The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.

Protein-losing enteropathy secondary to collagenous colitis in a 2-year-old.

Protein-losing enteropathy associated with collagenous colitis (CC) is a rare but described entity in the adult population. However, literature regarding this in the pediatric population is scarce. Here we describe a 2-year-old female who presented with fevers, accompanied by nonbloody, watery diarrhea, and decreased oral intake. Work-up was significant for severe hypoalbuminemia at 1.5 grams per deciliter (g/dL), pancytopenia, and elevated fecal alpha-1-antitrypsin at 1.13 milligrams per grams (mg/g). Gastrointestinal mucosal evaluation was normal endoscopically; however, histology was consistent with CC. She responded to 12-week treatment with budesonide with resolution of symptoms and laboratory values. At this point, she has not had a recurrence 1 year later.

Unsaturated or saturated dietary fat-mediated steatosis impairs hepatic regeneration following partial hepatectomy in mice.

BACKGROUND: Partial hepatectomy is a preferred treatment option for many patients with hepatocellular carcinoma however, pre-existing pathological abnormalities originating from hepatic steatosis can alter the decision to perform surgery or postoperative outcomes as a consequence of the impact steatosis has on liver regeneration. AIM: The aim of this study was to investigate the role of a saturated or unsaturated high fat diet-mediated steatosis on liver regeneration following partial hepatectomy. METHODS: Mice were fed a low-fat control diet (CD, 13% fat), lard-based unsaturated (LD, 60% fat) or milk-based saturated high fat diet (MD, 60% fat) for 16 weeks at which time partial hepatectomy (approx. 70% resection) was performed. At days-2 and 7 post hepatectomy, one hour prior to euthanization, mice were injected with 5-bromo-2'-deoxyuridine in order to monitor hepatic regeneration. Serum was collected and assessed for levels of ALT and AST. Resected and regenerated liver tissue were examined for inflammation-indicative markers employing RT-PCR, Western blots, and histological methods. RESULTS: Mice fed LD or MD exhibited higher NAFLD scores, increased expression of inflammatory cytokines, neutrophil infiltration, macrophage accumulation, increased apoptosis, and elevated levels of serum ALT and AST activities, a decrease in the number of BrdU-incorporated-hepatocytes in the regenerated livers compared to the mice fed CD. Mice fed MD showed significantly lower percent of BrdU-incorporated hepatocytes and a higher trend of inflammation compared to the mice fed LD. CONCLUSION: A diet rich in saturated or unsaturated fat results in NASH with decreased hepatic regeneration however unsaturated fat diet cause lower inflammation and higher regeneration than the saturated fat diet following partial hepatectomy in mice.

Analysis of N-linked Glycan Alterations in Tissue and Serum Reveals Promising Biomarkers for Intrahepatic Cholangiocarcinoma.

There is an urgent need for the identification of reliable prognostic biomarkers for patients with intrahepatic cholangiocarcinoma (iCCA) and alterations in N-glycosylation have demonstrated an immense potential to be used as diagnostic strategies for many cancers, including hepatocellular carcinoma (HCC). N-glycosylation is one of the most common post-translational modifications known to be altered based on the status of the cell. N-glycan structures on glycoproteins can be modified based on the addition or removal of specific N-glycan residues, some of which have been linked to liver diseases. However, little is known concerning the N-glycan alterations that are associated with iCCA. We characterized the N-glycan modifications quantitatively and qualitatively in three cohorts, consisting of two tissue cohorts: a discovery cohort (n = 104 cases) and a validation cohort (n = 75), and one independent serum cohort consisting of patients with iCCA, HCC, or benign chronic liver disease (n = 67). N-glycan analysis in situ was correlated to tumor regions annotated on histopathology and revealed that bisected fucosylated N-glycan structures were specific to iCCA tumor regions. These same N-glycan modifications were significantly upregulated in iCCA tissue and serum relative to HCC and bile duct disease, including primary sclerosing cholangitis (PSC) (P < 0.0001). N-glycan modifications identified in iCCA tissue and serum were used to generate an algorithm that could be used as a biomarker of iCCA. We demonstrate that this biomarker algorithm quadrupled the sensitivity (at 90% specificity) of iCCA detection as compared with carbohydrate antigen 19-9, the current "gold standard" biomarker of CCA. Significance: This work elucidates the N-glycan alterations that occur directly in iCCA tissue and utilizes this information to discover serum biomarkers that can be used for the noninvasive detection of iCCA.

Utilizing multimodal mass spectrometry imaging for profiling immune cell composition and N-glycosylation across colorectal carcinoma disease progression.

Colorectal cancer (CRC) stands as a leading cause of death worldwide, often arising from specific genetic mutations, progressing from pre-cancerous adenomas to adenocarcinomas. Early detection through regular screening can result in a 90% 5-year survival rate for patients. However, unfortunately, only a fraction of CRC cases are identified at pre-invasive stages, allowing progression to occur silently over 10-15 years. The intricate interplay between the immune system and tumor cells within the tumor microenvironment plays a pivotal role in the progression of CRC. Immune cell clusters can either inhibit or facilitate tumor initiation, growth, and metastasis. To gain a better understanding of this relationship, we conducted N-glycomic profiling using matrix-assisted laser desorption-ionization mass spectrometry imaging (MALDI-MSI). We detected nearly 100 N-glycan species across all samples, revealing a shift in N-glycome profiles from normal to cancerous tissues, marked by a decrease in high mannose N-glycans. Further analysis of precancerous to invasive carcinomas showed an increase in pauci-mannose biantennary, and tetraantennary N-glycans with disease progression. Moreover, a distinct stratification in the N-glycome profile was observed between non-mucinous and mucinous CRC tissues, driven by pauci-mannose, high mannose, and bisecting N-glycans. Notably, we identified immune clusters of CD20+ B cells and CD3/CD44+ T cells distinctive and predictive with signature profiles of bisecting and branched N-glycans. These spatial N-glycan profiles offer potential biomarkers and therapeutic targets throughout the progression of CRC.

Nodular Regenerative Hyperplasia of the Liver in Rheumatic Disease: Cases and Review of the Literature.

Nodular regenerative hyperplasia (NRH) is a rare disease that is characterized by benign transformation of the hepatic parenchyma into small nodules with little to no fibrosis. Nodular regenerative hyperplasia is a cause of noncirrhotic portal hypertension. Symptoms can range from asymptomatic disease to more serious complications of portal hypertension such as esophageal varices and ascites. Nodular regenerative hyperplasia has been described in association with a variety of different rheumatologic, hematologic, and oncologic diseases, as well as in immune deficiency states and with exposures to certain toxins. Diagnosis is made by histology, and the treatment involves addressing the underlying disease. The first description of this rare disease was actually described in a patient with rheumatoid arthritis, neutropenia, and splenomegaly (Felty's Syndrome). We describe 2 cases of NRH associated with underlying rheumatic disorders, in one of which NRH was actually the presenting feature of the patient's underlying autoimmune condition. Subsequently, we provide a brief review of the literature of NRH in autoimmune disease with respect to epidemiology, cause, clinical manifestations, diagnosis, and treatment.

Immune Responses Vary in Preinvasive Colorectal Lesions by Tumor Location and Histology.

Immune responses vary in colorectal cancers, which strongly influence prognosis. However, little is known about the variance in immune response within preinvasive lesions. The study aims to investigate how the immune contexture differs by clinicopathologic features (location, histology, dysplasia) associated with progression and recurrence in early carcinogenesis. We performed a cross-sectional study using preinvasive lesions from the surgical pathology laboratory at the Medical University of South Carolina. We stained the tissues with immunofluorescence antibodies, then scanned and analyzed expression using automated image analysis software. We stained CD117 as a marker of mast cells, CD4/RORC to indicate Th17 cells, MICA/B as a marker of NK-cell ligands, and also used antibodies directed against cytokines IL6, IL17A, and IFNγ. We used negative binomial regression analysis to compare analyte density counts by location, histology, degree of dysplasia adjusted for age, sex, race, and batch. All immune markers studied (except IL17a) had significantly higher density counts in the proximal colon than distal colon and rectum. Increases in villous histology were associated with significant decreases in immune responses for IL6, IL17a, NK ligand, and mast cells. No differences were observed in lesions with low- and high-grade dysplasia, except in mast cells. The lesions of the proximal colon were rich in immune infiltrate, paralleling the responses observed in normal mucosa and invasive disease. The diminishing immune response with increasing villous histology suggests an immunologically suppressive tumor environment. Our findings highlight the heterogeneity of the immune responses in preinvasive lesions, which may have implications for prevention strategies. PREVENTION RELEVANCE: Our study is focused on immune infiltrate expression in preinvasive colorectal lesions; our results suggest important differences by clinicopathologic features that have implications for immune prevention research.

N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate the tumor heterogeneity. Previous work has identified significant changes in the N-linked glycosylation of HCC tumors but has not accounted for the heterogeneous genetic and molecular nature of HCC. To determine the correlation between HCC-specific N-glycosylation changes and genetic/molecular tumor features, we profiled HCC tissue samples with MALDI-IMS and correlated the spatial N-glycosylation with a widely used HCC molecular classification (Hoshida subtypes). MALDI-IMS data displayed trends that could approximately distinguish between subtypes, with subtype 1 demonstrating significantly dysregulated N-glycosylation versus adjacent nontumor tissue. Although there were no individual N-glycan structures that could identify specific subtypes, trends emerged regarding the correlation of branched glycan expression to HCC as a whole and fucosylated glycan expression to subtype 1 tumors specifically. IMPLICATIONS: Correlating N-glycosylation to specific subtypes offers the specific detection of subtypes of HCC, which could both enhance early HCC sensitivity and guide targeted clinical therapies.

Preinvasive Colorectal Lesions of African Americans Display an Immunosuppressive Signature Compared to Caucasian Americans.

BACKGROUND: African Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease. METHODS: We selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch. RESULTS: We observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001). CONCLUSIONS: Overall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.

The Utility of Liver Biopsy in the Evaluation of Liver Disease and Abnormal Liver Function Tests.

OBJECTIVES: We aimed to assess the value of liver biopsy in the evaluation of abnormal liver tests. METHODS: We analyzed consecutive liver biopsy specimens performed for evaluation of unexplained abnormal liver tests from 2014 to 2018. Diagnoses were categorized histologically and clinically. We determined whether histologic examination led to a specific diagnosis and whether prebiopsy laboratory variables predicted the underlying etiology. RESULTS: Among the 383 liver biopsy specimens included, chronic hepatitis was the most common histologic (25%) and clinical (17%) diagnosis. Liver biopsy led to a clinical diagnosis in 87% of patients. The most likely clinical diagnoses were autoimmune hepatitis, nonalcoholic fatty liver disease, and drug-induced liver injury (38, 33, and 32 patients, respectively). Using sensitivity, specificity, and positive and negative predictive values, we found that liver tests were not predictive of a specific diagnosis. In patients with no history of liver disease or clinical features of portal hypertension, biopsy specimens revealed histologic cirrhosis in 5% of patients. CONCLUSIONS: Histopathologic diagnoses were made in 85% of patients undergoing liver biopsy for investigation of unexplained liver tests, leading to a clinical diagnosis in 87% of patients. However, neither liver tests themselves nor their patterns were useful in predicting histologic or clinical diagnoses.

Imaging Mass Spectrometry and Lectin Analysis of N-Linked Glycans in Carbohydrate Antigen-Defined Pancreatic Cancer Tissues.

The early detection of pancreatic ductal adenocarcinoma (PDAC) is a complex clinical obstacle yet is key to improving the overall likelihood of patient survival. Current and prospective carbohydrate biomarkers carbohydrate antigen 19-9 (CA19-9) and sialylated tumor-related antigen (sTRA) are sufficient for surveilling disease progression yet are not approved for delineating PDAC from other abdominal cancers and noncancerous pancreatic pathologies. To further understand these glycan epitopes, an imaging mass spectrometry (IMS) approach was used to assess the N-glycome of the human pancreas and pancreatic cancer in a cohort of patients with PDAC represented by tissue microarrays and whole-tissue sections. Orthogonally, these same tissues were characterized by multiround immunofluorescence that defined expression of CA19-9 and sTRA as well as other lectins toward carbohydrate epitopes with the potential to improve PDAC diagnosis. These analyses revealed distinct differences not only in N-glycan spatial localization across both healthy and diseased tissues but importantly between different biomarker-categorized tissue samples. Unique sulfated biantennary N-glycans were detected specifically in normal pancreatic islets. N-glycans from CA19-9-expressing tissues tended to be biantennary, triantennary, and tetra-antennary structures with both core and terminal fucose residues and bisecting GlcNAc. These N-glycans were detected in less abundance in sTRA-expressing tumor tissues, which favored triantennary and tetra-antennary structures with polylactosamine extensions. Increased sialylation of N-glycans was detected in all tumor tissues. A candidate new biomarker derived from IMS was further explored by fluorescence staining with selected lectins on the same tissues. The lectins confirmed the expression of the epitopes in cancer cells and revealed different tumor-associated staining patterns between glycans with bisecting GlcNAc and those with terminal GlcNAc. Thus, the combination of lectin-immunohistochemistry and lectin-IMS techniques produces more complete information for tumor classification than the individual analyses alone. These findings potentiate the development of early assessment technologies to rapidly and specifically identify PDAC in the clinic that may directly impact patient outcomes.

Synchronous Upper Intestinal Neurofibromas and Duodenal Periampullary Well-Differentiated Neuroendocrine Tumor Associated With Neurofibromatosis 1.

Neurofibromatosis type I (NF1) is an autosomal dominant genetic disorder associated with characteristic skin findings, as well as a fourfold increase in risk of malignancy. NF1 patient malignancies commonly include the central and peripheral nervous system, but these patients are also at high risk of developing gastrointestinal (GI) tumors. While most often these GI tumors are benign upper GI neurofibromas; clinicians should have a high suspicion for malignant tumors, degeneration into a malignant peripheral nerve sheath tumor or less common associated malignancies such as well-differentiated neuroendocrine tumor (formerly carcinoid tumor), when patients present with multiple GI tumors. Our patient underwent a Whipple for symptomatic neurofibromas associated with NF1 and was unexpectedly discovered to have a metastatic duodenal well-differentiated neuroendocrine tumor. The patient is a 66-year-old man with NF1 who presented with hematemesis and was found to have large gastric neurofibromas and an ampullary neurofibroma based on endoscopy and radiological imaging. Another ostensive neurofibroma was noted distally. A pancreatoduodenectomy was performed. Pathological examination identified the neurofibromas but the tumor measuring 1.4cm and arising from the minor duodenal papilla was, in fact, a synchronous well-differentiated neuroendocrine tumor metastatic to regional lymph nodes, consistent with pT2 pN1, Stage IIIB cancer. NF1 patients with multiple GI tumors are at an increased risk for malignancy. Therefore, a high index of suspicion for malignancy in any patient with NF1 presenting with gastrointestinal symptoms has implications for a surgeon, warranting not only a further diagnostic investigation, but also an appropriate surgical intervention and sampling for nodal spread. Because of the possibility of a simultaneous cancer, it is crucial to assess all suspicious tumors even if the masses appear endoscopically benign.

Platelet and hemoglobin count at diagnosis are associated with survival in African American and Caucasian patients with colorectal cancer.

BACKGROUND: African Americans (AAs) compared to Caucasian Americans (CAs) with colorectal cancer (CRC) have lower stage-specific survival. CRC patients often present with several hematopathologies (such as thrombocytosis, thrombocytopenia, anemia) at diagnosis, which is associated with poorer survival. However, whether these measures impact the racial disparity in survival is not known. METHODS: The study population was composed of 581 histologically confirmed CRCs at the Medical University of South Carolina (393 CA, 188 AA) diagnosed between 01/01/2000 and 06/30/2013. We used Cox proportional hazards regression to estimate the association between thrombocytosis, thrombocytopenia, or anemia at diagnosis and risk of death by race. This analysis was adjusted for age, sex, stage and first-line treatment. RESULTS: In all patients combined, thrombocytosis, thrombocytopenia, and anemia (vs. the normal ranges) were associated with significantly higher risks of death. In the race-specific analyses, AAs (HR 2.51 [95 % CI: 1.52-4.15]) vs. CAs (HR 1.15 [95 % CI: 0.75-1.75]) with thrombocytosis compared to normal had a higher risk of death (p for difference = 0.03). CONCLUSIONS: Abnormal thrombocyte and hemoglobin levels at diagnosis were associated with poorer survival. AAs compared to CAs with elevated platelets at diagnosis had a higher risk of death. Our study is the first to examine the role of race, hematologic measures at diagnosis, and risk of death in colorectal cancer patients. These results suggest that the racial differences in the immune response may contribute to the racial disparity in survival.

Relationship Between Sleep and Behavior in Autism Spectrum Disorder: Exploring the Impact of Sleep Variability.

OBJECTIVE: The relationship between sleep (caregiver-reported and actigraphy-measured) and other caregiver-reported behaviors in children and adults with autism spectrum disorder (ASD) was examined, including the use of machine learning to identify sleep variables important in predicting anxiety in ASD. METHODS: Caregivers of ASD (n = 144) and typically developing (TD) (n = 41) participants reported on sleep and other behaviors. ASD participants wore an actigraphy device at nighttime during an 8 or 10-week non-interventional study. Mean and variability of actigraphy measures for ASD participants in the week preceding midpoint and endpoint were calculated and compared with caregiver-reported and clinician-reported symptoms using a mixed effects model. An elastic-net model was developed to examine which sleep measures may drive prediction of anxiety. RESULTS: Prevalence of caregiver-reported sleep difficulties in ASD was approximately 70% and correlated significantly (p < 0.05) with sleep efficiency measured by actigraphy. Mean and variability of actigraphy measures like sleep efficiency and number of awakenings were related significantly (p < 0.05) to ASD symptom severity, hyperactivity and anxiety. In the elastic net model, caregiver-reported sleep, and variability of sleep efficiency and awakenings were amongst the important predictors of anxiety. CONCLUSION: Caregivers report problems with sleep in the majority of children and adults with ASD. Reported problems and actigraphy measures of sleep, particularly variability, are related to parent reported behaviors. Measuring variability in sleep may prove useful in understanding the relationship between sleep problems and behavior in individuals with ASD. These findings may have implications for both intervention and monitoring outcomes in ASD.

Modeling rectal cancer to advance neoadjuvant precision therapy.

Progress in rectal cancer therapy has been hindered by the lack of effective disease-specific preclinical models that account for the unique molecular profile and biology of rectal cancer. Thus, we developed complementary patient-derived xenograft (PDX) and subsequent in vitro tumor organoid (PDTO) platforms established from preneoadjuvant therapy rectal cancer specimens to advance personalized care for rectal cancer patients. Multiple endoscopic samples were obtained from 26 Stages 2 and 3 rectal cancer patients prior to receiving 5FU/RT and implanted subcutaneously into NSG mice to generate 15 subcutaneous PDXs. Second passaged xenografts demonstrated 100% correlation with the corresponding human cancer histology with maintained mutational profiles. Individual rectal cancer PDXs reproduced the 5FU/RT response observed in the corresponding human cancers. Similarly, rectal cancer PDTOs reproduced significant heterogeneity in cellular morphology and architecture. PDTO in vitro 5FU/RT treatment response replicated the clinical 5FU/RT neoadjuvant therapy pathologic response observed in the corresponding patient tumors (p < 0.05). The addition of cetuximab to the 5FU/RT regiment was significantly more sensitive in the rectal cancer PDX and PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05). Considering the close relationship between the patient's cancer and the corresponding PDX/PDTO, rectal cancer patient-derived research platforms represent powerful translational research resources as population-based tools for biomarker discovery and experimental therapy testing. In addition, our findings suggest that cetuximab may enhance RT effectiveness by improved patient selection based on mutational profile in addition to KRAS or by developing a protocol using PDTOs to identify sensitive patients.

Clinical Validation of the Autism Behavior Inventory: Caregiver-Rated Assessment of Core and Associated Symptoms of Autism Spectrum Disorder.

There is a need for measures to track symptom change in autism spectrum disorder (ASD). We conducted a validation study on a revised version of the Autism Behavior Inventory (ABI), and a short form (ABI-S). Caregivers of individuals (6-54 years) with confirmed diagnoses of ASD (N = 144) completed the ABI and other rating scales at 4 time points. Scale consistency for each domain, 3-5 day test-retest reliability, and construct validity, determined by comparison to pre-specified scales, were all good. Change in the ABI was congruent with changes in other instruments. Collectively, results suggest incipient suitability of the ABI as a measure of changes in core and associated symptoms of ASD.Trial Registration NCT02299700.

An Observational Study With the Janssen Autism Knowledge Engine (JAKE®) in Individuals With Autism Spectrum Disorder.

Objective: The Janssen Autism Knowledge Engine (JAKE®) is a clinical research outcomes assessment system developed to more sensitively measure treatment outcomes and identify subpopulations in autism spectrum disorder (ASD). Here we describe JAKE and present results from its digital phenotyping (My JAKE) and biosensor (JAKE Sense) components. Methods: An observational, non-interventional, prospective study of JAKE in children and adults with ASD was conducted at nine sites in the United States. Feedback on JAKE usability was obtained from caregivers. JAKE Sense included electroencephalography, eye tracking, electrocardiography, electrodermal activity, facial affect analysis, and actigraphy. Caregivers of individuals with ASD reported behaviors using My JAKE. Results from My JAKE and JAKE Sense were compared to traditional ASD symptom measures. Results: Individuals with ASD (N = 144) and a cohort of typically developing (TD) individuals (N = 41) participated in JAKE Sense. Most caregivers reported that overall use and utility of My JAKE was "easy" (69%, 74/108) or "very easy" (74%, 80/108). My JAKE could detect differences in ASD symptoms as measured by traditional methods. The majority of biosensors included in JAKE Sense captured sizable amounts of quality data (i.e., 93-100% of eye tracker, facial affect analysis, and electrocardiogram data was of good quality), demonstrated differences between TD and ASD individuals, and correlated with ASD symptom scales. No significant safety events were reported. Conclusions: My JAKE was viewed as easy or very easy to use by caregivers participating in research outside of a clinical study. My JAKE sensitively measured a broad range of ASD symptoms. JAKE Sense biosensors were well-tolerated. JAKE functioned well when used at clinical sites previously inexperienced with some of the technologies. Lessons from the study will optimize JAKE for use in clinical trials to assess ASD interventions. Additionally, because biosensors were able to detect features differentiating TD and ASD individuals, and also were correlated with standardized symptom scales, these measures could be explored as potential biomarkers for ASD and as endpoints in future clinical studies. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02668991 identifier: NCT02668991.

Caregiver Daily Reporting of Symptoms in Autism Spectrum Disorder: Observational Study Using Web and Mobile Apps.

BACKGROUND: Currently, no medications are approved to treat core symptoms of autism spectrum disorder (ASD). One barrier to ASD medication development is the lack of validated outcome measures able to detect symptom change. Current ASD interventions are often evaluated using retrospective caregiver reports that describe general clinical presentation but often require recall of specific behaviors weeks after they occur, potentially reducing accuracy of the ratings. My JAKE, a mobile and Web-based mobile health (mHealth) app that is part of the Janssen Autism Knowledge Engine-a dynamically updated clinical research system-was designed to help caregivers of individuals with ASD to continuously log symptoms, record treatments, and track progress, to mitigate difficulties associated with retrospective reporting. OBJECTIVE: My JAKE was deployed in an exploratory, noninterventional clinical trial to evaluate its utility and acceptability to monitor clinical outcomes in ASD. Hypotheses regarding relationships among daily tracking of symptoms, behavior, and retrospective caregiver reports were tested. METHODS: Caregivers of individuals with ASD aged 6 years to adults (N=144) used the My JAKE app to make daily reports on their child's sleep quality, affect, and other self-selected specific behaviors across the 8- to 10-week observational study. The results were compared with commonly used paper-and-pencil scales acquired over a concurrent period at regular 4-week intervals. RESULTS: Caregiver reporting of behaviors in real time was successfully captured by My JAKE. On average, caregivers made reports 2-3 days per week across the study period. Caregivers were positive about their use of the system, with over 50% indicating that they would like to use My JAKE to track behavior outside of a clinical trial. More positive average daily reporting of overall type of day was correlated with 4 weekly reports of lower caregiver burden made at 4-week intervals (r=-0.27, P=.006, n=88) and with ASD symptoms (r=-0.42, P<.001, n=112). CONCLUSIONS: My JAKE reporting aligned with retrospective Web-based or paper-and-pencil scales. Use of mHealth apps, such as My JAKE, has the potential to increase the validity and accuracy of caregiver-reported outcomes and could be a useful way of identifying early changes in response to intervention. Such systems may also assist caregivers in tracking symptoms and behavior outside of a clinical trial, help with personalized goal setting, and monitoring of progress, which could collectively improve understanding of and quality of life for individuals with ASD and their families. TRIAL REGISTRATION: ClinicalTrials.gov NCT02668991; https://clinicaltrials.gov/ct2/show/NCT02668991.