Specialized interferon action in COVID-19.

The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications.

Dysregulated Lymphocyte Antigen Receptor Signaling in Common Variable Immunodeficiency with Granulomatous Lymphocytic Interstitial Lung Disease.

PURPOSE: A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling in CVID and CVID with GLILD (CVID/GLILD) remain undefined, hindering discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches. METHODS: To identify perturbations of immune cell subsets and TCR/BCR signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients. RESULTS: Patients with CVID, regardless of GLILD status, had increased frequency of HLADR+CD4+ T cells, CD57+CD8+ T cells, and CD21lo B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients only, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21lo B cells showed perturbed BCR-mediated phospholipase C gamma and extracellular signal-regulated kinase activation, while HLADR+CD4+ T cells and CD57+CD8+ T cells displayed disrupted TCR-mediated activation of kinases most proximal to the receptor. CONCLUSION: Both CVID and CVID/GLILD patients demonstrate an activated T and B cell phenotype compared to HC. However, only CVID/GLILD patients exhibit altered TCR/BCR signaling in the activated lymphocyte subsets. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD.

Enhanced Reactivity for Aromatic Bromination via Halogen Bonding with Lactic Acid Derivatives.

We report a new method for regioselective aromatic bromination using lactic acid derivatives as halogen bond acceptors with N-bromosuccinimide (NBS). Several structural analogues of lactic acid affect the efficiency of aromatic brominations, presumably via Lewis acid/base halogen-bonding interactions. Rate comparisons of aromatic brominations demonstrate the reactivity enhancement available via catalytic additives capable of halogen bonding. Computational results demonstrate that Lewis basic additives interact with NBS to increase the electropositive character of bromine prior to electrophilic transfer. An optimized procedure using catalytic mandelic acid under aqueous conditions at room temperature was developed to promote aromatic bromination on a variety of arene substrates with complete regioselectivity.

Modeling broadband cloaking using 3D nano-assembled plasmonic meta-structures.

The concept of "cloaking" an object is a very attractive one, especially in the visible (VIS) and near infra-red (NIR) regions of the electromagnetic spectrum, as that would reduce the visibility of an object to the eye. One possible route to achieving this goal is by leveraging the plasmonic property of metallic nanoparticles (NPs). We model and simulate light in the VIS and NIR scattered by a core of a homogeneous medium, covered by plasmonic cloak that is a spherical shell composed of gold nanoparticles (AuNPs). To consider realistic, scalable, and robust plasmonic cloaks that are comparable, or larger, in size to the wavelength, we introduce a multiscale simulation platform. This model uses the multiple scattering theory of Foldy and Lax to model interactions of light with AuNPs combined with the method of fundamental solutions to model interactions with the core. Numerical results of our simulations for the scattering cross-sections of core-shell composite indicate significant scattering suppression of up to 50% over a substantial portion of the desired spectral range (400 - 600 nm) for cores as large as 900 nm in diameter by a suitable combination of AuNP sizes and filling fractions of AuNPs in the shell.

Radical Benzylation of Quinones via C-H Abstraction.

Herein we report the development of radical benzylation reactions of quinones using Selectfluor and catalytic Ag(I) initiators. The reaction is believed to proceed via a C-H abstraction mechanism after Ag(I)-mediated reduction of Selectfluor. This reaction occurs under mild conditions and is effective for a variety of quinones and radical precursors bearing primary benzylic carbons. The use of preformed Ag(4-OMePy)2NO3 as a catalyst proved effective in improving the reaction efficiency by reducing unwanted degradation pathways available to Selectfluor.

Practical and innate carbon-hydrogen functionalization of heterocycles.

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings.

The control of regiochemistry is a considerable challenge in the development of a wide array of catalytic processes. Simple π-components such as alkenes, alkynes, 1,3-dienes, and allenes are among the many classes of substrates that present complexities in regioselective catalysis. Considering an internal alkyne as a representative example, when steric and electronic differences between the two substituents are minimal, differentiating among the two termini of the alkyne presents a great challenge. In cases where the differences between the alkyne substituents are substantial, overcoming those biases to access the regioisomer opposite that favored by substrate biases often presents an even greater challenge. Nickel-catalyzed reductive couplings of unsymmetrical π-components make up a group of reactions where control of regiochemistry presents a challenging but important objective. In the course of our studies of aldehyde-alkyne reductive couplings, complementary solutions to challenges in regiocontrol have been developed. Through careful selection of the ligand and reductant, as well as the more subtle reaction variables such as temperature and concentration, effective protocols have been established that allow highly selective access to either regiosiomer of the allylic alcohol products using a wide range of unsymmetrical alkynes. Computational studies and an evaluation of reaction kinetics have provided an understanding of the origin of the regioselectivity control. Throughout the various procedures described, the development of ligand-substrate interactions plays an essential role, and the overall kinetic descriptions were found to differ between protocols. Rational alteration of the rate-determining step plays a key role in the regiochemistry reversal strategy, and in one instance, the two possible regioisomeric outcomes in a single reaction were found to operate by different kinetic descriptions. With this mechanistic information in hand, the empirical factors that influence regiochemistry can be readily understood, and more importantly, the insights suggest simple and predictable experimental variables to achieving a desired reaction outcome. These studies thus present a detailed picture of the influences that control regioselectivity in a specific catalytic reaction, but they also delineate strategies for regiocontrol that may extend to numerous classes of reactions. The work provides an illustration of how insights into the kinetics and mechanism of a catalytic process can rationalize subtle empirical findings and suggest simple and rational modifications in procedure to access a desirable reaction outcome. Furthermore, these studies present an illustration of how important challenges in organic synthesis can be met by novel reactivity afforded by base metal catalysis. The use of nickel catalysis in this instance not only provides an inexpensive and sustainable method for catalysis but also enables unique reactivity patterns not accessible to other metals.

Dimer involvement and origin of crossover in nickel-catalyzed aldehyde-alkyne reductive couplings.

The mechanism of nickel(0)-catalyzed reductive coupling of aldehydes and alkynes has been studied. Extensive double-labeling crossover studies have been conducted. While previous studies illustrated that phosphine- and N-heterocyclic carbene-derived catalysts exhibited differing behavior, the origin of these effects has now been evaluated in detail. Many variables, including ligand class, sterics of the ligand and alkyne, temperature, and ring size being formed in intramolecular versions, all influence the extent of crossover observed. A computational evaluation of these effects suggests that dimerization of a key metallacyclic intermediate provides the origin of crossover. Protocols that proceed with crossover are typically less efficient than those without crossover given the thermodynamic stability and low reactivity of the dimeric metallacycles involved in crossover pathways.

Innate C-H trifluoromethylation of heterocycles.

Direct methods for the trifluoromethylation of heteroaromatic systems are in extremely high demand in nearly every sector of chemical industry. Here we report the discovery of a general procedure using a benchtop stable trifluoromethyl radical source that functions broadly on a variety of electron deficient and rich heteroaromatic systems and demonstrates high functional group tolerance. This C-H trifluoromethylation protocol is operationally simple (avoids gaseous CF(3)I), scalable, proceeds at ambient temperature, can be used directly on unprotected molecules, and is demonstrated to proceed at the innately reactive positions of the substrate. The unique and orthogonal reactivity of the trifluoromethyl radical relative to aryl radicals has also been investigated on both a complex natural product and a pharmaceutical agent. Finally, preliminary data suggest that the regioselectivity of C-H trifluoromethylation can be fine-tuned simply by judicious solvent choice.

SARS-CoV-2 Vaccine-Elicited Immunity after B Cell Depletion in Multiple Sclerosis.

The impact of B cell deficiency on the humoral and cellular responses to SARS-CoV2 mRNA vaccination remains a challenging and significant clinical management question. We evaluated vaccine-elicited serological and cellular responses in 1) healthy individuals who were pre-exposed to SARS-CoV-2 (n = 21), 2) healthy individuals who received a homologous booster (mRNA, n = 19; or Novavax, n = 19), and 3) persons with multiple sclerosis on B cell depletion therapy (MS-αCD20) receiving mRNA homologous boosting (n = 36). Pre-exposure increased humoral and CD4 T cellular responses in immunocompetent individuals. Novavax homologous boosting induced a significantly more robust serological response than mRNA boosting. MS-α CD20 had an intact IgA mucosal response and an enhanced CD8 T cell response to mRNA boosting compared with immunocompetent individuals. This enhanced cellular response was characterized by the expansion of only effector, not memory, T cells. The enhancement of CD8 T cells in the setting of B cell depletion suggests a regulatory mechanism between B and CD8 T cell vaccine responses.

A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.

Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients' T cells show residual TCR signal transduction and proliferation following anti-CD3/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck-/-) versus partial (LckP440S/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck-/- and LckP440S/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells-leading to intestinal inflammation.

Innate and guided C-H functionalization logic.

The combustion of organic matter is perhaps the oldest and most common chemical transformation utilized by mankind. The generation of a C-O bond at the expense of a C-H bond during this process may be considered the most basic form of C-H functionalization. This illustrates the extreme generality of the term "C-H functionalization", because it can describe the conversion of literally any C-H bond into a C-X bond (X being anything except H). Therefore, it may be of use to distinguish between what, in our view, are two distinct categories of C-H functionalization logic: "guided" and "innate". Guided C-H functionalizations, as the name implies, are guided by external reagents or directing groups (covalently or fleetingly bound) to install new functional groups at the expense of specifically targeted C-H bonds. Conversely, innate C-H functionalizations may be broadly defined as reactions that exchange C-H bonds for new functional groups based solely on natural reactivity patterns in the absence of other directing forces. Two substrates that illustrate this distinction are dihydrojunenol and isonicotinic acid. The C-H functionalization processes of hydroxylation or arylation, respectively, can take place at multiple locations on each molecule. Innate functionalizations lead to substitution patterns that are dictated by the inherent bias (steric or electronic) of the substrate undergoing C-H cleavage, whereas guided functionalizations lead to substitution patterns that are controlled by external directing forces such as metal complexation or steric bias of the reagent. Although the distinction between guided and innate C-H functionalizations may not always be clear in cases that do not fit neatly into a single category, it is a useful convention to consider when analyzing reactivity patterns and strategies for synthesis. We must emphasize that although a completely rigorous distinction between guided and innate C-H functionalization may not be practical, we have nonetheless found it to be a useful tool at the planning stage of synthesis. In this Account, we trace our own studies in the area of C-H functionalization in synthesis through the lens of "guided" and "innate" descriptors. We show how harnessing innate reactivity can be beneficial for achieving unique bond constructions between heterocycles and carbonyl compounds, enabling rapid and scalable total syntheses. Guided and innate functionalizations were used synergistically to create an entire family of terpenes in a controlled fashion. We continue with a discussion of the synthesis of complex alkaloids with high nitrogen content, which required the invention of a uniquely chemoselective innate C-H functionalization protocol. These findings led us to develop a series of innate C-H functionalization reactions for forging C-C bonds of interest to the largest body of practicing organic chemists: medicinal chemists. Strategic use of C-H functionalization logic can have a dramatically positive effect on the efficiency of synthesis, whether guided or innate.

Characterization of wear debris in total elbow arthroplasty.

BACKGROUND: The purpose of this study was to evaluate wear debris in periprosthetic tissues at the time of revision total elbow arthroplasty. Polyethylene, metallic, and bone cement debris were characterized, and the tissue response was quantified. MATERIALS AND METHODS: Capsular and medullary tissue samples were collected during revision surgery. Polyethylene debris was characterized by scanning electron microscopy after tissue digestion. The concentrations of metal and cement debris were quantified by inductively coupled plasma mass spectrometry. Tissue response was graded with a semiquantitative histologic method. RESULTS: Polyethylene particle size varied from the submicron range to over 100 µm. The mean diameter ranged from 0.6 µm to about 1 µm. Particles in the synovial tissues were larger and less abundant than those in tissues from the medullary canal. Cement, titanium alloy, and low levels of cobalt-chrome debris were also present, with cement predominating over metal debris. Histiocyte response was associated with small polyethylene particles (0.5-2 µm), and giant cells were associated with large polyethylene particles (>2 µm). Histiocyte scores positively correlated with the polyethylene particle number and the presence of metal. DISCUSSION: We have shown that periprosthetic tissues of total elbow patients who have undergone revision for loosening and osteolysis contain polyethylene, cement, and metal debris. Although the polyethylene particles were of a size and shape that have been previously shown to result in activation of phagocytic cells, osteolysis after total elbow arthroplasty is a multimodal process. Because of the presence of multiple wear particle sources, a cause-and-effect relationship between polyethylene debris and osteolysis cannot be established with certainty.

The development and deployment of electronic personal health records records: a strategic positioning perspective.

PURPOSE: The purpose of this study is to examine the impact of strategic position on the ability of an entrepreneurial firm to successfully develop and deploy electronic personal health records technology within the US healthcare industry. DESIGN/METHODOLOGY/APPROACH: This study uses an in-depth longitudinal case study methodology. FINDINGS: The study contributes by juxtaposing a longitudinal view of how the focal firm proposed and acted on different strategic positions in an attempt to achieve development and deployment success. In doing so, the study also elaborates on Porter's recognition that firms need to make trade-offs when choosing a strategic position, as the purposeful limitation of service offerings can protect against the degradation of existing value creating activities. RESEARCH LIMITATIONS/IMPLICATIONS: The authors' study highlights the enormous challenge of facilitating the adoption and diffusion of technology enabled interventions in the US healthcare ecosystem. Future research that combines both interdisciplinary and multi-level investigation and analysis is sorely needed to develop a more sophisticated understanding of the phenomenon and to encourage the development and deployment of useful technology enabled interventions within the US healthcare industry. PRACTICAL IMPLICATIONS: While the fragmented nature of the healthcare industry provides opportunities for entrepreneurial firms, such complexity within the ecosystem should not be underestimated as a reason for concern for small firms. SOCIAL IMPLICATIONS: Total economic burden due to chronic diseases and other healthcare-related expenses is massive for the USA. Consequently, prevention and early detection of future disease states has become a core component of the current healthcare reform debate. EPHRs are considered one core component of a broader healthcare strategy to improve health outcomes and lower costs. By deepening our understanding of how best to develop and deploy such interventions, society will surely benefit. ORIGINALITY/VALUE: The longitudinal nature of the authors' study provides a unique opportunity to understand the dynamic interrelationships between context, position, and performance within the US healthcare industry.

Innate and Adaptive Cell-Mediated Immune Responses to a COVID-19 mRNA Vaccine in Young Children.

Background: There is little information on cell-mediated immunity (CMI) to COVID-19 mRNA vaccines in children. We studied adaptive and innate CMI in vaccinated children aged 6 to 60 months. Methods: Blood obtained from participants in a randomized placebo-controlled trial of an mRNA vaccine before and 1 month after the first dose was used for antibody measurements and CMI (flow cytometry). Results: We enrolled 29 children with a mean age of 28.5 months (SD, 15.7). Antibody studies revealed that 10 participants were infected with SARS-CoV-2 prevaccination. Ex vivo stimulation of peripheral blood mononuclear cells with SARS-CoV-2 spike peptides showed significant increases pre- to postimmunization of activated conventional CD4+ and γδ T cells, natural killer cells, monocytes, and conventional dendritic cells but not mucosa-associated innate T cells. Conventional T-cell, monocyte, and conventional dendritic cell responses in children were higher immediately after vaccination than after SARS-CoV-2 infection. The fold increase in CMI pre- to postvaccination did not differ between children previously infected with SARS-CoV-2 and those uninfected. Conclusions: Children aged 6 to 60 months who were vaccinated with a COVID-19 mRNA vaccine developed robust CMI responses, including adaptive and innate immunity.

Expansion of extrafollicular B and T cell subsets in childhood-onset systemic lupus erythematosus.

Introduction: Most childhood-onset SLE patients (cSLE) develop lupus nephritis (cLN), but only a small proportion achieve complete response to current therapies. The prognosis of children with LN and end-stage renal disease is particularly dire. Mortality rates within the first five years of renal replacement therapy may reach 22%. Thus, there is urgent need to decipher and target immune mechanisms that drive cLN. Despite the clear role of autoantibody production in SLE, targeted B cell therapies such as rituximab (anti-CD20) and belimumab (anti-BAFF) have shown only modest efficacy in cLN. While many studies have linked dysregulation of germinal center formation to SLE pathogenesis, other work supports a role for extrafollicular B cell activation in generation of pathogenic antibody secreting cells. However, whether extrafollicular B cell subsets and their T cell collaborators play a role in specific organ involvement in cLN and/or track with disease activity remains unknown. Methods: We analyzed high-dimensional mass cytometry and gene expression data from 24 treatment naïve cSLE patients at the time of diagnosis and longitudinally, applying novel computational tools to identify abnormalities associated with clinical manifestations (cLN) and disease activity (SLEDAI). Results: cSLE patients have an extrafollicular B cell expansion signature, with increased frequency of i) DN2, ii) Bnd2, iii) plasmablasts, and iv) peripheral T helper cells. Most importantly, we discovered that this extrafollicular signature correlates with disease activity in cLN, supporting extrafollicular T/B interactions as a mechanism underlying pediatric renal pathogenesis. Discussion: This study integrates established and emerging themes of extrafollicular B cell involvement in SLE by providing evidence for extrafollicular B and peripheral T helper cell expansion, along with elevated type 1 IFN activation, in a homogeneous cohort of treatment-naïve cSLE patients, a point at which they should display the most extreme state of their immune dysregulation.

SARS-CoV-2 mRNA vaccination induces an antigen-specific T cell response correlating with plasma interferon-gamma in B cell depleted patients.

Emerging evidence is encouraging and suggests that a substantial proportion of patients without antibody responses (due to anti-CD20 therapy or other etiologies) to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines develop T cell responses. However, antigen-specific T cellular responses are notoriously difficult to assess clinically, given the lack of such assays under satisfactory CAP/CLIA regulation, and the laborious nature of the flow cytometric assessment. To evaluate the ability to apply a clinically feasible assay to measure T cellular responses to SARS-CoV-2 mRNA vaccination, we compared flow cytometric and enzyme-linked immunosorbent assay (ELISA) based assays in 24 participants treated with anti-CD20 therapy. T cellular activation (CD69 + CD137+ surface expression, i.e., activation induced markers [AIM]) and intracellular interferon gamma (INFγ) production via flow cytometry was compared to plasma Interferon Gamma Release Assay (IGRA) via ELISA. Plasma INFγ production measured by IGRA correlated with the percent of INFγ-producing AIM positive T cells, supporting the use of IGRA assay as a robust assessment of T cellular response to the SARS-CoV-2 vaccine for B-cell depleted patients that is clinically feasible, time efficient, and cost effective.

Mechanistic rationalization of unusual kinetics in Pd-catalyzed C-H olefination.

Detailed kinetic studies and novel graphical manipulations of reaction progress data in Pd(II)-catalyzed olefinations in the presence of mono-N-protected amino acid ligands reveal anomalous concentration dependences (zero order in o-CF(3)-phenylacetic acid concentration, zero order in oxygen pressure, and negative orders in both olefin and product concentrations), leaving the catalyst concentration as the sole positive driving force in the reaction. NMR spectroscopic studies support the proposal that rate inhibition by the olefinic substrate and product is caused by formation of reversible off-cycle reservoirs that remove catalyst from the active cycle. NMR studies comparing the interaction between the catalyst and substrate in the presence and absence of the ligand suggest that weak coordination of the ligand to Pd prevents formation of an inactive mixed acetate species. A fuller understanding of these features may lead to the design of more efficient Pd(II) catalysts for this potentially powerful C-H functionalization reaction.

A new reagent for direct difluoromethylation.

Molecular scaffolds containing alkylfluorine substituents are desired in many areas of chemical research from materials to pharmaceuticals. Herein, we report the invention of a new reagent (Zn(SO(2)CF(2)H)(2), DFMS) for the innate difluoromethylation of organic substrates via a radical process. This mild, operationally simple, chemoselective, and scalable difluoromethylation method is compatible with a range of nitrogen-containing heteroarene substrates of varying complexity as well as select classes of conjugated π-systems and thiols. Regiochemical comparisons suggest that the CF(2)H radical generated from the new reagent possesses nucleophilic character.

Compositional Data Analysis using Kernels in mass cytometry data.

MOTIVATION: Cell-type abundance data arising from mass cytometry experiments are compositional in nature. Classical association tests do not apply to the compositional data due to their non-Euclidean nature. Existing methods for analysis of cell type abundance data suffer from several limitations for high-dimensional mass cytometry data, especially when the sample size is small. RESULTS: We proposed a new multivariate statistical learning methodology, Compositional Data Analysis using Kernels (CODAK), based on the kernel distance covariance (KDC) framework to test the association of the cell type compositions with important predictors (categorical or continuous) such as disease status. CODAK scales well for high-dimensional data and provides satisfactory performance for small sample sizes (n < 25). We conducted simulation studies to compare the performance of the method with existing methods of analyzing cell type abundance data from mass cytometry studies. The method is also applied to a high-dimensional dataset containing different subgroups of populations including Systemic Lupus Erythematosus (SLE) patients and healthy control subjects. AVAILABILITY AND IMPLEMENTATION: CODAK is implemented using R. The codes and the data used in this manuscript are available on the web at http://github.com/GhoshLab/CODAK/. CONTACT: prudra@okstate.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Advances online.