Challenges In Clinical Research Research Articles

Injectable hydrogels for Fenton-like Mn2+/Fe2+ delivery with enhanced chemodynamic therapy prevent osteosarcoma recurrence and promote wound healing after excision surgery

Local recurrence of osteosarcoma and wound healing after excision surgery are major challenges in clinical research. The present anti-tumor treatments could inhibit normal tissues, resulting in difficulties in surgical wound healing. In this study, we constructed an injectable hydrogel as a platform to co-deliver MnO2 nanoparticles and ferrocene Fc, termed as (MnO2/Fc)@PLGA for osteosarcoma treatment and wound healing after excision. By simple local injection, the hydrogel could form a protective barrier on the surgical wound after osteosarcoma excision, which could promote wound healing and steady release of MnO2/Fc nanoparticles. The released MnO2/Fc might undergo the Fenton reaction through Mn2+/Fe2+ to inhibit osteosarcoma cells with chemodynamic therapy (CDT). Furthermore, MnO2 could catalyze endogenous H2O2 to produce O2, which eliminates the adverse effects of H2O2 and remodels the hypoxic state in the local lesions. The increased O2 facilitated surgical wound healing and anti-tumor effects by regulating the hypoxia inducible factor-1 functions. In conclusion, (MnO2/Fc)@PLGA hydrogel could effectively prevent local recurrence of osteosarcoma and promote wound healing after excision surgery, thereby providing a novel strategy for tumor treatment and tissue repair.

Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors.

The most remarkable finding in synthetic lethality (SL) is the hypersensitivity to PARP inhibitors (PARPis) of the tumors harboring defects in genes involved in homologous repair (HR) such as BRCA1/2. Despite initial responsiveness to PARPi, the penetrance of the synthetic lethal interactions between BRCA1/2 genes and PARPi is incomplete. Thus, a significant proportion of HR-defective tumors experience intrinsic or acquired resistance, representing a key challenge of clinical research. An expanded concept of SL is opening new ways and includes novel forms of genetic interactions, investigating not only traditional SL of pairs genes but also SL between biological pathways that regulate the same essential survival cell function. In this context, recent research showed that HR and theta-mediated end-joining (TMEJ) pathways exhibit SL. DNA polymerase theta (Polθ) is encoded by the POLQ gene and is a key component of the TMEJ, an essential backup pathway, intrinsically mutagenic, to repair resected double-strand breaks (DSBs) when the non-homologous end joining (NHEJ) and HR are impaired. Polθ is broadly expressed in normal tissues, overexpressed in several cancers, and typically associated with poor outcomes and shorter relapse-free survival. Notably, HR-deficient tumor cells present the characteristic mutational signatures of the error-prone TMEJ pathway. According to this observation, the loss of HR proteins, such as BRCA1 or BRCA2, contributes to increasing the TMEJ-specific genomic profile, suggesting synthetic lethal interactions between loss of the POLQ and HR genes, and resulting in the emerging interest for Polθ as a potential therapeutic target in BRCA1/2-associated tumors.This review summarizes the converging roles of the POLQ and HR genes in DNA DSB repair, the early-stage clinical trials using Polθ inhibitor to treat HR-defective tumors and to overcome BRCA-reversion mutations responsible for therapeutic resistance, and the novel pleiotropic effects of Polθ, paving the way for the development of unexplored synthetic lethality strategies.

Difficulties and challenges of clinical research in out-of-hospital emergency settings

Difficulties and challenges of clinical research in out-of-hospital emergency settings

Postextrasystolic repolarization changes of ventricular premature beats correlate with structural heart disease and suggest prognostic implications

Ventricular premature beats (VPBs) can potentially lead to life-threatening arrhythmias, especially in patients with structural heart disease (SHD). However, identifying dangerous VPBs has always been a topic and challenge in clinical research. This study aimed to evaluate the relationship of postextrasystolic repolarization changes of VPBs with SHD and its possible additional prognostic value. 125 cases of frequent VPBs with SHD and 156 cases without SHD were included. VPBs were stratified selected from 24 h Holter recording according to the scale of heart rate. Average QTDV (difference value of QT interval between the first beat follow VPB with beats preceding VPB) and max QTDV were significantly longer in SHD group than that in the non-SHD group. For identifying patients with SHD, the best cutoff value were 19 ms for average QTDV (AUC = 0.931) and 29 ms for max QTDV (AUC = 0.910) respectively. For Tu morphology analysis, PT2 (postextrasystolic T wave amplitude change ≥2 mV), reversed T wave, and Pu (postextrasystolic u wave) change were all highly specific, but low sensitive as identification of SHD. Compared with average QTDV < 19 ms patients, average QTDV ≥ 19 ms patients had significantly larger left heart size and wores left cardiac function. The presence of non-persistent ventricular tachycardia runs was higher in average QTDV ≥ 19 ms group and positive Pu change group than that in control groups. The findings indicated that postextrasystolic repolarization changes of VPBs correlated with SHD and suggested potential value in prognosis asssessment.

Post-Dobbs Challenges in Research and Patient Protections

This Viewpoint describes the challenges for clinical research and participant protections following the US Supreme Court ruling in Dobbs v Jackson Women’s Health Organization.

Current status and challenges of clinical research and development of new drugs for liver diseases

Liver disease is a serious public health problem worldwide, affecting human health. However, there are still many unmet needs for the treatment of liver disease, especially with new therapeutic drugs. At present, there is no treatment method to eradicate the hepatitis B virus, nor are there therapeutic drugs for liver fibrosis, liver failure, and others. Chemotherapy and targeted immunotherapy are still unsatisfactory for liver cancer. This article provides an overview of the current status and challenges that arise in new drug research and development for liver diseases.

Amygdala-Targeted Relief of Neuropathic Pain: Efficacy of Repetitive Transcranial Magnetic Stimulation in NLRP3 Pathway Suppression

This study investigates the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a nonpharmacological approach to treating neuropathic pain (NP), a major challenge in clinical research. Conducted on male Sprague-Dawley rats with NP induced through chronic constriction injury of the sciatic nerve, the research assessed pain behaviors and the impact of rTMS on molecular interactions within the amygdala. Through a comprehensive analysis involving Mechanical Withdrawal Threshold (MWT), Thermal Withdrawal Latency (TWL), RNA transcriptome sequencing, RT-qPCR, Western blotting, immunofluorescence staining, and Co-Immunoprecipitation (Co-IP), the study focused on the expression and interaction of integrin αvβ3 and its receptor P2X7R. Findings reveal that rTMS significantly influences the expression of integrin αvβ3 in NP models, suggesting an inhibition of the NP-associated NLRP3 inflammatory pathway through the disruption of integrin αvβ3-P2X7R interactions. These outcomes highlight the potential of rTMS in alleviating NP by targeting molecular interactions within the amygdala, offering a promising therapeutic avenue for managing NP.

Correlation of Glycolysis-immune-related Genes in the Follicular Microenvironment of Endometriosis Patients with ART Outcomes.

Endometriosis (EMT) -related infertility has been a challenge for clinical research. Many studies have confirmed that abnormal alterations in the immune microenvironment and glycolysis are instrumental in causing EMT-related infertility. Recently, our research team identified several key glycolysis-immune-related genes in the endometrial cells of EMT patients. This study aimed to further investigate the expression patterns of pyruvate dehydrogenase kinase 3 (PDK3), glypican-3 (GPC3), and alcohol dehydrogenase 6 (ADH6), which are related to glycolysis and immunity, in the follicular microenvironment of infertile patients with EMT using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR) assays. According to the results, compared to the patients with tubal factor infertility, the concentrations of PDK3 and GPC3 were considerably increased in the follicular environment of EMT patients, while ADH6 expression was significantly reduced. The number of oocytes retrieved, the transferable embryo rate, and the cumulative clinical pregnancy rate of EMT patients were significantly reduced, and there was a correlation with the level of PDK3, GPC3, and ADH6 in Follicular Fluid (FF). The area under the receiver operating characteristic (ROC) curve for predicting clinical pregnancy in infertile patients with EMT for PDK3, GPC3, ADH6, and their combination was 0.732, 0.705, 0.855, and 0.879, respectively (P < 0.05). In conclusion, our research indicates that glycolysis-immune-related genes may contribute to infertility in EMT patients through immune infiltration, and disruption of mitochondrial and oocyte functions. The combined detection of PDK3, GPC3, and ADH6 in FF helps to predict clinical pregnancy outcomes in infertile patients with EMT.

Childhood Trauma Questionnaire (CTQ): Greek translation and psychometric validation in general and clinical population.

Exposure to childhood trauma experiences shows a high prevalence worldwide, with approximately two-thirds of the general population reporting traumatic experiences during childhood. The valid psychometric assessment of childhood trauma experience represents, however, a significant challenge in clinical research and practice. The Childhood Trauma Questionnaire - Short Form (CTQ-SF) embodies the most valid and internationally widely used tool for the retrospective assessment of traumatic experiences during childhood to date. The purpose of this study was the Greek translation of the questionnaire and its validation in both a general and clinical population. Participants completed electronically the Greek translation of the CTQ-SF, the Early Trauma Questionnaire (ETI-SR-SF), the Trauma Symptom Checklist (TSC-40), the Positive and Negative Affect Scale (PANAS- SF), the Well-Being Index (WHO-5) and the Patient Health Questionnaire (PHQ-4) to examine psychometric properties of the questionnaire (e.g., internal consistency, concurrent, convergent and divergent validity), but also to investigate the relationship between childhood trauma exposure and psychological well-being and symptoms of anxiety and depression. The total study sample (TS) consisted of 722 adults (606 women), of which 155 declared the existence of a psychiatric diagnosis (PD) and 567 constituted the general population (GP) sample. The most common trauma types reported were emotional abuse (29.1%), emotional neglect (23.7%), and physical abuse (24.6%). The CTQ-SF questionnaire showed high levels of internal consistency based on the Cronbach α coefficient (TS = 0.92, PD = 0.92, GP = 0.92), high concurrent and convergent validity and satisfactory convergent validity. In addition, self-reported childhood trauma was highly positively correlated to negative affect and anxiety and depression symptoms, as well as negatively to psychological well-being. Our results confirm that the Greek Version of Childhood Trauma Questionnaire (CTQ-SF) is a reliable and valid tool that can be used for the retrospective assessment of traumatic childhood experiences both in the general and in the clinical adult Greek population.

Photon and Proton irradiation in Patient-derived, Three-Dimensional Soft Tissue Sarcoma Models

BackgroundDespite their heterogeneity, the current standard preoperative radiotherapy regimen for localized high-grade soft tissue sarcoma (STS) follows a one fits all approach for all STS subtypes. Sarcoma patient-derived three-dimensional cell culture models represent an innovative tool to overcome challenges in clinical research enabling reproducible subtype-specific research on STS. In this pilot study, we present our methodology and preliminary results using STS patient-derived 3D cell cultures that were exposed to different doses of photon and proton radiation. Our aim was: (i) to establish a reproducible method for irradiation of STS patient-derived 3D cell cultures and (ii) to explore the differences in tumor cell viability of two different STS subtypes exposed to increasing doses of photon and proton radiation at different time points.MethodsTwo patient-derived cell cultures of untreated localized high-grade STS (an undifferentiated pleomorphic sarcoma (UPS) and a pleomorphic liposarcoma (PLS)) were exposed to a single fraction of photon or proton irradiation using doses of 0 Gy (sham irradiation), 2 Gy, 4 Gy, 8 Gy and 16 Gy. Cell viability was measured and compared to sham irradiation at two different time points (four and eight days after irradiation).ResultsThe proportion of viable tumor cells four days after photon irradiation for UPS vs. PLS were significantly different with 85% vs. 65% (4 Gy), 80% vs. 50% (8 Gy) and 70% vs. 35% (16 Gy). Proton irradiation led to similar diverging viability curves between UPS vs. PLS four days after irradiation with 90% vs. 75% (4 Gy), 85% vs. 45% (8 Gy) and 80% vs. 35% (16 Gy). Photon and proton radiation displayed only minor differences in cell-killing properties within each cell culture (UPS and PLS). The cell-killing effect of radiation sustained at eight days after irradiation in both cell cultures.ConclusionsPronounced differences in radiosensitivity are evident among UPS and PLS 3D patient-derived sarcoma cell cultures which may reflect the clinical heterogeneity. Photon and proton radiation showed similar dose-dependent cell-killing effectiveness in both 3D cell cultures. Patient-derived 3D STS cell cultures may represent a valuable tool to enable translational studies towards individualized subtype-specific radiotherapy in patients with STS.

The Challenge of Clinical Research and Suicidality: Participant Feedback on a Safety Protocol.

Objective: Clinical studies of depression have historically excluded participants with suicidal ideation. Research participant safety protocols are critical to allow for the much-needed study of suicide risk. This report summarizes participant feedback about the safety protocol used in a national, remote study of perinatal women with suicidal ideation.Methods: Upon completion of the study, participants who had triggered the suicidality safety protocol during the study were invited to complete a brief survey with questions about their experiences with the protocol. The survey included 4 Likert-scale questions and 1 open text question where participants could provide feedback, suggestions, and comments to the research team. Participant feedback survey data were collected between October 2021 and April 2022, and this research was funded by the National Institute of Mental Health.Results: Of the 45 participants enrolled in the UPWARD-S study, 16 triggered the safety protocol. All eligible participants (N = 16) completed the survey. Among respondents, most were at least neutral to very comfortable with the call from the study psychiatrist (75% [n = 12]) and reported that the call had a "positive impact" on their well-being (69% [n = 11]). After the call with the study psychiatrist, 50% of participants (n = 8) reported that they increased engagement with treatment for depression, and the other 50% reported no change in treatment. We also report on themes from the qualitative feedback regarding suggestions of how to modify or improve the safety protocol.Conclusions: Learning from the experiences of research participants will provide unique insight into satisfaction with, and impact of, the implemented suicidality safety protocol. Findings from this study could inform the refinement and implementation of safety protocols used in depression studies as well as future research on the impact of such protocols.

Cognitive Health in Underrepresented Populations—Early Learnings From INTUITION: A Brain Health Study (P14-6.009)

<h3>Objective:</h3> The aims of INTUITION (NCT 05058950)—an observational, 2-year, virtual study—are to develop real-world, high-accuracy classifiers that distinguish mild cognitive impairment from healthy aging and to construct a trackable cognitive health score. Brain health in underrepresented populations is less studied. Consequently, various recruitment and engagement strategies have been used in INTUITION to enroll a representative population. <h3>Background:</h3> Recruitment and retention of demographically diverse populations is an evolving challenge in clinical research. It remains to be seen how digital decentralized studies might transform the engagement landscape for research that aims to enroll cohorts reflective of large, heterogeneous populations, such as those in the United States. Given that socioeconomic factors are associated with vulnerability to cognitive decline and are potential determinants of health, research characterizing risks to brain health should use strategies to enroll representative populations. <h3>Design/Methods:</h3> The study recruitment strategy includes multiple channels, such as email/direct mail campaigns, paid search, and social media, word-of-mouth, and event-based outreach in collaboration with patient advocacy groups. This study collects digital, multimodal, longitudinal data via iPhone and Apple Watch, coupled with the results of validated cognitive tests and behavioral surveys. We will compare recruitment strategies and evaluate adherence to digital tool use, with a focus on data from underrepresented populations by age group and cognitive status. <h3>Results:</h3> INTUITION has enrolled &gt;95% of its total target population since the study launch. The study population comprises individuals from generally underrepresented populations with varying degrees of risk for cognitive decline. The most successful recruitment strategies were word-of-mouth and email/direct mail campaigns. Up-to-date study population characteristics and an assessment of the recruitment strategies will be presented. <h3>Conclusions:</h3> INTUITION demonstrates that virtual studies offer the potential to enroll populations that accurately reflect the diversity of the larger society. <b>Disclosure:</b> Mr. Hobbs has received personal compensation for serving as an employee of Biogen. Mr. Hobbs has stock in Biogen. Dr. Au has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Au has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Au has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Au has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NovoNordisk. Dr. Au has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GSK. Dr. Au has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Dr. Au has received publishing royalties from a publication relating to health care. Dr. Au has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant with Davos Alzheimer’s Collaborative. Dr. Au has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant with High Lantern. Dr. Becker has received personal compensation for serving as an employee of Biogen. Dr. Butler has received personal compensation for serving as an employee of Biogen. Dr. Butler has stock in Biogen. Dr. Lenyoun has received personal compensation for serving as an employee of Apple. Dr. Lenyoun has stock in Apple. Mr. Kenny has received personal compensation for serving as an employee of Biogen. Mr. Kenny has stock in Biogen. Dr. Brown has received personal compensation for serving as an employee of Biogen. Dr. Brown has stock in Biogen. Dr. Saha-Chaudhuri has received personal compensation for serving as an employee of Biogen. Dr. Saha-Chaudhuri has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Saha-Chaudhuri has stock in Biogen. Matt Bianchi has nothing to disclose. Dr. Williams has received personal compensation for serving as an employee of Biogen. Dr. Williams has received stock or an ownership interest from Biogen. Audrey Gabelle has nothing to disclose. Dr. Belachew has received personal compensation for serving as an employee of Biogen Inc. Dr. Belachew has received stock or an ownership interest from Biogen Inc.

Photo-Elicitation Technique: Utility and Challenges in Clinical Research

Photo-elicitation interview techniques, a method in which researchers incorporate images to enrich the interview experience, have been gaining traction in numerous spheres of research over the last two decades. Little is, however, written about the utility of the technique in studies involving vulnerable populations in clinical contexts. Drawing on research where researcher-generated photographs were used to elicit mothers’ experiences of pain and perceptions about use of pain-relieving strategies in critically ill infants, we aim to demonstrate (a) how the method can be used to generate harmonized and detailed accounts of experiences from diverse groups of participants of limited literacy levels, (b) the ethical and methodological consideration when employing photo-elicitation interview techniques and the (c) possible limitations of employing photo-elicitation interview techniques in clinical research.

MOSAIC: a European cohort study of human Mpox - the challenges of clinical research in outbreaks.

MOSAIC: a European cohort study of human Mpox - the challenges of clinical research in outbreaks.

MOSAIC: a European cohort study of human Mpox - the challenges of clinical research in outbreaks

MOSAIC: a European cohort study of human Mpox - the challenges of clinical research in outbreaks

Mechanisms by which culturally‐informed narratives may promote ADRD research enrollment among African American adults

AbstractBackgroundInsufficient racial and ethnic diversity is a pervasive challenge in clinical research on Alzheimer’s disease (AD). The Recruitment Innovations for Diversity Enhancement (RIDE) in AD research study is grounded in the premise that culturally informed narratives of research participation can inspire other individuals from a given culture‐sharing group (in this case, African Americans) to consider enrolling in research. RIDE involved developing and disseminating narrative materials to share the research participation experiences of African American adults who are enrolled in AD research with those who are not. The current analysis aims to examine factors associated with interest in AD research following exposure to RIDE narrative campaign materials.MethodA community‐based sample of 500 individuals, primarily in mid to late life, identifying as Black or African American adults were invited to view a RIDE study video (∼2 minute story of AD research participation) online and complete a survey of perceptions about research and researchers, AD risk, and likelihood of enrolling in AD research. Logistic regression models were used to identify predictors of self‐reported likelihood of participating in AD research and potential mediators were tested to examine the causal pathway between predictors and likelihood of enrollment.ResultMost (n = 376; 72%) participants reported interest in being contacted to learn more about local AD research opportunities. After controlling for demographic variables and perceived AD risk, prior experience with clinical research and trust in medical researchers emerged as independent predictors of likelihood of enrolling in AD research. Mediation analysis revealed that perceived burdens of AD research mediated 40.5% of the effect of prior research experience and 25.3% of the effect of trust on likelihood of enrollment (P&lt;0.05). Perceived benefits of AD research also played a mediating role, accounting for 35.3% of the effect of trust on likelihood of enrollment (P = 0.006).ConclusionThis study is a first step to understand the mechanisms by which narrative may function to enhance diversity in AD research. Findings suggest that participant narratives should address experiences that speak to the burdens and potential benefits of AD research participation as these factors may influence decisions leading to subsequent research enrollment.

Evaluation of machine learning methods for covariate data imputation in pharmacometrics.

Missing data create challenges in clinical research because they lead to loss of statistical power and potentially to biased results. Missing covariate data must be handled with suitable approaches to prepare datasets for pharmacometric analyses, such as population pharmacokinetic and pharmacodynamic analyses. To this end, various statistical methods have been widely adopted. Here, we introduce two machine-learning (ML) methods capable of imputing missing covariate data in a pharmacometric setting. Based on a previously published pharmacometric analysis, we simulated multiple missing data scenarios. We compared the performance of four established statistical methods, listwise deletion, mean imputation, standard multiple imputation (hereafter "Norm"), and predictive mean matching (PMM) and two ML based methods, random forest (RF) and artificial neural networks (ANNs), to handle missing covariate data in a statistically plausible manner. The investigated ML-based methods can be used to impute missing covariate data in a pharmacometric setting. Both traditional imputation approaches and ML-based methods perform well in the scenarios studied, with some restrictions for individual methods. The three methods exhibiting the best performance in terms of least bias for the investigated scenarios are the statistical method PMM and the two ML-based methods RF and ANN. ML-based approaches had comparable good results to the best performing established method PMM. Furthermore, ML methods provide added flexibility when encountering more complex nonlinear relationships, especially when associated parameters are suitably tuned to enhance predictive performance.

Efficient Isolation of Circulating Tumor Cells Using Ultra-Convenient Substrates Based on Self-Assembled Hollow MnO2 Nanoparticles

An efficient and active sorting platform of circulating tumor cells (CTCs) is still a challenge in clinical research. In this paper, we design a novel system based on hollow MnO2 nanoparticles for the capture and release of CTCs. Using the self-assembly method, we prepared rough MnO2 nanomaterial substrates that provide more binding sites for antibody grafting, increase the contact probability between cells and materials and improve the capture efficiency. The highest capture efficiency was 83.2% under the incubation time of 120 min. The MnO2 nanosubstrate was dissolved by employing a 2 × 10−3 M concentration of oxalic acid to release the captured cells. The cell release efficiency was up to 91.46% with a reaction time of 60 s. The released cells had a strong ability to proliferate after being collected and re-cultured for 24 h. Identifying and counting CTCs from the peripheral blood of breast cancer patients through the three-color immunocytochemistry method proved the effectiveness of our design platform. Such a simple and economical approach provides a promising platform for the capture and release of cells in clinical research.

Consensus guidelines on the construct validity of rodent models of restless legs syndrome.

ABSTRACTOur understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most appropriate for a rodent model of RLS. We also identified parameters by which to assess and quantify these bioequivalents. Investigating these factors, both individually and in combination, will help to identify their specific roles in the expression of rodent RLS-like phenotypes, which should provide significant translational implications for the diagnosis and treatment of RLS.

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations

Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. Areview of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.