Preservation or removal of the lateral nasal wall in endoscopic management of maxillary sinus neoplasia: A comparison of approach related morbidity.

BACKGROUND: The endoscopic modified medial maxillectomy (MMM) and prelacrimal approach (PLA) are two routinely performed endoscopic approaches to the maxillary sinus when access via a middle meatal antrostomy is insufficient. However, there is no data in the literature that has compared outcomes and complication profile between the two procedures to determine which approach is superior. OBJECTIVE: To compare the approach related morbidity of PLA and MMM. METHODS: A retrospective cohort study of all consecutive adult patients undergoing either MMM or PLA from 2009 to 2023 were identified. The primary outcome was development of epistaxis, paraesthesia, lacrimal injury, iatrogenic sinus dysfunction within a minimum of 3 months post-operative follow up. RESULTS: 39 patients (44 sides) underwent PLA and 96 (96 sides) underwent MMM. There were no statistically significant differences between the rates of paraesthesia (9.1 % vs 14.6 %, p = 0.367) or prolonged paraesthesia (2.3 % vs 5.2 %, p = 0.426), iatrogenic maxillary sinus dysfunction (2.3 % vs 5.2 %, p = 0.426) or adhesions requiring removal (4.5 % vs 4.2 %, p = 0.918). No cases of epiphora or nasal cavity stenosis occurred in either arm in our study. CONCLUSIONS: According to our data, the endoscopic modified medial maxillectomy and prelacrimal approach are both equally safe approaches with their own benefits to access.

Myomodulation Using Botulinum Toxin in Septorhinoplasty for Crooked Noses: Introducing the Concept and Application of Nasal Muscle Imbalance Theory.

The role of septorhinoplasty for adequate correction of deviated nose is well documented, but the rationales and patterns for recurrences after proper rhinoplasty remain unclear. There has also been little attention given to the influence of nasal musculatures on the stability of nasal structures after septorhinoplasty. The aim of this article is to propose our nasal muscle imbalance theory, which may explain the potential reason for redeviation of the noses in the initial period after septorhinoplasty. We postulate that in a chronically deviated nose, the nasal muscles on the convex side will be stretched and develop hypertrophy after prolonged period of increased contractile activity. On the contrary, the nasal muscles on the concave side will undergo atrophy due to reduced load requirement. In the initial period of recovery after a septorhinoplasty to bring the nose back to midline, this muscle imbalance is still uncorrected with unequal pulling forces on the nasal structure because the stronger nasal muscles on the previously convex side is still hypertrophied and exert stronger forces compared with the previously concave side, therefore increasing the risk of redeviation of the nose back to the preoperative side until muscle atrophy occurs in the convex side and a balanced nasal muscle pull is achieved. We believe that postseptorhinoplasty botulinum toxin injections can be used as an adjunct in rhinoplasty surgery to effectively block the pulling actions of the stronger or overacting nasal muscles by speeding up the atrophy process while allowing patient's nose to heal and stabilize in the desired position. However, further studies to objectively confirm this hypothesis is required, which include comparing topographic measurements, imaging and electromyography signals before and after injections in postseptorhinoplasty patients. The authors have already planned a multicenter study to further evaluate this theory.

The Psychometric Structure of Executive Functions: A Satisfactory Measurement Model? An Examination Using Meta-Analysis and Network Modeling.

A long-standing debate among cognitive scientists has focused on describing the underlying nature of executive functions, which has important implications for both theoretical and applied research. Miyake et al.'s three-factor model has often been considered the gold-standard representation of executive functions and has driven much research in the field. More recently, however, there have been increasing concerns that the three-factor model does not adequately describe a highly complex construct such as executive functions. The current project presents two studies that examine the veracity of Miyake et al.'s model and propose a new approach (i.e., network modeling) for detecting the underlying nature of executive functions. The current results raise questions about the psychometric strength and adequacy of the three-factor model. Further, the studies presented here provide evidence that network modeling provides a better understanding of executive functions as it better captures (relative to latent variable modeling) the complexity of cognitive processes. Theoretical and applied implications are discussed.

Improving Cognitive Abilities in School-Age Children via Computerized Cognitive Training: Examining the Effect of Extended Training Duration.

Critical neuropsychological capabilities such as working memory, cognitive flexibility, and processing speed are foundational to many daily activities. For children, such skills are essential for school success. Thus, children who demonstrate weaknesses in these abilities may experience impaired academic performance; this is especially true for students identified with learning differences who often exhibit less developed cognitive abilities. The purpose of this project was to examine the efficacy of a cognitive training program implemented during the school day to improve abilities predictive of academic achievement. Ninety-five children completed two training activities that were counterbalanced across participants. Analyses of baseline working memory, cognitive flexibility, and processing speed performance relative to those following training showed a strong treatment effect. Moreover, there is notable evidence of greater intervention efficacy with extended engagement with the training program. Implications for neuropsychological research and practice are discussed.

Separated and reunified: An apparent time investigation of the voice quality differences between Hong Kong Cantonese and Guangzhou Cantonese.

Hong Kong Cantonese (HKC) and Guangzhou Cantonese (GZC) are two major accents of Cantonese spoken in two geographically non-contiguous cities in Southern China. Previous studies were unable to identify the phonetic features that discern the two accents since they share the same phonological system. This study attempted to solve the puzzle by investigating the voice quality differences between the two accents through acoustic analysis on the speech output of 191 talkers in three age groups ranging from 18 to 65 years old. Among the various spectral and noise measurements of voice quality, we found that Cepstral Peak Prominence (CPP) was the best acoustic measure to discern the two accents. Based on the CPP measure, GZC had overall increased noise than HKC. Covariation of voice quality and tones was studied. The greatest CPP differences between the two accents were found in the two extreme tones: the high-level and the extra-low-level tones. Furthermore, creaky voice was found mainly tied to the extra-low-level tone in both accents. However, HKC exhibited higher frequency of creaky voice than GZC. The creaky voice in GZC was characterized by increased noise and increased tension, compared to those of HKC. Finally, age was found to be a mediating factor in the voice quality of the two accents. Adopting the Apparent Time Framework, voice quality in the two cities has undergone changes over time. The voice quality of the young generations of the two accents have become merged among the three low tones. Furthermore, the prevalence of creaky voice was increasing across age groups in both accents, and it increased at a faster rate in HKC than GZC.

Reproductive decision-making and the utilization of preimplantation genetic testing among individuals with inherited aortic or vascular disease.

Preimplantation genetic testing for monogenic disorders (PGT-M) is a reproductive technology used in conjunction with in-vitro fertilization (IVF) to reduce the risk of passing on a known genetic condition from parent to child. There is limited research describing the experience and emotional impact of PGT-M among individuals with inherited aortic or vascular disease (IAVD). Our qualitative study aims to explore the factors that influence reproductive decision-making and the uptake of PGT-M within this population. Individuals diagnosed with IAVD who have considered PGT-M, and/or their reproductive partner, were recruited using internal clinical databases and advocacy organizations. Virtual semi-structured interviews were conducted using an interview guide that included questions related to participants' lived experience of their condition, risk perception, reproductive history, familiarity with PGT-M/IVF, and financial/psychosocial considerations. A total of 17 interviews were completed (13 affected individuals, 4 unaffected partners) and analyzed using thematic analysis. Emergent themes included: (1) the lived experience and perceived severity of disease; (2) need for comprehensive, balanced, and timely information; (3) and impact of personal values and circumstances. When discussing the impact of lived experience on reproductive decision-making, participants identified the physical and emotional impact of disease and variability of disease as factors influencing the uptake of PGT-M. Many described PGT-M as the only reproductive option presented to them by providers. Even so, participants expressed gaps in their understanding of PGT-M, particularly regarding cost/insurance coverage and the experience of IVF. Finally, participants recognized that the decision to pursue PGT-M primarily requires introspection and evaluation of one's values, but that cost remains a significant consideration. The findings from our study highlight the complexity of reproductive decision-making for individuals with IAVD and provide insight into their psychological and informational needs when engaging in this process. Providers can use these findings to tailor their discussions about reproductive decision-making with this patient cohort.

Combined genioplasty, chondrolaryngoplasty, and glottoplasty: A novel scarless procedure in facial feminization surgery.

Facial feminization is a long process with multiple surgical steps that is known to improve quality of life in transgender patients. Visible scars are a frequent complaint by this community as it adds to the stigmatization in this population. Combined procedures have been shown to be effective, by reducing the number of hospitalizations and the total length of recovery periods. In this context, we propose a novel scarless procedure combining a chondrolaryngoplasty, a glottoplasty, and a genioplasty using solely a transoral approach. First, we perform a glottoplasty according to the technique described by Wendler et al. and then a contraction genioplasty. Finally, the thyroid cartilage is approached by a subplatysmal dissection, between the mandibular osteotomy fragments. For now, 15 patients have benefited from this procedure in our department. Preliminary results demonstrate that this is an easy and safe procedure with good esthetic results and good patient satisfaction.

An artificial intelligence algorithm for the classification of sphenoid sinus pneumatisation on sinus computed tomography scans.

BACKGROUND: Classifying sphenoid pneumatisation is an important but often overlooked task in reporting sinus CT scans. Artificial intelligence (AI) and one of its key methods, convolutional neural networks (CNNs), can create algorithms that can learn from data without being programmed with explicit rules and have shown utility in radiological image classification. OBJECTIVE: To determine if a trained CNN can accurately classify sphenoid sinus pneumatisation on CT sinus imaging. METHODS: Sagittal slices through the natural ostium of the sphenoid sinus were extracted from retrospectively collected bone-window CT scans of the paranasal sinuses for consecutive patients over 6 years. Two blinded Otolaryngology residents reviewed each image and classified the sphenoid sinus pneumatisation as either conchal, presellar or sellar. An AI algorithm was developed using the Microsoft Azure Custom Vision deep learning platform to classify the pattern of pneumatisation. RESULTS: Seven hundred eighty images from 400 patients were used to train the algorithm, which was then tested on a further 118 images from 62 patients. The algorithm achieved an accuracy of 93.2% (95% confidence interval [CI] 87.1-97.0), 87.3% (95% CI 79.9-92.7) and 85.6% (95% CI 78.0-91.4) in correctly identifying conchal, presellar and sellar sphenoid pneumatisation, respectively. The overall weighted accuracy of the CNN was 85.9%. CONCLUSION: The CNN described demonstrated a moderately accurate classification of sphenoid pneumatisation subtypes on CT scans. The use of CNN-based assistive tools may enable surgeons to achieve safer operative planning through routine automated reporting allowing greater resources to be directed towards the identification of pathology.

Associations between birth defects with neural crest cell origins and pediatric embryonal tumors.

BACKGROUND: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins. METHODS: With the use of a multistate, registry-linkage cohort study, BDNCO-embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal tumors included neuroblastoma, nephroblastoma, and hepatoblastoma. Potential HR modification (HRM) was investigated by infant sex, maternal race/ethnicity, maternal age, and maternal education. RESULTS: The risk of embryonal tumors among those with BDNCOs was 0.09% (co-occurring n = 105) compared to 0.03% (95% CI, 0.03%-0.04%) among those without a birth defect. Children with BDNCOs were 4.2 times (95% CI, 3.5-5.1 times) as likely to be diagnosed with an embryonal tumor compared to children born without a birth defect. BDNCOs were strongly associated with hepatoblastoma (HR, 16.1; 95% CI, 11.3-22.9), and the HRs for neuroblastoma (3.1; 95% CI, 2.3-4.2) and nephroblastoma (2.9; 95% CI, 1.9-4.4) were elevated. There was no notable HRM by the aforementioned factors. CONCLUSIONS: Children with BDNCOs are more likely to develop embryonal tumors compared to children without a birth defect. Disruptions of shared developmental pathways may contribute to both phenotypes, which could inform future genomic assessments and cancer surveillance strategies of these conditions.

Perceived usefulness of, engagement with, and effectiveness of virtual reality environments in learning industrial operations: the moderating role of openness to experience.

The development of virtual reality (VR) in enhancing the effectiveness of the learning process, with its interactive, immersive, and intuitive pedagogical environment, has become a necessity for corporations with increasingly complex operations. However, VR users' perceptions, openness and learning effectiveness are seldom comprehensively evaluated, particularly in learning complex industrial operations. In this study, grounded in the technology acceptance model, a moderated mediation model of perceived usefulness, ease of use, openness to experience, and engagement in VR-based learning was developed. The model was empirically validated using responses collected from 321 users who were trained on aircraft and cargo terminal operations powered by a novel VR-based learning platform. A survey to measure openness to experience and a pre-training performance test were carried out, followed by a post-training survey of learners' intrinsic factors, including the influence of perceived usefulness, openness to experience, and attitude towards learning. The study revealed that learners with an open attitude towards experiencing new technology tend to perceive VR technology as a useful platform for training. In addition, the learners with more positive views of VR technology-supported training were more engaged in learning.

Modelling the effects of post-FESS middle turbinate synechiae on sinonasal physiology: A computational fluid dynamics study.

OBJECTIVE(S): Chronic rhinosinusitis (CRS) is common and often requires surgical intervention. Surgical failure may lead to persistent symptoms and recalcitrant disease, often secondary to synechiae between the middle turbinate (MT) and lateral nasal wall. Synechiae prevention techniques have been extensively investigated, however evidence for the effect of synechiae on sinonasal physiology is lacking. We aimed to model the effects of MT synechiae on a post-functional endoscopic sinus surgery (FESS) sinonasal cavity using computational fluid dynamics (CFD). METHODS: DICOM data from a CT-sinus of a healthy 25-year-old female was segmented to create a three-dimensional model. Virtual surgery was performed to simulate a "full-house" FESS procedure. Multiple models were created, each with a single unilateral virtual MT synechia of varying extent. CFD analysis was performed on each model and compared with a post-FESS control model without synechiae. Airflow velocity, humidity and mucosal surface and air temperature values were calculated. RESULTS: All synechiae models demonstrated aberrant downstream sinonasal airflow. There was reduced ventilation of the ipsilateral frontal, ethmoid and sphenoid sinuses, with a concentrated central "jet" in the middle meatus region. Effects were proportionate to the size of synechiae. The impact on bulk inspired airflow was negligible. CONCLUSION: Post-FESS synechiae between the MT and lateral nasal wall significantly disrupt local downstream sinus ventilation and nasal airflow. These findings may explain the persistent symptoms seen in post-FESS CRS patients with MT synechiae, reinforcing the importance of prevention and adhesiolysis. Larger cohort studies with multiple models of actual post-FESS patients with synechiae are required to validate these findings.

Smell-related quality of life changes after total laryngectomy: a multi-centre study.

PURPOSE: A total laryngectomy creates an alternate airway for gas exchange that bypasses the upper aerodigestive tract. The subsequent reduction in nasal airflow, and therefore, reduction in deposition of particles to the olfactory neuroepithelium leads to hyposmia or anosmia. The aim of this study was to assess the quality of life impairment conferred by anosmia following laryngectomy and identify any specific patient-related risk factors that are associated with poorer outcomes. METHODS: Consecutive patients with a total laryngectomy presenting for review at three tertiary head and neck services (in Australia, the United Kingdom and India) over a 12-month period were recruited. Patient demographic and clinical data were collected, and each subject completed the validated assessment of self-reported olfactory functioning and olfaction-related quality of life questionnaire (ASOF). Dichotomous comparisons were performed using the student's unpaired t-test for continuous variables (SRP), a chi-squared test for categorical variables, and a Kendall's tau-b for ordinal variables (SOC) to assess for a correlation with poorer questionnaire scores. RESULTS: A total of 66 laryngectomees (13.4% female; age 65.7 ± 8.6 years) were included in the study. The mean SRP score of the cohort was found to be 15.6 ± 7.4, while the mean ORQ score was noted to be 16.4 ± 8.1. No other specific risk factors associated with poorer quality of life were identified. CONCLUSION: A significant quality of life detriment from hyposmia is conferred following laryngectomy. Further research to assess treatment options and the patient population that would best benefit from these interventions is required.

The Modified Medial Maxillectomy as a Radical or Extended,-yet Still Functional,-Technique in Sinus Surgery.

BACKGROUND: Endoscopic sinus surgery with a middle meatal antrostomy is a common intervention in the treatment algorithm for maxillary sinus pathologies. However, this procedure has its origins in a time when simple ventilation of the sinus cavity was the primary (and only often) goal of surgery. In some patients, persistent mucociliary dysfunction occurs despite ventilatory surgery. Although the endoscopic modified medial maxillectomy (MMM) was originally described for tumour surgery, it provides a radical yet still functional option to overcome chronic sinus dysfunction. OBJECTIVE: The goal of this study was to describe the functional status of a post-MMM sinus cavity. METHODS: A consecutive series of patients who underwent at least a unilateral MMM by three tertiary rhinologists were retrospectively reviewed. Prospectively collected data included patient demographics (including age, gender, smoking status and comorbidities), disease-specific factors, microbiology, and preoperative patient-reported symptoms based on the 22-item Sinonasal Outcome Test-22 (SNOT-22) and radiology. The primary outcome of the study was the presence of sinus dysfunction, defined by mucostasis or pooling on endoscopic examination at the last follow-up. Secondary outcomes included the need for revision surgery as a result of sinus dysfunction and the improvement in SNOT-22 score. RESULTS: A total of 551 medial maxillectomies (47.0% female, 52.9 ± 16.8 years) were performed. Very few patients experienced post-operative sustained mucostasis following MMM (10.2%) and even fewer required revision surgery (5.0%). Chronic obstructive pulmonary disease (odds ratio (OR) = 6.82, P < 0.002.) and asthma (OR = 2.48, P = 0.03) were associated with mucostasis. Patients who underwent an MMM experienced a notable postoperative improvement in SNOT-22 score (45.9 ± 23.7 (pre-op) vs. 23.6 ± 19.4 (post-op); paired t-test, P < 0.0001). CONCLUSION: The MMM, whether performed for access to pathology or with the intent to avoid mucous 'sumping' with the sinus, can provide a long-term functional maxillary sinus cavity with minimal morbidity.

Spatiotemporally dynamic electric fields for brain cancer treatment: anin vitroinvestigation.

Objective. The treatment of glioblastoma (GBM) using low intensity electric fields (∼1 V cm-1) is being investigated using multiple implanted bioelectrodes, which was termed intratumoral modulation therapy (IMT). Previous IMT studies theoretically optimized treatment parameters to maximize coverage with rotating fields, which required experimental investigation. In this study, we employed computer simulations to generate spatiotemporally dynamic electric fields, designed and purpose-built an IMT device forin vitroexperiments, and evaluated the human GBM cellular responses to these fields.Approach. After measuring the electrical conductivity of thein vitroculturing medium, we designed experiments to evaluate the efficacy of various spatiotemporally dynamic fields: (a) different rotating field magnitudes, (b) rotating versus non-rotating fields, (c) 200 kHz versus 10 kHz stimulation, and (d) constructive versus destructive interference. A custom printed circuit board (PCB) was fabricated to enable four-electrode IMT in a 24-well plate. Patient derived GBM cells were treated and analyzed for viability using bioluminescence imaging.Main results. The optimal PCB design had electrodes placed 6.3 mm from the center. Spatiotemporally dynamic IMT fields at magnitudes of 1, 1.5, and 2 V cm-1reduced GBM cell viability to 58%, 37% and 2% of sham controls respectively. Rotating versus non-rotating, and 200 kHz versus 10 kHz fields showed no statistical difference. The rotating configuration yielded a significant reduction (p< 0.01) in cell viability (47 ± 4%) compared to the voltage matched (99 ± 2%) and power matched (66 ± 3%) destructive interference cases.Significance. We found the most important factors in GBM cell susceptibility to IMT are electric field strength and homogeneity. Spatiotemporally dynamic electric fields have been evaluated in this study, where improvements to electric field coverage with lower power consumption and minimal field cancellations has been demonstrated. The impact of this optimized paradigm on cell susceptibility justifies its future use in preclinical and clinical trial investigations.

A Pooled Electronic Consultation Program to Improve Access to Genetics Specialists.

Innovative service delivery models are needed to increase access to genetics specialists. Electronic consultation (e-Consult) programs can connect clinicians with specialists. At Massachusetts General Hospital, an e-Consult service was created to address genomics-related questions. In its first year, the e-Consult service triaged 153 requests and completed 122 in an average of 3.2 days. Of the 95 e-Consults with actionable recommendations, there was documentation that most ordering clinicians followed through (82%). A variety of providers used the service, although the majority (77%) were generalists. E-Consult models should be considered as one way to increase access to genetics care.

The Impact of Adhesions on Nasal Airflow: A Quantitative Analysis Using Computational Fluid Dynamics.

BACKGROUND: Nasal adhesions (NAs) are a known complication of nasal airway surgery. Even minor NAs can lead to significant postoperative nasal airway obstruction (NAO). Division of such NAs often provides much greater relief than anticipated. OBJECTIVE: We examine the impact of NAs at various anatomical sites on nasal airflow and mucosal cooling using computational fluid dynamics (CFD) and multiple test subjects. METHODS: CT scans of healthy adult subjects were used to construct three-dimensional nasal airway computational models. A single virtual 2.5 mm diameter NA was placed at one of five sites commonly seen following NAO surgery within each nasal cavity bilaterally, resulting in 10 NA models and 1 NA-free control for each subject. CFD analysis was performed on each NA model and compared with the subject's NA-free control model. RESULTS: 4 subjects were recruited to create 44 computational models. The NAs caused the airflow streamlines to separate, leading to a statistically significant increase in mucosal temperature immediately downstream to the NAs (wake region). Changes in the mucosal temperature in the wake region of the NAs were most prominent in anteriorly located NAs with a mean increase of 1.62 °C for the anterior inferior turbinate NAs (P < .001) and 0.63 °C for the internal valve NAs (P < .001). CONCLUSION: NAs result in marked disruption to airflow patterns and reduced mucosal cooling on critical surfaces, particularly in the wake region. Reduced wake region mucosal cooling may be a contributing factor to the exaggerated perception of nasal obstruction experienced by patients with NAs.

Convolutional Neural Networks in ENT Radiology: Systematic Review of the Literature.

INTRODUCTION: Convolutional neural networks (CNNs) represent a state-of-the-art methodological technique in AI and deep learning, and were specifically created for image classification and computer vision tasks. CNNs have been applied in radiology in a number of different disciplines, mostly outside otolaryngology, potentially due to a lack of familiarity with this technology within the otolaryngology community. CNNs have the potential to revolutionize clinical practice by reducing the time required to perform manual tasks. This literature search aims to present a comprehensive systematic review of the published literature with regard to CNNs and their utility to date in ENT radiology. METHODS: Data were extracted from a variety of databases including PubMED, Proquest, MEDLINE Open Knowledge Maps, and Gale OneFile Computer Science. Medical subject headings (MeSH) terms and keywords were used to extract related literature from each databases inception to October 2020. Inclusion criteria were studies where CNNs were used as the main intervention and CNNs focusing on radiology relevant to ENT. Titles and abstracts were reviewed followed by the contents. Once the final list of articles was obtained, their reference lists were also searched to identify further articles. RESULTS: Thirty articles were identified for inclusion in this study. Studies utilizing CNNs in most ENT subspecialties were identified. Studies utilized CNNs for a number of tasks including identification of structures, presence of pathology, and segmentation of tumors for radiotherapy planning. All studies reported a high degree of accuracy of CNNs in performing the chosen task. CONCLUSION: This study provides a better understanding of CNN methodology used in ENT radiology demonstrating a myriad of potential uses for this exciting technology including nodule and tumor identification, identification of anatomical variation, and segmentation of tumors. It is anticipated that this field will continue to evolve and these technologies and methodologies will become more entrenched in our everyday practice.

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.