Medicine and Health Sciences Commons^™

Complementary Vertebrate Wac Models Exhibit Phenotypes Relevant To Desanto-Shinawi Syndrome, Kang-Han Lee, Marwan Shinawi, Et Al.

2020-Current year OA Pubs

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes, including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the

Assessment Of Timp1, Transgelin-2, And Procalcitonin As Protein Biomarkers For Diagnosis And Prognosis Of Bloodstream Infection In A Critically Ill Cohort, Sajal Tiwary, Caroline A O'Neil, Sydney Lawless, Olivia Arter, Meghan Brown, Brittany Roemmich, Carleigh Samuels, Jennie H Kwon, Christopher W Farnsworth

2020-Current year OA Pubs

BACKGROUND: Bloodstream infections (BSI) are a significant contributor to morbidity and mortality among hospitalized patients. Rapid diagnosis of BSI is critical for timely and appropriate clinical management, but current diagnostic strategies have a prolonged turnaround time or only identify select pathogens with minimal prognostic information.

METHODS: We examined serial serologic samples from 77 intensive care unit (ICU) patients at time points before, during, and after diagnosis of presumptive BSI to identify host-derived protein biomarkers associated with specific organisms and with clinical outcomes in BSI. ICU patients with and without BSI were included. Two candidate biomarkers, tissue metalloproteinase 1 (TIMP-1) and …

Benchmarking Institutional Support For Point-Of-Care Testing Programs: Scale, Staffing, And Operational Challenges, Min Yu, Nam K Tran, Julie L V Shaw, Nicholas E Larkey, Nicole V Tolan, Andrew Szczembara, Leslie J Donato, Robert D Maynard, Adil I Khan

2020-Current year OA Pubs

BACKGROUND: Point-of-care testing (POCT) has expanded rapidly across healthcare systems, increasing both program scale and operational complexity. However, quantitative benchmarking data describing how POCT programs are structured and supported across institutions remain limited.

METHODS: We conducted a cross-sectional survey to characterize POCT program support, including program scope, staffing, operational practices, governance, and challenges. The survey was distributed electronically through professional networks, and 93 institutional responses were analyzed. Descriptive analyses were performed, and derived metrics, including sites per point-of-care testing coordinator (POCC), were used to evaluate the relationship between program scale and staffing.

RESULTS: POCT programs demonstrated substantial variability in scale, …

Current State And Needs Of Clinical Laboratories In Selected Countries In Africa, Merih Tesfazghi, Anne E Tebo, Roa Harb, Anthony O Okorodudu, Lee Schroeder, Jeannette Guarner, Christine Bales, Jack Ladenson, Allison Targowski, Kerry Cosby, Olajumoke Oladipo

2020-Current year OA Pubs

The Africa Working Group, under the auspices of the Global Laboratory Quality Initiative of the Association for Diagnostics & Laboratory Medicine (ADLM), conducted several educational workshops in Africa to promote laboratory quality in the region. The challenges faced in maintaining quality in clinical laboratories in low-resource countries may differ from region to region and country to country. To better understand current gaps and inform our engagement with partners in Africa, a needs assessment survey was distributed to 1427 ADLM members in Africa and further disseminated through local partners, resulting in 121 responses from participants across 8 countries in the region. …

Cracking The Code: Genotype-Phenotype Correlation Models In Sarcoglycanopathies, Leonela Luce, Conrad C Weihl, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Sarcoglycanopathies are among the most severe limb-girdle muscular dystrophies (LGMD), though milder presentations have been described. These diseases are primarily caused by missense variants, but the limited predictability of their effect on protein maturation, complex formation, and transport has hindered reliable genotype-phenotype correlations. This study aimed to establish accurate genotype-phenotype correlations for LGMDR3, LGMDR4, and LGMDR5.

METHODS: We analyzed the largest sarcoglycanopathy cohort to date (n = 541). Clinical data, including age at symptom onset and loss of ambulation, were collected and used to define phenotype severity. Predictive models were developed considering the impact of non-truncating variants on secondary …

Opioid Dispensing Volume And Per-Patient Intensity In Sickle Cell Disease, Kevin Y Xu, Brandon K Attell, Joanna L Buss, Tashalee R Brown, Charles R Jonassaint, Richard A Grucza, Allison A King, Max Jordan Nguemeni Tiako

2020-Current year OA Pubs

IMPORTANCE: Opioids remain central to management of acute and chronic pain in sickle cell disease (SCD). Opioid dispensing declined over the 2010s amid opioid stewardship efforts, but patterns since 2020 are less clear. Analyses aggregating opioids into morphine milligram equivalents (MME) may obscure agent-specific patterns.

OBJECTIVE: To characterize opioid dispensing volume and per-recipient frequency, duration, and dose among individuals with SCD.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of commercially insured and Medicaid-enrolled patients with SCD using the Merative MarketScan databases across 3 periods from January 2011 to February 2016, March 2016 to December 2020, and January 2021 to …

Parent-Child Neural Dynamics During A Stressful Task: Probing Associations With Temperament And Anxiety, Joscelin Rocha-Hidalgo, Harmony Nguyen, Dakota Reis, Denny Schaedig, Kahlil I Thompson, Susan B Perlman, Koraly E Pérez-Edgar

2020-Current year OA Pubs

Dynamic social interactions between parents and children can contribute to anxiety risk, amplifying shared genetic risk. Research has focused on observed behaviors to explain intergenerational transmission. Neural synchrony may contribute as a biological conduit for behavioral transmission of risk. We examined 109 parent-child dyads (

Spinal Cord Imaging For Multiple Sclerosis: Advances, Priorities, And Opportunities, Cornelia Laule, Matthew R Brier, Et Al.

2020-Current year OA Pubs

The spinal cord plays a central role in the pathophysiology and clinical manifestations of multiple sclerosis (MS), yet remains under-studied compared with the brain. This review summarizes key insights from the 2025 North American Imaging in MS Spinal Cord Imaging Workshop, highlighting recent advances, ongoing challenges, and future opportunities in MS spinal cord imaging. We review pathological studies and outline the clinical relevance of spinal cord lesions and atrophy for diagnosis, prognosis, and disease monitoring, highlighting emerging biomarkers of progression independent of relapse activity. Correlations between magnetic resonance imaging, histopathology, and clinical outcomes support the validation and translational potential of …

Heritable Transgenic Schistosomes As A Living Platform For Sars-Cov-2 Neutralizing Antibody Secretion, Wannaporn Ittiprasert, Bruce A Rosa, Sergej Djuranovic, Makedonka Mitreva, Et Al.

2020-Current year OA Pubs

We report the generation and propagation of not only the first heritable transgenic schistosome line but also a line that secretes a functional therapeutic protein in vivo. Using multiplexed CRISPR/Cas-mediated homology-directed knock-in targeted to a predicted genomic safe-harbor, we inserted a VHH-IgG1 Fc (termed C5-Fc) transgene into Schistosoma mansoni eggs. Single-miracidium infections of Biomphalaria glabrata yielded parental P0 lines; serial passage through snail and mouse hosts produced an F2 cohort in which all parasites carried the C5-Fc transgene and secreted C5-Fc into the murine venous circulation. Molecular assays confirmed chromosomal insertion, germline transmission and systemic secretion. Sera from mice harboring …

Altered Postnatal Chromatin Development In The Nucleus Accumbens Primes Enduring Stress Sensitivity, Rebekah L Rashford, Lisa Z Fang, Michael Deberardine, Hye Ji J Kim, Laura W Hirschfield, Ella Cervi, Mason R Barrett, Jeremy M Thompson, Meaghan C Creed, Catherine Jensen Peña

2020-Current year OA Pubs

Early life stress (ELS) sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc)-a key limbic and reward-associated brain region-ELS sensitizes both cellular and transcriptional response to later stress, which are programmed by enduring epigenetic changes. Among the histone modifications persistently enriched by ELS in NAc is H3K4me1, which is associated with open chromatin and epigenetic priming of genomic enhancers. Here, we sought to determine whether H3K4me1 enrichment in NAc was sufficient to prime cellular and behavioral responses to adult stress. Viral-mediated overexpression of the histone H3 monomethyltransferase

Premarket Clinical Evidence Strength And Recalls Of High-Risk Therapeutic Medical Devices, Maryam Mooghali, Faaizah Arshad, Vinay K Rathi, Kushal T Kadakia, Alexander O Everhart, Joseph S Ross, Sanket S Dhruva

2020-Current year OA Pubs

IMPORTANCE: High-risk medical devices approved through the US Food and Drug Administration (FDA) premarket approval (PMA) pathway may be supported by limited premarket clinical evidence, leaving uncertainties about safety. Whether device, premarket clinical evidence, or regulatory characteristics are associated with subsequent device recalls is unknown.

OBJECTIVE: To examine the association between device, premarket clinical evidence, and regulatory characteristics and serious recalls among high-risk therapeutic devices.

DESIGN AND SETTING: This cross-sectional study reviewed 193 high-risk therapeutic medical devices approved through the FDA's PMA pathway between January 1, 2014, and December 31, 2023. Data were analyzed between August 2025 and December 2025. …

Sex-Aware Causal Inference Assessment Of The Immune System In Complex Neurodegenerative Diseases, Frida Lona-Durazo, Ross P Byrne, Marc-Olivier Pilon, Michael D Greicius, Marie-Pierre Dubé, Michael E Belloy, Russell L Mclaughlin, Sarah A Gagliano Taliun

2020-Current year OA Pubs

Sex differences, in terms of prevalence, symptoms and disease progression, are established in the aetiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence from genetic and functional analyses affirming the role of the immune system in such diseases, but a thorough assessment of sex differences in the link between the immune system and neurodegenerative diseases remains lacking. Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases …

Achilles Tendon Injuries In Major League Soccer: A 10-Year Analysis Of Injury Rate, Return To Play, And Performance Metrics, Brian Forsythe, Catherine Hand, Francis Hand, Henry Eilen, Matthew Varano, Jared Sasaki, Camden Bohn, Anne Timmermann, Lauren Fertig, Eric Giza, Robert H Brophy, Bert Mandelbaum, Kirk Mccullough

2020-Current year OA Pubs

BACKGROUND: Injuries to the Achilles tendon, such as tears or ruptures, are commonly observed among elite athletes. These injuries can be debilitating for professional soccer players, leading to prolonged recovery and potential performance declines.

PURPOSE: To investigate the annual incidence, return-to-play (RTP) duration, and postinjury performance outcomes of Major League Soccer (MLS) players who sustained Achilles tendon injuries from 2010 to 2021.

STUDY DESIGN: Cohort study; Level of evidence, 3.

METHODS: This retrospective matched-cohort study evaluated MLS players with Achilles tendon injuries from 2010 to 2021, identified through the MLS Injury Surveillance database, and compared outcomes, including RTP duration, between …

Acute Opioid Responses Are Modulated By Dynamic Interactions Of Oprm1 And Fgf12, Paige M Lemen, Alexander S Hatoum, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

We generated time-series data for 105 morphine- and naloxone-related traits across ~700 BXD mice (64 diverse strains for both sexes) for 3 hr after a single morphine injection. Variations in responses were mapped using genome sequencing-based genotypes. The locomotor responses to morphine mapped to the µ opioid receptor gene (

Loss Of Nemp1 Disrupts Female Meiosis And Activates A Conserved Atm-Chk2 Checkpoint, Bilal Ahmad Hakim, Yonit Tsatskis, Ling Zhang, Esther Choi, Ying Zhang, Didier Hodzic, Que Wu, Muyun Zhang, Maryam Pashaei, Kyungwon Ha, Jannette Rusch, Julie A Brill, Miguel Angel Brieño-Enríquez, Andrea Jurisicova, Helen Mcneill

2020-Current year OA Pubs

Female germ cells must preserve the integrity of their genome and generate genetic diversity via meiotic recombination. This challenging process is error prone. Highly conserved checkpoint pathways detect errors in recombination and DNA damage, inducing the death of defective oocytes. Nuclear Envelope Membrane Protein (NEMP) homologs are highly conserved proteins critical for fertility in flies, worms, fish and mice. They localize to the inner nuclear envelope where they provide mechanical support. However, why NEMP homologs are specifically required for fertility is still unclear. Using both Drosophila and mouse models, we establish that loss of NEMP homologs leads to activation of …

Recent Advances In Alzheimer's Disease: From Molecular Mechanisms To Therapeutic Strategies, Michelle D Rudman, Jason D Ulrich, David M Holtzman

2020-Current year OA Pubs

Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker …

Tgf-Β Drives The Conversion Of Conventional Nk Cells Into Uterine Tissue-Resident Nk Cells To Support Murine Pregnancy, Josselyn D Barahona, Liping Yang, D Michael Nelson, Wayne M Yokoyama

2020-Current year OA Pubs

Tissue microenvironments shape lymphocyte differentiation to align immune function with local physiological demands. Uterine natural killer (NK) cells are critical for reproductive success, yet the molecular cues in the uterus that instruct their specialized identities remain incompletely understood. Here, we identify a TGF-β-dependent differentiation pathway by which circulating conventional NK cells convert into uterine tissue-resident NK cells during murine pregnancy. Loss of TGF-β receptor II expression in

Multiple Event Segmentation Mechanisms In The Human Brain, Tan T Nguyen, Joset A Etzel, Matthew A Bezdek, Jeffrey M Zacks

2020-Current year OA Pubs

The human brain segments continuous experience into discrete events, with theoretical accounts proposing two distinct mechanisms: creating boundaries at points of high

Subunit Composition Of The Katp Channels That Modulate Contractility Of Skeletal Muscle During Fatigue, Rosa Scala, Yuezhou Chen, Berk Mizrak, Gretchen A Meyer, Colin G Nichols

2020-Current year OA Pubs

ATP-sensitive potassium (KATP) channels are among the most expressed ion channels in skeletal muscle sarcolemma. While all KATP subunits can be detected in skeletal muscles, transcripts are enriched for KCNJ11 and ABCC9, suggesting that noncanonical Kir6.2/SUR2A assembly may constitute the majority of sarcolemmal KATP channels, but there has been no systematic dissection of KATP makeup in skeletal muscles. Here, we used a unique collection of murine lines selectively lacking specific channel-forming subunits (knockout, KO), and combined a genetic and pharmacological approach to determine which subunits of KATP channels are functionally relevant for skeletal muscle contraction. Under fatiguing conditions, isometric tetanic …

Long-Term Inactivation Mediated By Different Fgf-A Homologues On Heterologously Expressed Nav1.2 Currents, Yenisleidy Lorenzo-Ceballos, Pedro L Martinez-Espinosa, Xiao-Ming Xia, Christopher J Lingle

2020-Current year OA Pubs

A-isoforms of cytosolic growth factor homologous factors (FGF11-14) mediate long-term inactivation (LTI) of voltage-dependent sodium (NaV) channels. LTI is a rapid onset process that is competitive with the fast inactivation (IF) intrinsic to NaV channels, with little or no interconversion between inactivated states. Since recovery from LTI is orders of magnitude slower than recovery from IF, repetitive depolarizations lead to use-dependent accumulation of NaV channels in slow recovery states, thereby limiting NaV availability during trains of action potentials. Of the two or more N-terminal splice variants of the various FGF homologues, LTI specifically arises only from the A-isoform of each …

Multi-Center Comparison Of Corticotropin Releasing Hormone Vs. Desmopressin Stimulation Responses In Inferior Petrosal Sinus Sampling For Cushing's Disease, Samuel A Tenhoeve, Julie M Silverstein, Albert H Kim, Et Al.

2020-Current year OA Pubs

OBJECTIVES: Inferior petrosal sinus sampling (IPSS) is important for confirming Cushing's Disease (CD). Due to lack of corticotropin releasing hormone (CRH) availability, desmopressin/DDAVP is being used as the alternative stimulating agent but has limited data regarding testing cutoffs.

DESIGN: We compared the stimulation profiles of desmopressin and CRH in patients with CD.

METHODS: Data from the multi-center Registry of Adenomas of the PItuitary and Related Disorders (RAPID) was evaluated. 93 patients with CD confirmed by pathology or biochemical remission that underwent IPSS testing prior to surgical resection (desmopressin [n = 57], CRH [n = 36] or both [n = 1]). …

Diagnostic Stewardship Of Respiratory Cultures Using Clinical Decision Support In The Picu, Anna C Sick-Samuels, John C Lin, Rebecca G Same, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Endotracheal aspirate culture (EAC) practices for evaluation of ventilator-associated infections (VAI) vary widely across pediatric hospitals, and overuse can contribute to overdiagnosis and overtreatment for VAI. Diagnostic stewardship strategies to optimize EAC testing practices may reduce overtesting and unnecessary antibiotic treatment.

OBJECTIVE: To evaluate the association of diagnostic stewardship of EACs using clinical decision support with culture rates, antibiotic use, and patient outcomes across a multicenter collaborative of pediatric intensive care units (PICUs).

DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter cohort study with a pre-post study design among the BrighT STAR (Testing Stewardship for Antibiotic Reduction) Quality Improvement …

Patient-Centered Approach To Surgical Prevention Of Ovarian Cancer: A Nonrandomized Clinical Trial, Karen H Lu, Andrea R Hagemann, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Risk-reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high-risk individuals, but adverse effects from premature menopause are a barrier to uptake. Interval salpingectomy with delayed oophorectomy (ISDO) may be an effective alternative.

OBJECTIVE: To evaluate the association of ISDO vs RRSO and sexual function and menopausal symptoms.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter, nonrandomized (patient preference) clinical trial was performed among Women Choosing Surgical Prevention participants with a pathogenic or likely pathogenic germline variant conferring an increased risk for ovarian cancer. Patients from 9 US centers were enrolled from June 2, 2016, to October …

Prescribed Short-Acting Hormonal Contraceptive Use Among Premenopausal Females, Israel Bacha, Suleepon Uttamapinan, Hannah Harsanyi, Abigail Liberty, Lin Yang, Adetunji T Toriola

2020-Current year OA Pubs

IMPORTANCE: Hormonal contraceptive use has important implications for both reproductive and general health. However, the patterns and trends of short-acting hormonal contraceptive use among US premenopausal females remain insufficiently characterized.

OBJECTIVE: To evaluate trends in and factors associated with prescribed short-acting hormonal contraceptive use among US premenopausal females.

DESIGN, SETTING, AND PARTICIPANTS: Serial, cross-sectional analyses were conducted using US nationally representative data from the National Health and Nutrition Examination Survey (NHANES), including 10 survey cycles between 1999 to 2000 and 2017 to 2020 (before the COVID-19 pandemic). Participants included noninstitutionalized premenopausal females aged 15 years to younger than 60 years …

Maternal Health And Sociodemographic Characteristics Influence Infant Growth To 24 Months In The Tunza Mwana Cohort: A Prospective Cohort Study, David Taylor Hendrixson, Mark J Manary, Et Al.

2020-Current year OA Pubs

Upstream pathways influencing child growth are complex. Weight-for-age z-score (WAZ) reflects both ponderal and linear growth and can identify children at high mortality risk. Using data from a prospective cohort of 326 mother-child pairs in Kenya, we evaluated whether associations between maternal exposures and child growth outcomes in early and later childhood. Growth trajectories were examined using locally weighted scatterplot smoothing and piecewise linear mixed-effect models with a knot at age 3 months. Poisson regression models examined associations between maternal characteristics and child underweight (WAZ <  -2) and stunting (LAZ <  -2) before and after 3 months. Mean WAZ increased to a peak at 3 months before declining steadily through 24 months. Lower maternal education (adjusted β [aβ] -0.18; 95% CI: -0.24, -0.13), household crowding (aβ -0.2; 95% CI: -0.28, -0.11), lower wealth quintile (aβ -0.04; 95% CI: -0.06, -0.02) and multiparity (aβ -0.16; 95% CI: -0.23, -0.1) were associated with lower monthly rate of change in WAZ prior to age 3 months. Younger maternal age was associated with an increased monthly rate of change in WAZ (aβ = 0.13; 95% CI: 0.08, 0.18) before 3 months and decreased monthly WAZ (aβ -0.02; 95% CI: -0.03, -0.01) after 3 months. Preterm birth was associated with increased risk of underweight in both periods (aRR 2.77; 95% CI: 1.39-5.50). Maternal mental health, intimate partner violence and adverse childhood experiences were not significantly associated with child growth. Maternal nutritional, socio-economic and household-level factors shape early growth, emphasising the need for cross-sectoral programs to support growth.

Beyond Lactate: Real-Time Resuscitation Targets For Septic Shock During Critical Care Transport, James L Li, Aaron J Lacy, Michael J Defilippo

2020-Current year OA Pubs

No abstract provided.

A Call To Investigate The Association Between Histoplasmosis And Fatigue, Christian Hendrix, Julio Zuniga-Moya, Andrej Spec, Patrick Mazi

2020-Current year OA Pubs

Historically, infections are subjectively associated with fatigue, a common yet poorly delineated syndrome. The impact on patient quality of life is the ultimate justification to evaluate fatigue in patients with infections. While fungal infections are subjectively associated with fatigue, there are minimal quantifiable fungal research outcomes that evaluate histoplasmosis and fatigue.

Evaluation Of The Impact Of A Pathology Trainee-Driven Manual Review Process For Reference Testing At A Large Academic Center, Carly Maucione, Christopher W Farnsworth, Mark A Zaydman

2020-Current year OA Pubs

BACKGROUND: Increasing reliance on and complexity of laboratory testing necessitates laboratory stewardship initiatives to ensure appropriate test ordering, especially as reference testing costs continue to rise. Prospective manual review processes, although demanding of resources, have been shown to be cost-effective, but literature addressing the value of such a process is lacking.

METHODS: The pathology trainee-driven manual review process of 444 chemistry and microbiology tests on approval at a large academic center was reviewed. Data were extracted from an internal-use call-log and analyzed for test volumes, cancellation rates, and cost savings. A hypergeometric distribution was used to model random variation in …

Modern Molecular Profiling Recontextualizes The Nrg/Rtog 0539 Trial And Reveals Hidden High-Risk And Radiotherapy-Resistant Meningiomas, Leeor S Yefet, Clifford Robinson, Et Al.

2020-Current year OA Pubs

BACKGROUND: Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response.

METHODS: Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death …

Enhancing Validation Of Case-Control Omics Signatures Through "Minimalist" Single-Subject Analysis (N-Of-1 Trials): Proof Of Concept In Sepsis, Liam S Wilson, Nima Pouladi, Rachel F Nelson, Elizabeth A Middleton, Neal D Tolley, Mahdieh Shabanian, Colleen Kenost, Robert A Campbell, Matthew T Rondina, Yves A Lussier

2020-Current year OA Pubs

OBJECTIVE: To evaluate if a single-subject study (S3) design, utilizing paired transcriptome samples from the same patient (eg, "sepsis" vs "recovered"), can replicate transcriptomic signatures from small case-control studies, addressing challenges in patient accrual for rare or sub-stratified diseases.

METHODS: We generated a sepsis gene signature (SGS) comprising 300 differentially expressed genes (DEGs; FDR <  5%) from a human sepsis case-control cohort using general linear models (GLMs). Reproducibility of SGS was assessed through three approaches applied to sub-sampled independent datasets: single-subject analyses (N-of-1-MixEnrich), anticipated to perform better; conventional paired-sample GLM analyses; and a traditional case-control GLM analysis.

RESULTS: SGS reproducibility in GLM analyses was inconsistent at smaller cohort sizes (∼80% reproducibility; n = 5) but stabilized at cohort sizes >6. Remarkably, the single-subject-study approach consistently reproduced SGS in each of the 18 subjects individually (100% reproducibility; n = 1).

DISCUSSION: Conventional GLMs are …