Biostatistics Commons^™

Burden Of Disease Attributable To High Body Mass Index: An Analysis Of Data From The Global Burden Of Disease Study 2021, Xiao-Dong Zhou, Qin-Fen Chen, Wah Yang, Mauricio Zuluaga, Giovanni Targher, Christopher Byrne, Luca Valentu, Fei Luo, Christos Katsouras, Christopher Opio

Internal Medicine, East Africa

Background: Obesity represents a major global health challenge with important clinical implications. Despite its recognized importance, the global disease burden attributable to high body mass index (BMI) remains less well understood.

Methods: We systematically analyzed global deaths and disability-adjusted life years (DALYs) attributable to high BMI using the methodology and analytical approaches of the Global Burden of Disease Study (GBD) 2021. High BMI was defined as a BMI over 25 kg/m2 for individuals aged ≥20 years. The Socio-Demographic Index (SDI) was used as a composite measure to assess the level of socio-economic development across different regions. Subgroup analyses considered age, …

Genomic And Socioeconomic Determinants Of Racial Disparities In Breast Cancer Survival: Insights From The All Of Us Program, Nubaira Rizvi, Hui Lyu, Leah Vaidya, Xiao Cheng Wu, Lucio Miele, Qingzhao Yu

School of Public Health Faculty Publications

Background: Breast cancer outcomes are worse among Black women in the U.S. compared to White women. While extensive research has focused on risk factors contributing to breast cancer; the role of genomic elements in health disparities between these racial groups remains unclear. This study aims to identify genomic variants and socioeconomic status (SES) determinants influencing racial disparities in breast cancer survival through multiple mediation analyses. Methods: Our investigation is based on the NIH-supported All of Us (AoU) program and analyzes 7452 female participants with malignant tumors of breast, including 5073 with genomic data. A log-rank test reveals significant racial differences …

Improvement And Evaluation Of Multiple Imputation By Heckman's One-Step Mle For Binary Mnar Outcomes And Various Types Of Mar Covariates, Xin W. Shore

Mathematics & Statistics ETDs

Missing data is inevitable in clinical epidemiology. It becomes one of the major challenges in the analyses and can potentially undermine the validity of results and conclusions. Although methods for handling missing data with mechanisms of missing completely at random (MCAR) or missing at random (MAR) have been widely researched, methods adapted for the missing not at random (MNAR) mechanism are less studied. Galimard et al. (2018) have derived a method to use multiple imputation by Heckman's One-Step ML Estimation for binary MNAR outcome and continuous MAR covariates (MIHEml). This dissertation focuses on updating MIHEml in terms of …

Assessing The Adequacy Of A Prediction Model, Abhaya Indrayan, Sakshi Mishra Ms

COBRA Preprint Series

No abstract provided.

Effect Of Correlation Boundaries On Collinearity And Bias In Ordinary Least Square Regression, Yumo Xue

All ETDs from UAB

Linear regression (LM) stands as one of the prevailing methods used to assess the association between a dependent variable and independent variables, typically estimated using ordinary least squares. However, this approach frequently faces obstacles when applied to biomedical data, due to the issue of correlated independent variables (collinearity). Collinearity is a potential issue in observational studies, where researchers might omit less significant correlated variables from their model. This is often guided by the rule of thumb that a Variance Inflation Factor (VIF) of 10 indicates severe collinearity. Our hypothesis is that relying on this rule of thumb is arbitrary, and …

Risk Factors For Cognitive Impairment In Adult Population Of Coastal Area: A Cross-Sectional Study In Maringkik Island, Indonesia, Herpan Syafii Harahap, Arina Windri Rivarti, Nurhidayati Nurhidayati, Fitriannisa Faradina Zubaidi, Dini Suryani, Legis Ocktaviana Saputri, Yanna Indrayana, Athalita Andhera, Muhammad Hilam, Abiyyu Didar Haq

Kesmas

Cognitive impairment is a medical condition commonly found in elderly populations, which can be due to vascular risk factors in patients. There remains limited data on risk factors for cognitive impairment among coastal region populations. This study aimed to investigate risk factors for cognitive impairment in the adult population of Maringkik Island, West Nusa Tenggara Province, Indonesia. Data collected were age, sex, education level, hypertension, antihypertensive treatment, diabetes mellitus, cigarette smoking, and body mass index status. A total of 114 participants were recruited using a consecutive sampling method. The participants’ cognitive function assessment used the Mini-Cog instrument. The cognitive impairment …

Variation And Predictors Of Covid-19 Mortality In Hospitalized Cases In West Sumatra Province, Indonesia: A Retrospective Observational Study, Defriman Djafri, Ade Suzana Eka Putri, Yudi Pradipta

Kesmas

During 2020, the year of the COVID-19 pandemic, different Indonesian provinces had different numbers of COVID-19 infections and fatalities, particularly in West Sumatra Province. This study aimed to investigate the variation of confirmed COVID-19 cases and determine predictors of mortality in hospitalized patients across districts in West Sumatra Province. A retrospective observational study was conducted during the COVID-19 pandemic. From March 2020 to June 2021, 46,005 confirmed cases were collected in the province, of which 42,308 were hospitalized and analyzed. Confirmed cases and deaths were compared by geographic location using spatial analysis. The risk predictors of death were estimated using …

Exploration Of Positive Deviance In Prevention Of Underweight In The Under-Five: A Qualitative Study On Low-Income Urban Families, Irwan Budiono, Lukman Fauzi, Dewi Sari Rochmayani

Kesmas

Children under the age of five (the under-five) from low-income families are more vulnerable to experience underweight. This nutritional vulnerability is evident in the preliminary study, where 35.1% of the under-five experience underweight, and 28.48% are low-income families. This study aimed to explore Positive Deviance (PD) behaviors in preventing underweight among the under-five. The study applied a qualitative approach with a case study design. Data collection took place in July-August 2022, focusing on low-income families in the Gunung Brintik area. Data were collected through two focus group discussions, seven in-depth interviews, and five key informant interviews. Coding, subtheme, and theme …

Simulation Study On Count Data Based On Double Poisson Distribution, Chao Ma

Theses and Dissertations

This thesis delves into the double Poisson distribution. Regression based on the double Poisson distribution, as proposed by Efron in 1986, offers an alternative approach that allows for more accurate regression models when dealing with discrete data that exhibit either over- or under-dispersion compared to the Poisson distribution. In this thesis, two methods of calculating the exact double Poisson density are compared: one utilizes the exact probability with the normalizing constant c(mu, theta) by definition or the “finite sum” method, while the other employs an approximation of the normalizing constant c(mu, theta). Furthermore, a simulation was …

Cluster Effect For Snp-Snp Interaction Pairs For Predicting Complex Traits, Hui Yi Lin, Harun Mazumder, Indrani Sarkar, Po Yu Huang, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth R. Muir, Johanna Schleutker, Nora Pashayan, Jyotsna Batra, David E. Neal, Sune F. Nielsen, Børge G. Nordestgaard, Henrik Grönberg, Fredrik Wiklund, Robert J. Macinnis, Christopher A. Haiman, Ruth C. Travis, Janet L. Stanford, Adam S. Kibel, Cezary Cybulski, Kay Tee Khaw, Christiane Maier, Stephen N. Thibodeau, Manuel R. Teixeira, Lisa Cannon-Albright, Hermann Brenner, Radka Kaneva, Hardev Pandha, Et Al

School of Public Health Faculty Publications

Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP-SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a …

The Impact Of “Multiple Looks” When Performing Survival Analysis, Quentin Eloise

Electronic Theses and Dissertations

Survival analysis is a critical statistical method in healthcare to assess patient treatment effects and disease progression. Another critical area of statistical methodology in health care is the practice of adaptive designs. Adaptive designs allow for interim analyses to take place during a study and various decisions and actions can take place more ethically. This is beneficial for studies that take multiple years to complete and allows administrators and healthcare providers to make sound decisions as early as possible. A challenging aspect of adaptive designs is that the number of interim analyses is known in advance which is applicable in …

Disparities And Protective Factors In Pandemic-Related Mental Health Outcomes: A Louisiana-Based Study, Ariane L. Rung, Evrim Oral, Tyler Prusisz, Edward S. Peters

School of Public Health Faculty Publications

Introduction: The COVID-19 pandemic has had a wide-ranging impact on mental health. Diverse populations experienced the pandemic differently, highlighting pre-existing inequalities and creating new challenges in recovery. Understanding the effects across diverse populations and identifying protective factors is crucial for guiding future pandemic preparedness. The objectives of this study were to (1) describe the specific COVID-19-related impacts associated with general well-being, (2) identify protective factors associated with better mental health outcomes, and (3) assess racial disparities in pandemic impact and protective factors. Methods: A cross-sectional survey of Louisiana residents was conducted in summer 2020, yielding a sample of 986 Black …

Bayesian And Deep Generative Modeling In Immunology, Yuqiu Yang

Statistical Science Theses and Dissertations

Due to the accumulation of a large volume of data of different natures such as sequencing data, proteomics data, and clinical data, statistical methods and deep learning algorithms have become increasingly important in the field of immunology. By leveraging the diverse datasets as well as interdisciplinary knowledge from areas like biology and public health, these quantitative methods have revolutionized this field by providing powerful tools for data analysis, modeling, and prediction. This has led to a deeper understanding of the immune system, accelerated the development of novel therapies, and paved the way for personalized and precision medicine approaches in immunology. …

Non-Receptor Tyrosine Kinases: Their Structure And Mechanistic Role In Tumor Progression And Resistance, Abdulaziz M. Eshaq, Thomas W. Flanagan, Sofie Yasmin Hassan, Sara A. Al Asheikh, Waleed A. Al-Amoudi, Simeon Santourlidis, Sarah Lilly Hassan, Maryam O. Alamodi, Marcelo L. Bendhack, Mohammed O. Alamodi, Youssef Haikel, Mossad Megahed, Mohamed Hassan

School of Graduate Studies Faculty Publications

Protein tyrosine kinases (PTKs) function as key molecules in the signaling pathways in addition to their impact as a therapeutic target for the treatment of many human diseases, including cancer. PTKs are characterized by their ability to phosphorylate serine, threonine, or tyrosine residues and can thereby rapidly and reversibly alter the function of their protein substrates in the form of significant changes in protein confirmation and affinity for their interaction with protein partners to drive cellular functions under normal and pathological conditions. PTKs are classified into two groups: one of which represents tyrosine kinases, while the other one includes the …

Random Forest For High-Dimensional Data, George Ekow Quaye

Open Access Theses & Dissertations

The exponential growth of data has led to a rapid increase in high-dimensional datasets across various domains, presenting significant challenges in data analysis, particularly in predictive modeling tasks. Traditional Random Forest (RF), while robust, often struggles with datasets filled with numerous noisy or non-informative features, compromising both performance and accuracy. This study introduces an advanced algorithm, High-Dimensional Random Forests (HDRF), designed to address these challenges by integrating robust multivariate feature selection techniques directly into the decision tree construction process. Unlike standard RF, HDRF incorporates ridge regression-based variable screening at each decision split, enhancing its ability to identify and utilize the …

Bayesian Approaches In Multi-State Markov Models And High Dimensional Time-To-Event Data., Yuchen Han

Electronic Theses and Dissertations

This dissertation consists of two projects. The first one involves nonparametric methods on Continuous Time Markov Chains (CTMCs). The second one is centered around Bayesian shrinkage models for detecting prognostic and predictive biomarkers in high-dimensional clinical data. Both these projects build on methods from across the frequentist and Bayesian paradigm to offer novel solutions. In the first project, we aim to model the nonlinear effects of continuous variables within multistate framework in a non-parametrically by appealing to the rich mathematical framework of Reproducing Kernel Hilbert Spaces (RKHS). Then we adapted the classical Representer Theorem to penalized (squared norm) log-likelihood which …

Dynamic Prediction Of Disease Progression With Longitudinal Data, Wenhao Li

Dissertations and Theses (Open Access)

Dynamic prediction plays a pivotal role in clinical research, especially when forecasting time-to-event outcomes based on evolving longitudinal data. This process often leverages the integration of longitudinal and time-to-event data through joint modeling, a prevalent technique. Alongside joint modeling, landmark modeling stands as another key approach in the realm of longitudinal studies. These methodologies are instrumental in dynamically predicting clinical events by utilizing predictor variables measured over time, up until the moment predictions are made. Within this framework, Chapter 2 addresses the challenge of comparing joint modeling and landmark modeling for dynamic prediction in longitudinal studies, introducing a novel algorithm …

Exploring The Diagnostic Potential Of Radiomics-Based Pet Image Analysis For T-Stage Tumor Diagnosis, Victor Aderanti

Electronic Theses and Dissertations

Cancer is a leading cause of death globally, and early detection is crucial for better

outcomes. This research aims to improve Region Of Interest (ROI) segmentation

and feature extraction in medical image analysis using Radiomics techniques

with 3D Slicer, Pyradiomics, and Python. Dimension reduction methods, including

PCA, K-means, t-SNE, ISOMAP, and Hierarchical Clustering, were applied to highdimensional features to enhance interpretability and efficiency. The study assessed the ability of the reduced feature set to predict T-staging, an essential component of the TNM system for cancer diagnosis. Multinomial logistic regression models were developed and evaluated using MSE, AIC, BIC, and Deviance …

An Application Of An In-Depth Advanced Statistical Analysis In Exploring The Dynamics Of Depression, Sleep Deprivation, And Self-Esteem, Muslihat Gaffari

Electronic Theses and Dissertations

Depression, intertwined with sleep deprivation and self-esteem, presents a significant challenge to mental health worldwide. The research shown in this paper employs advanced statistical methodologies to unravel the complex interactions among these factors. Through log-linear homogeneous association, multinomial logistic regression, and generalized linear models, the study scrutinizes large datasets to uncover nuanced patterns and relationships. By elucidating how depression, sleep disturbances, and self-esteem intersect, the research aims to deepen understanding of mental health phenomena. The study clarifies the relationship between these variables and explores reasons for prioritizing depression research. It evaluates how statistical models, such as log-linear, multinomial logistic regression, …

Interpregnancy Interval And Adverse Perinatal Outcomes: A Within-Individual Comparative Method, Maria Sevoyan, Marco Geraci, Edward A. Frongillo, Jihong Liu, Nansi S. Boghossian

Faculty Publications

Background and Aim: Previously observed associations between interpregnancy interval (IPI) and perinatal outcomes using a between-individual method may be confounded by unmeasured maternal factors. This study aims to examine the association between IPI and adverse perinatal outcomes using within-individual comparative analyses. Methods: We studied 10,647 individuals from the National Institute of Child Health and Human Development Consecutive Pregnancies Study in Utah with ≥3 liveborn singleton pregnancies. We matched two IPIs per individual and used conditional logistic regression to examine the association between IPI and adverse perinatal outcomes, including preterm birth (PTB, < 37 weeks’ gestation), small-for-gestational-age (SGA, < 10th percentile of sex-specific birthweight for gestational age), low birthweight (LBW, < 2,500 g), and neonatal intensive care unit (NICU) admission. Point and 95% confidence interval (CI) estimates were adjusted for factors that vary across pregnancies within individuals. Results: CIs did not unequivocally support either an increase or a decrease in the odds of PTB (adjusted odds ratio [aOR]: 1.31, 95% CI: 0.87, 1.96), SGA (aOR: 0.81, 95% CI: 0.51, 1.28), LBW (aOR: 1.59, 95% CI: 0.90, 2.80), or NICU admission (aOR: 0.96, 95% CI: 0.66, 1.40) for an IPI < 6 months compared to 18–23-months IPI (reference), and neither did the CIs for the aOR of IPIs of 6–11 and 12–18 months compared to the reference. In contrast, an IPI ≥24 months was associated with increased odds of LBW (aOR: 1.66, 95% CI: 1.03, 2.66 for 24–29 months; aOR: 2.27, 95% CI: 1.21, 4.29 for 30–35 months; and aOR: 2.09, 95% CI: 1.17, 3.72 for ≥36 months). Conclusions: Using a within-individual comparative method, we did not find evidence that a short IPI compared to the recommended IPI of 18–23 months was associated with increased odds of PTB, SGA, LBW, and NICU admission. IPI ≥ 24 months was associated with increased odds of delivering an LBW infant.

Visualization Of Species Tree Likelihood Under The Multispecies Coalescent Model, Jaimasan Sutton

Mathematics & Statistics ETDs

A commonly used tool for evolutionary biologists is a phylogenetic tree that represents the ancestry of a set of species and the evolution of traits. Statistical models can be used to predict the probabilities of gene trees which represent ancestral relationships of genes sampled from species. Because of this, we are able to represent the likelihood of a species tree, which represents the evolutionary history of a set of species, as a function of the counts of gene tree topologies, where each gene tree represents the ancestry of a specific genetic locus for multiple species. Because we can represent these …

Childhood Sexual Abuse And Compulsive Sexual Behavior Among Men Who Have Sex With Men Newly Diagnosed With Hiv, Monique J. Brown, Medinat Omobola Osinubi, Daniel Amoatika, Mohammad Rifat Haider, Sally Kirklewski, Patrick Wilson, Nathan B. Hansen

Faculty Publications

Childhood sexual abuse (CSA) continues to be a public health challenge. The prevalence of experiencing CSA is higher among men who have sex with men (MSM) than the general population. CSA has been linked to compulsive sexual behavior (CSB) among varying populations but has not been examined among MSM who were newly diagnosed with HIV. Therefore, the aims of this study were to assess the direct association between CSA and CSB among newly diagnosed MSM living with HIV, and to identify the potential mediating roles of depressive symptoms and emotion regulation in the association between CSA and CSB. The study …

A Probabilistic Approach To Estimate The Temporal Order Of Pathway Mutations Accounting For Intra-Tumor Heterogeneity, Menghan Wang, Yanqi Xie, Jinpeng Liu, Austin Li, Li Chen, Arnold Stromberg, Susanne Arnold, Chunming Liu, Chi Wang

Markey Cancer Center Faculty Publications

The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumori- genesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this …

Mathematical Modeling Of Tumor Response Dynamics To Predict Progression-Free Survival In Patients With Recurrent High-Grade Glioma, Daniel James Glazar

USF Tampa Graduate Theses and Dissertations

In this dissertation, I aim to develop a mathematical model describing tumor volume response dynamics to perform individual dynamic predictions of progression-free survival (PFS) on patients with recurrent high-grade glioma (rHGG).

Patients with rHGG have a dismal prognosis with median overall survival (OS) of <12 months and median PFS of <7 months. However, there is a wide heterogeneity in treatment responses. Therefore, to aid clinicians with making decisions to alter therapeutic protocol, I would like to predict patient-specific PFS.

To perform individual dynamic predictions, I employ the Claret tumor growth inhibition (TGI) model. I further develop this model by coupling it with two different survival models. Inter-patient heterogeneity is also taken into account through mixed effects, including covariate effects. Model PFS predictions were evaluated using receiver operating characteristic (ROC) curve analysis as well as Brier …

Primary Care Payment Models And Avoidable Hospitalizations In Ontario, Canada: A Multivalued Treatment Effects Analysis., Nibene Habib Somé, Rose Anne Devlin, Nirav Mehta, Sisira Sarma

Epidemiology and Biostatistics Publications

Improving access to primary care physicians' services may help reduce hospitalizations due to Ambulatory Care Sensitive Conditions (ACSCs). Ontario, Canada's most populous province, introduced blended payment models for primary care physicians in the early- to mid-2000s to increase access to primary care, preventive care, and better chronic disease management. We study the impact of payment models on avoidable hospitalizations due to two incentivized ACSCs (diabetes and congestive heart failure) and two non-incentivized ACSCs (angina and asthma). The data for our study came from health administrative data on practicing primary care physicians in Ontario between 2006 and 2015. We employ a …

Examining The Interaction Between Calcium Supplement Use, Demographics, And Lifestyle Factors On Bone Health In Women, Vix Talbot

University Honors Theses

Osteoporosis is a condition which poses a significant health threat, particularly among women during the menopause transition, where accelerated bone loss increases fracture risk. Calcium supplementation has been shown to be an important intervention to mitigate bone mineral density (BMD) decline during this and other periods of life. However, the efficacy of calcium supplementation is influenced by various individual factors, including demographics and lifestyle habits. This study investigates the interaction between calcium supplement use, and several interaction terms on bone health in women. Multiple linear regression analysis is employed to assess the impact of these factors on BMD. Data from …

Evaluating The Influence Of Perfluorooctane Sulfonic Acid Exposure On Blood Glucose Levels: A Comprehensive Multiple Regression Analysis Considering Confounding Factors, Henry Mensah

Theses and Dissertations

Perfluorooctane sulfonate (PFOS) are widely used for industrial and commercial purposes and have received increasing attention due to their adverse effects on health. This thesis investigates the relationship between PFOS exposure and blood glucose levels, considering potential confounding factors. Regression analysis was conducted on a dataset comprising demographic, lifestyle, and biomarker data from a diverse population sample. Sex exhibited a significant role, with females demonstrating an 11.77% increase in blood glucose levels in response to PFOS exposure compared to males, supported by a p-value of 1.04 × 109. Body mass index (BMI) also played a pivotal role, revealing a 2.17% …

A Modified Switching Procedure From Temporary To Tunneled Central Venous Dialysis Catheters, Johannes Eberhard, Constantin Bedau, Andrew Genius Chapple, Julia Klein, Christoph Reissfelder, Anna Isabelle Kaelsch, Andreas Lutz Heinrich Gerken, Sebastian Zach, Kay Schwenke

School of Medicine Faculty Publications

Background: Tunneled central venous catheters are commonly used for dialysis in patients without a functional permanent vascular access. In an emergent setting, a non-tunneled, temporary central venous catheter is often placed for immediate dialysis. The most critical step in the catheter insertion is venipuncture, which is often a major cause for longer intervention times and procedure-related adverse events. To avoid this critical step when placing a more permanent tunneled catheter, an exchange over a previously placed temporary one can be considered. In this paper, we present a modified switching approach with a separate access site. Methods: In this retrospective analysis …

Access To Prostate-Specific Antigen Testing And Mortality Among Men With Prostate Cancer, Hari S. Iyer, Benjamin V. Stone, Charlotte Roscoe, Mei Chin Hsieh, Antoinette M. Stroup, Charles L. Wiggins, Fredrick R. Schumacher, Scarlett L. Gomez, Timothy R. Rebbeck, Quoc Dien Trinh

School of Public Health Faculty Publications

Importance: Prostate-specific antigen (PSA) screening for prostate cancer is controversial but may be associated with benefit for certain high-risk groups. Objectives: To evaluate associations of county-level PSA screening prevalence with prostate cancer outcomes, as well as variation by sociodemographic and clinical factors. Design, Setting, and Participants: This cohort study used data from cancer registries based in 8 US states on Hispanic, non-Hispanic Black, and non-Hispanic White men aged 40 to 99 years who received a diagnosis of prostate cancer between January 1, 2000, and December 31, 2015. Participants were followed up until death or censored after 10 years or December …

A Guide To Successful Management Of Collaborative Partnerships In Quantitative Research: An Illustration Of The Science Of Team Science., Alyssa Platt, Tracy Truong, Mary Boulos, Nichole E Carlson, Manisha Desai, Monica M Elam, Emily Slade, Alexandra L Hanlon, Jillian H Hurst, Maren K Olsen, Laila M Poisson, Lacey Rende, Gina-Maria Pomann

Biostatistics Faculty Publications

Data-intensive research continues to expand with the goal of improving healthcare delivery, clinical decision-making, and patient outcomes. Quantitative scientists, such as biostatisticians, epidemiologists, and informaticists, are tasked with turning data into health knowledge. In academic health centres, quantitative scientists are critical to the missions of biomedical discovery and improvement of health. Many academic health centres have developed centralized Quantitative Science Units which foster dual goals of professional development of quantitative scientists and producing high quality, reproducible domain research. Such units then develop teams of quantitative scientists who can collaborate with researchers. However, existing literature does not provide guidance on how …