Subtype Membership Research Articles

Stability of symptom-based subtypes in Sjogren’s disease

ObjectivesThe Newcastle Sjogren’s Stratification Tool (NSST) stratifies Sjogren’s disease patients into four subtypes. Understanding the stability of the subtypes is vital if symptom-based stratification is to be more broadly adopted....

Abstract IA003: Molecular subtypes and clinical benefit from neoadjuvant chemotherapy: A ten-year update

Abstract Ten years ago TCGA and two private groups reported that muscle-invasive bladder cancers (MIBCs) could be grouped into basal and luminal molecular subtypes that shared features with the corresponding subtypes of breast cancer. These and earlier studies by the group at Lund University demonstrated that molecular subtype membership was prognostic: patients whose tumors were assigned to basal/squamous subtypes had shorter survival than did patients whose tumors were assigned to the luminal subtypes, and these relationships were confirmed in subsequent studies. In addition, one of the studies included tumors from patients treated with neoadjuvant cisplatin-based combination chemotherapy (NAC), where patients whose tumors were infiltrated with smooth muscle cells and fibroblasts (the MD Anderson p53-like subtype) had the lowest response rates. Parallel comparisons of patients who either did or did not receive NAC concluded that patients with basal tumors derived the most clinical benefit in terms of disease-specific or overall survival. Thus, in addition to being prognostic, there was a suggestion that molecular subtypes might also be used to predict resistance to NAC. This work led to the design of two large collaborative projects that were designed to validate these observations and the conclusion that inactivating mutations in several DNA damage and repair (DDR) genes were also associated with response. One leveraged the S1314 Phase-2 “CoXEN” trial that was designed to prospectively validate another gene expression-based biomarker, and the other exploited pretreatment samples from the CALGB/Alliance 90601 Phase-3 trial of gemcitabine/cisplatin with or without bevacizumab in patients with advanced or metastatic disease. Comparisons of response rates as a function of molecular subtype membership in S1314 failed to validate the original link between the MD Anderson p53-like subtype and resistance, and patients with basal/squamous tumors in 90601 did not have better outcomes than did patients with luminal tumors. Thus, while the prognostic value of molecular subtype membership was confirmed, the predictive value was not. Developing biomarkers to predict response to chemotherapy remains a challenge not only for bladder cancer but also for other solid and hematopoietic malignancies. It seems likely that success will require the integration of measurements using multiple platforms, including liquid biopsies and others. The exciting results of the EV-302 clinical trial of enfortumab vedotin plus pembrolizumab have shifted the focus of biomarker work to these and other novel agents. Citation Format: David J McConkey. Molecular subtypes and clinical benefit from neoadjuvant chemotherapy: A ten-year update [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA003.

The evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis

The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are not well understood, and there is a lack of knowledge regarding the genomic and transcriptomic differences between primary and metastatic UTUC. To address these gaps, we integrate whole-exome sequencing, RNA sequencing, and Imaging Mass Cytometry using lanthanide metal-conjugated antibodies of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. We perform a spatially-resolved single-cell analysis of cancer, immune, and stromal cells to understand the evolution of primary to metastatic UTUC. We discover that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature are stable across primary and matched metastatic UTUC. Molecular and immune subtypes are consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single cells. Molecular subtypes at the single-cell level are highly conserved between primary and metastatic UTUC tumors within the same patient.

Identification of Concussion Subtypes Based on Intrinsic Brain Activity

The identification of brain activity-based concussion subtypes at time of injury has the potential to advance the understanding of concussion pathophysiology and to optimize treatment planning and outcomes. To investigate the presence of intrinsic brain activity-based concussion subtypes, defined as distinct resting state quantitative electroencephalography (qEEG) profiles, at the time of injury. In this retrospective, multicenter (9 US universities and high schools and 4 US clinical sites) cohort study, participants aged 13 to 70 years with mild head injuries were included in longitudinal cohort studies from 2017 to 2022. Patients had a clinical diagnosis of concussion and were restrained from activity by site guidelines for more than 5 days, with an initial Glasgow Coma Scale score of 14 to 15. Participants were excluded for known neurological disease or history of traumatic brain injury within the last year. Patients were assessed with 2 minutes of artifact-free EEG acquired from frontal and frontotemporal regions within 120 hours of head injury. Data analysis was performed from July 2021 to June 2023. Quantitative features characterizing the EEG signal were extracted from a 1- to 2-minute artifact-free EEG data for each participant, within 120 hours of injury. Symptom inventories and days to return to activity were also acquired. From the 771 participants (mean [SD] age, 20.16 [5.75] years; 432 male [56.03%]), 600 were randomly selected for cluster analysis according to 471 qEEG features. Participants and features were simultaneously grouped into 5 disjoint subtypes by a bootstrapped coclustering algorithm with an overall agreement of 98.87% over 100 restarts. Subtypes were characterized by distinctive profiles of qEEG measure sets, including power, connectivity, and complexity, and were validated in the independent test set. Subtype membership showed a statistically significant association with time to return to activity. In this cohort study, distinct subtypes based on resting state qEEG activity were identified within the concussed population at the time of injury. The existence of such physiological subtypes supports different underlying pathophysiology and could aid in personalized prognosis and optimization of care path.

Data‐driven comparison of neurodegeneration patterns between autosomal dominant and sporadic late‐onset Alzheimer’s disease

AbstractBackgroundAutosomal dominant Alzheimer’s disease (ADAD) and sporadic late‐onset AD (LOAD) have similar biomarker profiles, supporting a shared pathophysiology. While both ADAD and LOAD are known to be heterogeneous, there are few studies that have compared the heterogeneity of neurodegeneration as indexed by volumetric MRI in LOAD to that of ADAD. Here we apply a data‐driven model of brain atrophy subtypes from LOAD to characterize atrophy within ADAD.MethodWe used cross‐sectional MRI from ADNI (LOAD) and the Estudio de la Enfermaded de Alzheimer en Jalisciences (EEAJ; ADAD). We used 13 cortical and subcortical Freesurfer‐based regions from 1,912 ADNI participants to train a Subtype and Stage Inference (SuStaIn) model of brain atrophy progression within LOAD. We built a three‐subtype model and applied it to subtype and stage 61 EEAJ participants: 47 carriers of the A431E mutation in PSEN1 and 14 carriers of the V717I mutation in APP. To harmonize the two datasets, we removed the effects of age, sex, education years, ICV and study (ADNI vs. EEAJ flag) from each regional volumetric biomarker prior to analysis. We retained 47 of the 61 EEAJ participants with an estimate SuStaIn stage greater than zero (in any subtype) for subsequent analyses.ResultThe progression patterns for each of the three data‐driven brain atrophy subtypes (typical, cortical, subcortical) are presented in Figures 1 A‐C. These are consistent with previous findings in LOAD. We found no difference in the percentage of participants in each subtype between LOAD, ADAD‐PSEN1 and ADAD‐APP groups (χ2 = 1.5, p = 0.84; Figure 1D). Within ADAD, those assigned the typical subtype had a slightly lower average stage of progression than those in the other two subtypes (t = ‐2.0, p = 0.049; Figure 2A). The triangle plot shows the probability of subtype membership is mostly clustered around the typical and cortical subtypes (Figure 2B), while the estimated stages increase dramatically after disease onset, as expected (Figure 2C).ConclusionWe found a comparable distribution of LOAD‐based atrophy subtypes within both the PSEN1 and APP carriers groups in ADAD, showing that heterogeneous neurodegeneration is another commonality between ADAD and LOAD.

Similarities and differences between men with self-reported lifelong and acquired difficulty reaching ejaculation.

Men with delayed ejaculation are often categorized into lifelong and acquired subtypes, yet little is known about similarities and differences between these groups. In this study, we examined whether delayed ejaculation subtypes differed on various demographic, diagnostic, relationship, and sexual activity/satisfaction variables. We drew 140 men reporting moderately-severe to severe difficulty reaching ejaculation during partnered sex (occurring during ≥75% of sexual events) from a convenience sample of over 3000 respondents obtained through an opt-in, multinational, online survey. Respondents were further classified as having lifelong or acquired delayed ejaculation based on self-report. A series of alpha-adjusted analyses of covariance were then made between subtypes on subsets of variables. In addition, the extent to which two potential confounding variables, age and erectile function, might have been responsible for subtype differences was explored. Results indicated that compared with men with acquired delayed ejaculation, men with lifelong delayed ejaculation were younger (28.6 vs 44.7 years, η2p = 0.30, P < 0.001), reported greater delayed ejaculation symptomology (4.31 vs 3.98, P < 0.01, η2p = 0.02), were less likely to attribute their problem to a medical issue or medication (1.7% vs 12.2%, P < 0.05), and more likely to masturbate for anxiety/distress reduction than for pleasure. In contrast, delayed ejaculation subtype differences related to masturbation frequency, pornography use during masturbation, and condom use disappeared when age and erectile functioning differences were statistically controlled. Overall, lifelong and acquired delayed ejaculation subtypes showed more similarities than differences. Findings worthy of clinical note were the lower level of endorsement of medical issues/medication by the lifelong subtype, their higher level of delayed ejaculation symptomology, and-despite a high level of anxiety/distress reported by both groups-their particular vulnerability to anxiety/distress as indicated by their strong motive to masturbate for anxiety/distress reduction (44.3% vs 19.6%, P < 0.05). Other differences between delayed ejaculation subtypes were better explained by group differences in age and erectile function than by subtype membership per se.

Association between molecular subtype membership or hypoxia-associated gene expression signatures and clinical outcomes in the CALGB 90601 (Alliance) phase 3 clinical trial of gemcitabine and cisplatin (GC) plus bevacizumab (B) or placebo (P).

4562 Background: Our previous work showed that basal tumors were associated with the best clinical outcomes in a Phase 2 clinical trial of neoadjuvant dose-dense MVAC plus B, and in other work we showed that basal tumors were enriched with hypoxia-associated gene expression signatures. Here we attempted to validate these findings in the C90601 Phase 3 clinical trial of GC plus B versus GC plus P. Methods: Whole transcriptome RNAseq was performed on all available tumors using Ion Torrent’s Ampliseq platform (n = 189). Tumors were assigned to molecular subtypes using 3 different classifiers - BASE47 (k=2), MDA oneNN (k=3), and the Consensus classifier (k=6). Tumor hypoxia signature enrichment was determined using 2 different gene expression signatures and gene set variation analysis (GSVA). The proportional hazards model was used to correlate molecular subtype calls and hypoxia signature enrichment with overall survival (OS) and progression-free survival (PFS) adjusting for stratification factors and treatment arm (for PFS). Results: The median OS &amp; PFS by different signatures and the hazard ratios (HR) are presented in the Table. Conclusions: Predefined signatures associated with clinical benefit in the Phase-2 neoadjuvant clinical trial were not associated with benefit in C90601. Possible explanations include the lack of strong therapeutic effects of the treatments, potential heterogeneity (“subtype plasticity”) between the profiled tissue samples and the metastatic lesions under treatment pressure, and differences in biology associated with the disease states (muscle-invasive vs advanced/metastatic disease). Support: U10CA180821, U10CA180882, Department of Defense (CA160312), Genentech; ClinicalTrials.gov Identifier: NCT00942331. [Table: see text]

Data-Driven Subtyping of Parkinson’s Using Acoustic Analysis of Sustained Vowels and Cluster Analysis: Findings in the Parkinson’s Voice Initiative Study

People diagnosed with Parkinson’s (PwP) exhibit a diverse manifestation of heterogeneous symptoms which likely reflect different subtypes. However, there is no widely accepted consensus on the criteria for subtype membership assignment. We explored clustering PwP using a data-driven approach mining speech signals. We used data from the three English-speaking cohorts (Boston, Oxford, Toronto) in the Parkinson’s Voice Initiative (PVI), where speech and basic demographic information were collected over the standard telephone network. We acoustically characterized 2097 sustained vowel /a/ recordings from 1138 PwP (Boston cohort) using 307 dysphonia measures. We applied unsupervised feature selection to select a concise subset of the dysphonia measures and hierarchical clustering combined with 2D-data projections using t-distributed stochastic neighbor embedding (t-SNE) to facilitate visual exploration of PwP groups. We assessed cluster validity and consistency using silhouette plots and the cophenetic correlation coefficient. We externally validated cluster findings on the Oxford and Toronto PVI cohorts (n = 285 and 107 participants, respectively). We selected 21 dysphonia measures and found four main clusters which provide tentative insights into different dominating speech-associated characteristics (cophenetic coefficient = 0.72, silhouette score = 0.67). The cluster findings were consistent across the three PVI cohorts, strongly supporting the generalization of the presented methodology towards PwP subtype assignment, and were independently visually verified in 2D projections with t-SNE. The presented methodology with mining sustained vowels and clustering may provide an objective and streamlined approach towards informing PwP subtype assignment. This may have important implications towards developing more personalized clinical management of symptoms for PwP.

Trajectories of craving during medication-assisted treatment for opioid-use disorder: Subtyping for early identification of higher risk

AimsTo examine evidence for subtypes of opioid craving trajectories during medication for opioid use disorder (MOUD), and to (a) test whether these subtypes differed on MOUD-related outcomes, and (b) determine whether nonresponders could be identified before treatment initiation. Design, setting, and participantsOutpatients (n = 211) being treated with buprenorphine or methadone for up to 16 weeks. Growth mixture modeling was used to identify unobserved craving-trajectory subtypes. Support Vector Machines (SVM) were trained to predict subtype membership from pretreatment data. MeasurementsSelf-reported opioid craving (Ecological Momentary Assessment – EMA – three random moments per day). Participant-initiated EMA reports of drug use or higher-than-usual stress. Addiction Severity Index (ASI) pretreatment. FindingsFour craving trajectories were identified: Low (73%); High and Increasing (HIC) (10.9%); Increasing and Decreasing (8.5%); and Rapidly Declining (7.6%). The HIC subgroup reported the highest use of heroin, any opiate, and cannabis during treatment. The Low Craving subgroup reported the lowest use of heroin or any opiate use, and the lowest levels of stress and drug-cue exposure during treatment. SVM models predicting HIC membership before treatment initiation had a sensitivity of 0.70, specificity of 0.78, and accuracy of 0.77. Including 3 weeks of EMA reports increased sensitivity to 0.78, specificity to 0.84, and accuracy to 0.85. ConclusionsSubgroups of MOUD patients show distinct patterns of opioid craving during treatment. Subgroups differ on critical outcomes including drug-use lapse, stress, and exposure to drug cues. Data from enrollment and early in treatment may help focus clinical attention.

Neurophysiological Correlates of Sensory-Based Phenotypes in ASD.

Children with autism spectrum disorder frequently present with atypical behavioral responses to sensory stimuli, as well as differences in autonomic nervous system (ANS) and neuroendocrine activity. However, no one consistent pattern appears to explain these differences within this heterogeneous population. To conceptualize more homogenous ASD subgroups, sensory-based subtypes have been explored. One subtyping mechanism groups children by sensory responsivity pattern in addition to sensory domain. Differences in nervous system responsivity to sensory input within this sensory-based subtyping scheme have not yet been investigated. This exploratory study used ANS indices (respiratory sinus arrhythmia [RSA], skin conductance level) and neuroendocrine (salivary cortisol) response to examine patterns differentiating these subtypes. Significant differences in RSA were found during baseline, and during tactile, tone and movement stimuli (p < 0.05). Subtype membership was predicted by RSA changes during auditory stimulation and recovery periods (p < 0.05). Results confirm that children with an adaptive sensory responsivity subtype differ from those children with sensory processing dysfunction, however, physiological variables did not distinguish between children with different patterns of sensory processing dysfunction.

Young Adulthood Outcomes of Joint Mental Health Trajectories: A Group-Based Trajectory Model Analysis of a 13-Year Longitudinal Cohort Study

Developmental trajectories of common mental health issues such as ADHD symptoms, internalising problems, and externalising problems can often be usefully summarised in terms of a small number of ‘developmental subtypes’ (e.g., ‘childhood onset’, ‘adolescent onset’) that may differ in their profiles or levels of clinically meaningful variables such as etiological risk factors. However, given the strong tendency for symptoms in these domains to co-occur, it is important to consider not only developmental subtypes in each domain individually, but also the joint developmental subtypes defined by symptoms trajectories in all three domains together (e.g., ‘late onset multimorbid’, ‘pure internalising’, ‘early onset multimorbid’). Previous research has illuminated the joint developmental subtypes of ADHD symptoms, internalising problems, and externalising problems that emerge from normative longitudinal data using methods such as group-based trajectory modelling, as well as predictors of membership in these developmental subtypes. However, information on the long-term outcomes of developmental subtype membership is critical to illuminate the likely nature and intensity of support needs required for individuals whose trajectories fit different developmental subtypes. We, therefore, evaluated the relations between developmental subtypes previously derived using group-based trajectory modelling in the z-proso study (n = 1620 with trajectory data at ages 7, 8, 9, 10, 11, 12, 13, 15) and early adulthood outcomes. Individuals with multimorbid trajectories but not ‘pure’ internalising problem elevations showed higher levels of social exclusion and delinquency at age 20. These associations held irrespective of the specific developmental course of symptoms (e.g., early versus late onset versus remitting). There was also some evidence that intimate partner violence acts as a form of heterotypic continuity for earlier externalising problems. Results underline the need for early intervention to address the pathways that lead to social exclusion and delinquency among young people with multiple co-occurring mental health issues.

Identification of Typologies of Cocaine Use Based on Quantity, Frequency, and Duration of Use: A Latent Profile Analysis.

We identified the patterns of cocaine use during individuals' heaviest use period by considering quantity, frequency, and duration simultaneously and examined the correlates and risk profile for these patterns. Latent profile analysis was conducted among the 3117 individuals who reported lifetime use of cocaine in the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) with quantity, frequency, and duration used as indicators. Logistic regression analyses examined factors associated with subtype membership based on patterns of cocaine use and the relationships between these patterns and cocaine use disorder (CocUD) and its severity. Four patterns were identified: a "low use" class (72.6%), a "moderate use" class (8.2%), a "daily use" class (17.9%), and a "very high quantity use" class (1.3%). Relative to non-Hispanic White and the "low use" class, non-Hispanic Black was associated with increased odds to be in the "moderate use" and "daily use" classes. Higher prevalence of smoking crack cocaine and poly-route use was observed among the "very high quantity use" class relative to other classes; increased risk of using other substances was associated with the "daily use" class. Higher levels of cocaine use were associated with higher risks of CocUD and worse severity compared to the "low use" class. People who use cocaine are heterogeneous with different patterns of use and risks of CocUD. Reducing cocaine smoking and poly-route of use should be placed as the same priority as decreasing very high quantity of use in interventions.

Subtypes of Alcohol Dependence and 36-Year Mortality.

Chronic, heavy alcohol use is associated with multiple health problems, including premature death. Further, the clinical presentation of alcohol dependence may differentially affect and predict the long-term health consequences of affected individuals. Subtypes of alcohol dependence based upon treatment intake information can help identify homogenous groups of patients for treatment purposes, but have not been used to predict long-term outcomes. The current study examined mortality in a 36-year posttreatment interval among 4 subtypes of alcohol-dependent patients based upon their initial intake data. Extensive baseline data were collected from n=316 male and female patients receiving inpatient treatment for alcohol dependence between 1980 and 1982. Four alcohol dependent subtypes (Del Boca & Hesselbrock, Alcohol Health Res World, 20:56, 1996) derived from the baseline data were used to examine the 1-year posttreatment drinking status and the risk of death 36years postdischarge. Public records were used to determine patient deaths in the 36years since discharge. At the 36-year follow-up interval since discharge, 68.4% of the sample had died. The 4 subtypes were found to be associated with different rates of resumption of regular drinking in the first year posttreatment and a differential risk of mortality. An increased risk for returning to regular drinking (once a week or more) and early death were associated with subtypes defined, in part, by conduct problems and externalizing disorders. Regardless of subtype membership, women had the highest risk of death following treatment. This study demonstrates the clinical usefulness of subtypes of alcohol dependence for examining different alcohol use outcomes, including predicting mortality. The increased risks for returning to regular drinking once a week or more and early death posttreatment among subtypes associated with conduct problems and externalizing disorders suggest the need for continued monitoring and possible additional intervention postdischarge.

Neurobiological Divergence of the Positive and Negative Schizophrenia Subtypes Identified on a New Factor Structure of Psychopathology Using Non-negative Factorization: An International Machine Learning Study

BackgroundDisentangling psychopathological heterogeneity in schizophrenia is challenging, and previous results remain inconclusive. We employed advanced machine learning to identify a stable and generalizable factorization of the Positive and Negative Syndrome Scale and used it to identify psychopathological subtypes as well as their neurobiological differentiations. MethodsPositive and Negative Syndrome Scale data from the Pharmacotherapy Monitoring and Outcome Survey cohort (1545 patients; 586 followed up after 1.35 ± 0.70 years) were used for learning the factor structure by an orthonormal projective non-negative factorization. An international sample, pooled from 9 medical centers across Europe, the United States, and Asia (490 patients), was used for validation. Patients were clustered into psychopathological subtypes based on the identified factor structure, and the neurobiological divergence between the subtypes was assessed by classification analysis on functional magnetic resonance imaging connectivity patterns. ResultsA 4-factor structure representing negative, positive, affective, and cognitive symptoms was identified as the most stable and generalizable representation of psychopathology. It showed higher internal consistency than the original Positive and Negative Syndrome Scale subscales and previously proposed factor models. Based on this representation, the positive–negative dichotomy was confirmed as the (only) robust psychopathological subtypes, and these subtypes were longitudinally stable in about 80% of the repeatedly assessed patients. Finally, the individual subtype could be predicted with good accuracy from functional connectivity profiles of the ventromedial frontal cortex, temporoparietal junction, and precuneus. ConclusionsMachine learning applied to multisite data with cross-validation yielded a factorization generalizable across populations and medical systems. Together with subtyping and the demonstrated ability to predict subtype membership from neuroimaging data, this work further disentangles the heterogeneity in schizophrenia.

Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.

443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was &gt; = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]

DEPRESSIVE SYMPTOM SUBTYPES IN OLDER ADULTS AFTER HIP FRACTURE

Depressive symptoms after hip fracture are common, and psychosocial impairment impedes recovery. However, depression is clinically heterogenous; thus, the aim was to identify and describe depressive symptom subtypes in the year following hip fracture. Men (n=149) and women (n=155) 65 years or older from the Baltimore Hip Studies 7th Cohort with depressive symptoms measured at baseline (within 22 days post-admission) or 2, 6, or 12 months follow-up using the 20-item Center for Epidemiological Studies Depression (CES-D) scale were included (n=304). Longitudinal latent class analysis was applied to participant’s CES-D symptoms to identify subtypes with similar patterns of depressive symptoms during the yearlong hip fracture recovery period. Item-response probabilities were used to evaluate the symptomatic profiles for each subtype. Posterior probability estimates were used to assign time-specific subtype membership and describe changes in prevalence. Four depression subtypes were identified: “No Symptoms” (49.3%), “Moderate-Melancholic” (31.3%), “Severe-Melancholic” (12.0%), and “Severe-Anhedonic” (7.4%). “No Symptoms” had low item-response probabilities across all symptoms and increased in prevalence during recovery. “Moderate-Melancholic” and “Severe-Melancholic” were differentiated by higher item-response probabilities for symptoms of anhedonia, somatic criterion, and psychomotor agitation but prevalence for both groups decreased over time. “Severe-Anhedonic” had greater item-response probabilities for the inability to experience pleasure and prevalence remained constant. Findings revealed four distinct depressive symptom subtypes in older adults after hip fracture, which differ in prevalence and clinical presentation, and severe subtypes may be risk factors for poor recovery and require specific intervention.

Behaviour Change Strategies Endorsed by Gamblers Subtyped by Psychological Distress, Risky Alcohol Use, and Impulsivity.

Problem gambling is often accompanied by co-morbid psychiatric disorders and maladaptive personality traits. Subtyping gamblers based on these pervasive comorbidities has been attempted so as to aid understanding of the aetiology of problem gambling and inform treatment options. However, there has been less focus on subtyping gamblers with (past or current) or without a history of problem gambling, or on providing more specific treatment or self-help recommendations. The current study sought to subtype current-, past-, and non-problem gamblers using three common comorbidities; psychological distress, risky alcohol use, and impulsivity. Participants' endorsement of helpful behaviour change strategies was also examined by subtype membership. A total of 385 participants were recruited who had a current gambling problem (n = 128; 33%), a past gambling problem (n = 131, 34%) or never had a gambling problem (n = 126, 33%). Hierarchical cluster analysis identified distinct subtypes of current (i.e., low comorbidity, high psychological distress, risky alcohol use and high comorbidity), past (i.e., low comorbidity, high psychological distress and high comorbidity) and non-problem gamblers (i.e., low comorbidity, high psychological distress, risky alcohol use and moderate impulsivity). The most helpful change strategies for current and past gamblers were similar across subtypes (i.e., accept that gambling needs to change, remind yourself of the negative consequences). Non-problem gamblers reported the most helpful strategy as setting financial limits. This study indicated that treatment of psychological distress, risky alcohol use or impulsivity may be important for all gamblers regardless of their level of risk.

Latent class analysis of a heterogeneous international sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome

ABSTRACT Background: Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) routinely display differences in symptomatology, as well as illness course, onset, duration, and functional disability. Given such diversity, previous work has attempted to identify symptom-based ME/CFS subtypes. However, results have been inconsistent. Purpose: This study sought to elucidate potential subtypes of ME/CFS as well as explore the impact of subtype membership on health functioning. Methods: Twelve non-core (i.e. less frequently endorsed) symptoms were included in a latent class analysis of 1,210 adults with ME/CFS. Demographic and illness-related predictors of class membership were evaluated with a multinomial logistic regression. ANOVAs were then performed to determine if there were significant differences across class on the eight subscales of the Short-Form Health Survey (SF-36). Results: A six-class solution was selected, which consisted of one class that was likely to endorse all non-core symptoms, one class that was unlikely to endorse any non-core symptoms, and four classes that were likely to endorse either one or two non-core symptom domains (i.e. circulatory/neuroendocrine impairment, orthostatic intolerance, and gastro-intestinal distress). Significant functioning differences by class were present for all SF-36 subscales. Conclusions: These results are suggestive of subtypes of ME/CFS and, if replicated, may assist physicians in providing tailored treatment to patients and allow researchers to form more homogeneous samples.

Genomic analysis of same-patient metachronous upper-tract and bladder urothelial carcinoma.

449 Background: Despite similarities between upper-tract (UTUC) and bladder urothelial carcinoma (BUC), distinctive clinicopathologic and genomic differences are being described. We further investigate the genomic landscape of these two interrelated malignancies in same-patient metachronous (m) UTUC and BUC using next generation sequencing (NGS). Methods: Following institutional board approval, UTUC and BUC samples were obtained from patients via surgical resection or endoscopic biopsy. Tumors were macrodissected from unstained formalin-fixed, paraffin-embedded slides. Study inclusion was untreated patient samples of UTUC and/or BUC divided into 4 groups: 1) UTUC with mBUC, 2) BUC with mUTUC, 3) Synchronous BUC and UTUC, 4) UTUC with no bladder history. Exclusions were for inadequate clinical data or histological tumor purity &lt; 30%. Whole transcriptome RNA sequencing was performed and analyzed using BASE47 panel (includes basal, luminal, p53-like and cell cycle genes). Results: A total of 95 (UTUC = 61, BUC = 34) samples from 40 patients were analyzed. UTUC samples were 33 primary ureter and 28 renal pelvis cancer. Median age was 72 years, 68% male, 76% Caucasian, 60% former smokers. Groups samples were: 1) UTUC (n = 19), mBUC (n = 12); 2) BUC (n = 12), mUTUC (n = 9); 3) Synchronous UTUC/BUC (n = 10); and 4) UTUC (n = 23). Unsupervised hierarchical clustering segregated tumors into basal-like and luminal subtypes, with 87.5% of metachronous tumors displaying conserved subtype membership. For the groups with UTUC and BUC, only 3/24 (12.5%) clusters (2 patients in Group 2, and 1 patient in Group 3) had unmatched basal/luminal subtypes. Conclusions: NGS analysis of same-patient metachronous UTUC and BUC shows that the majority stay within the same molecular subtype regardless of chronologic development or anatomic origin. Additional studies are necessary to explore differences that may occur within the subtypes, the role of methylation, and clinical correlates.

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma.

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKε inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKε inhibitor-sensitive disease among nonresponders to current targeted therapy.Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKε inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov; 7(8); 832-51. ©2017 AACR.See related commentary by Jenkins and Barbie, p. 799This article is highlighted in the In This Issue feature, p. 783.