 yr, 86% female) were used for the external validation. We analyzed the associations between three preventive procedures (UIV+1 tethering [TH], teriparatide [TP], and multirod [MR]) and MF by multivariate logistic regression analysis (MRA). The values for the nearest integer of the β of the procedures were added to the six indices of the original PRISM to establish the PRISM2. The discriminative ability of the PRISM/ PRISM2 for MF was evaluated using the area under the receiver operating characteristic curve (AUC) and the precision-recall (PR) curve. The Cochran-Armitage test was used to analyze the trend between PRISM/PRISM2 scores and MF.Results
MF developed in 25% (34 cases). The β values for the preventive procedures calculated by MRA were TH: -2.5, TP: -3.0, and MR: -2.1. The Cochran-Armitage test showed an excellent trend between MF and PRISM/2. The diagnostic ability was superior for the PRISM2 compared with the PRISM (PRISM2; AUC = 0.94 [0.90-0.98], PRISM; AUC = 0.87 [0.81-0.93], difference = -0.07 [-0.11 to -0.03], P < 0.01). The AUC of the PRISM2 was 0.70 [0.59-0.81, P < 0.01] in the US patient cohort.Conclusion
We refined the PRISM by adding preventive procedures to the risk indices. Further validation and adjustment in a large different patient cohorts may improve the predictive probability of PRISM2.Level of Evidence: 3.Item Open Access Inductive determination of allele frequency spectrum probabilities in structured populations.(Theoretical population biology, 2019-10) Uyenoyama, Marcy K; Takebayashi, Naoki; Kumagai, SeijiWe present a method for inductively determining exact allele frequency spectrum (AFS) probabilities for samples derived from a population comprising two demes under the infinite-allele model of mutation. This method builds on a labeled coalescent argument to extend the Ewens sampling formula (ESF) to structured populations. A key departure from the panmictic case is that the AFS conditioned on the number of alleles in the sample is no longer independent of the scaled mutation rate (θ). In particular, biallelic site frequency spectra, widely-used in explorations of genome-wide patterns of variation, depend on the mutation rate in structured populations. Variation in the rate of substitution across loci and through time may contribute to apparent distortions of site frequency spectra exhibited by samples derived from structured populations.Item Open Access Influence of comorbid alcohol and psychiatric disorders on utilization of mental health services in the National Comorbidity Survey.(The American journal of psychiatry, 1999-08) Wu, LT; Kouzis, AC; Leaf, PJOBJECTIVE: This study sought to determine how comorbidity of psychiatric and substance abuse disorders affects the likelihood of using mental health services. METHOD: The analysis was based on data on adults aged 18-54 years in the National Comorbidity Survey (N = 5,393). Users and nonusers of mental health and substance abuse services were compared in terms of their demographic characteristics, recent stressful life events, social support, parental history of psychopathology, self-medication, and symptoms of alcohol abuse/dependence. RESULTS: The prevalence of service utilization varied by diagnostic configurations. Comorbid psychiatric or alcohol disorders were stronger predictors of service utilization than a pure psychiatric or alcohol disorder. Factors predicting utilization of services differed for each disorder. CONCLUSIONS: Since comorbidity increases the use of mental health and substance abuse services, research on the relationship of psychiatric and alcohol-related disorders to service utilization needs to consider the coexistence of mental disorders. Attempts to reduce barriers to help seeking for those in need of treatment should be increased.Item Open Access Integrating pharmacogenomics into clinical trials of hearing disorders.(The Journal of the Acoustical Society of America, 2022-11) Brutnell, Thomas P; Wang, Xinwen; Bao, JianxinIn 2019, the U.S. Food and Drug Administration issued guidance to increase the efficiency of drug development and support precision medicine, including tailoring treatments to those patients who will benefit based on genetic variation even in the absence of a documented mechanism of action. Although multiple advancements have been made in the field of pharmacogenetics (PGx) for other disease conditions, there are no approved PGx guidelines in the treatment of hearing disorders. In studies of noise-induced hearing loss (NIHL), some progress has been made in the last several years associating genomic loci with susceptibility to noise damage. However, the power of such studies is limited as the underlying physiological responses may vary considerably among the patient populations. Here, we have summarized previous animal studies to argue that NIHL subtyping is a promising strategy to increase the granularity of audiological assessments. By coupling this enhanced phenotyping capability with genetic association studies, we suggest that drug efficacy will be better predicted, increasing the likelihood of success in clinical trials when populations are stratified based on genetic variation or designed with multidrug combinations to reach a broader segment of individuals suffering or at risk from NIHL.Item Open Access Linked Sensitivity Analysis, Calibration, and Uncertainty Analysis Using a System Dynamics Model for Stroke Comparative Effectiveness Research.(Medical decision making : an international journal of the Society for Medical Decision Making, 2016-11) Tian, Yuan; Hassmiller Lich, Kristen; Osgood, Nathaniel D; Eom, Kirsten; Matchar, David BBackground
As health services researchers and decision makers tackle more difficult problems using simulation models, the number of parameters and the corresponding degree of uncertainty have increased. This often results in reduced confidence in such complex models to guide decision making.Objective
To demonstrate a systematic approach of linked sensitivity analysis, calibration, and uncertainty analysis to improve confidence in complex models.Methods
Four techniques were integrated and applied to a System Dynamics stroke model of US veterans, which was developed to inform systemwide intervention and research planning: Morris method (sensitivity analysis), multistart Powell hill-climbing algorithm and generalized likelihood uncertainty estimation (calibration), and Monte Carlo simulation (uncertainty analysis).Results
Of 60 uncertain parameters, sensitivity analysis identified 29 needing calibration, 7 that did not need calibration but significantly influenced key stroke outcomes, and 24 not influential to calibration or stroke outcomes that were fixed at their best guess values. One thousand alternative well-calibrated baselines were obtained to reflect calibration uncertainty and brought into uncertainty analysis. The initial stroke incidence rate among veterans was identified as the most influential uncertain parameter, for which further data should be collected. That said, accounting for current uncertainty, the analysis of 15 distinct prevention and treatment interventions provided a robust conclusion that hypertension control for all veterans would yield the largest gain in quality-adjusted life years.Conclusions
For complex health care models, a mixed approach was applied to examine the uncertainty surrounding key stroke outcomes and the robustness of conclusions. We demonstrate that this rigorous approach can be practical and advocate for such analysis to promote understanding of the limits of certainty in applying models to current decisions and to guide future data collection.Item Open Access Measuring blood pressure for decision making and quality reporting: where and how many measures?(Annals of internal medicine, 2011-06) Powers, Benjamin J; Olsen, Maren K; Smith, Valerie A; Woolson, Robert F; Bosworth, Hayden B; Oddone, Eugene ZBackground
The optimal setting and number of blood pressure (BP) measurements that should be used for clinical decision making and quality reporting are uncertain.Objective
To compare strategies for home or clinic BP measurement and their effect on classifying patients as having BP that was in or out of control.Design
Secondary analysis of a randomized, controlled trial of strategies to improve hypertension management. (ClinicalTrials.gov registration number: NCT00237692)Setting
Primary care clinics affiliated with the Durham Veterans Affairs Medical Center.Patients
444 veterans with hypertension followed for 18 months.Measurements
Blood pressure was measured repeatedly by using 3 methods: standardized research BP measurements at 6-month intervals; clinic BP measurements obtained during outpatient visits; and home BP measurements using a monitor that transmitted measurements electronically.Results
Patients provided 111,181 systolic BP (SBP) measurements (3218 research, 7121 clinic, and 100,842 home measurements) over 18 months. Systolic BP control rates at baseline (mean SBP<140 mm Hg for clinic or research measurement; <135 mm Hg for home measurement) varied substantially, with 28% classified as in control by clinic measurement, 47% by home measurement, and 68% by research measurement. Short-term variability was large and similar across all 3 methods of measurement, with a mean within-patient coefficient of variation of 10% (range, 1% to 24%). Patients could not be classified as having BP that was in or out of control with 80% certainty on the basis of a single clinic SBP measurement from 120 mm Hg to 157 mm Hg. The effect of within-patient variability could be greatly reduced by averaging several measurements, with most benefit accrued at 5 to 6 measurements.Limitation
The sample was mostly men with a long-standing history of hypertension and was selected on the basis of previous poor BP control.Conclusion
Physicians who want to have 80% or more certainty that they are correctly classifying patients' BP control should use the average of several measurements. Hypertension quality metrics based on a single clinic measurement potentially misclassify a large proportion of patients.Primary funding source
U.S. Department of Veterans Affairs Health Services Research and Development Service.Item Open Access Multiple, conserved cryptic recombination signals in VH gene segments: detection of cleavage products only in pro B cells.(J Exp Med, 2007-12-24) Davila, Marco; Liu, Feifei; Cowell, Lindsay G; Lieberman, Anne E; Heikamp, Emily; Patel, Anjali; Kelsoe, GarnettReceptor editing is believed to play the major role in purging newly formed B cell compartments of autoreactivity by the induction of secondary V(D)J rearrangements. In the process of immunoglobulin heavy (H) chain editing, these secondary rearrangements are mediated by direct V(H)-to-J(H) joining or cryptic recombination signals (cRSs) within V(H) gene segments. Using a statistical model of RS, we have identified potential cRSs within V(H) gene segments at conserved sites flanking complementarity-determining regions 1 and 2. These cRSs are active in extrachromosomal recombination assays and cleaved during normal B cell development. Cleavage of multiple V(H) cRSs was observed in the bone marrow of C57BL/6 and RAG2:GFP and microMT congenic animals, and we determined that cRS cleavage efficiencies are 30-50-fold lower than a physiological RS. cRS signal ends are abundant in pro-B cells, including those recovered from microMT mice, but undetectable in pre- or immature B cells. Thus, V(H) cRS cleavage regularly occurs before the generation of functional preBCR and BCR. Conservation of cRSs distal from the 3' end of V(H) gene segments suggests a function for these cryptic signals other than V(H) gene replacement.Item Open Access On SDEs with Partial Damping Inspired by the Navier-Stokes Equations(2019) Williamson, BrendanThe solution to the Navier Stokes equations on the 2D torus with stochastic forcing that is white noise in time, coloured in space has a Fourier series representation whose coordinates satisfy a countable system of Stochastic Differential Equations. Inspired by the structure of these equations, we construct a finite system of stochastic differential equations with a similar structure and explore the conditions under which the system has an invariant distribution. \\
Our main tool to prove existence of invariant distributions are Lyapunov functions, or more generally Lyapunov pairs. In particular, we construct the Lyapunov pairs piecewise over different regions and then use mollifiers to unify these disparate characterisations. We also apply some results from Algebraic Geometry and Matrix Perturbation Theory to study and exploit the geometry of the problem in high dimensions. \\
The combination of these methods allowed us to prove that a large class of the equations we constructed have an invariant distributions. Furthermore we have explicit tail estimates for these invariant distributions.