A neural circuit for spatial orientation derived from brain lesions.

There is disagreement regarding the major components of the brain network supporting spatial cognition. To address this issue, we applied a lesion mapping approach to the clinical phenomenon of topographical disorientation. Topographical disorientation is the inability to maintain accurate knowledge about the physical environment and use it for navigation. A review of published topographical disorientation cases identified 65 different lesion sites. Our lesion mapping analysis yielded a topographical disorientation brain map encompassing the classic regions of the navigation network: medial parietal, medial temporal, and temporo-parietal cortices. We also identified a ventromedial region of the prefrontal cortex, which has been absent from prior descriptions of this network. Moreover, we revealed that the regions mapped are correlated with the Default Mode Network sub-network C. Taken together, this study provides causal evidence for the distribution of the spatial cognitive system, demarking the major components and identifying novel regions.

Functional brain networks in Developmental Topographical Disorientation.

Despite a decade-long study on Developmental Topographical Disorientation, the underlying mechanism behind this neurological condition remains unknown. This lifelong selective inability in orientation, which causes these individuals to get lost even in familiar surroundings, is present in the absence of any other neurological disorder or acquired brain damage. Herein, we report an analysis of the functional brain network of individuals with Developmental Topographical Disorientation ($n = 19$) compared against that of healthy controls ($n = 21$), all of whom underwent resting-state functional magnetic resonance imaging, to identify if and how their underlying functional brain network is altered. While the established resting-state networks (RSNs) are confirmed in both groups, there is, on average, a greater connectivity and connectivity strength, in addition to increased global and local efficiency in the overall functional network of the Developmental Topographical Disorientation group. In particular, there is an enhanced connectivity between some RSNs facilitated through indirect functional paths. We identify a handful of nodes that encode part of these differences. Overall, our findings provide strong evidence that the brain networks of individuals suffering from Developmental Topographical Disorientation are modified by compensatory mechanisms, which might open the door for new diagnostic tools.

Influence of spatial orientation training in a centrifuge on the ability of fighter pilots to assess the bank angle during flight without visual references.

Without visual references, nonpilots exposed to coordinated flight turns underestimate the bank angle, because of discordant information of the roll-angular displacement from the otoliths, consistently signaling vertical position, versus the semicircular canals, enabling detection of the displacement. Pilots may also use their ability to perceive the G load and knowledge of the relation between load and angle to assess the bank angle. Our aim was to investigate whether the perception of bank angle can be improved by spatial orientation training in a centrifuge. Sixteen pilots/pilot students assessed their roll tilt, in complete darkness, during both real coordinated flight turns and gondola centrifugation, at roll tilts of 30° and 60°. The experiments were repeated after a 3-wk period, during which eight of the subjects performed nine training sessions in the centrifuge, comprising feedback on roll angle vs. G load, and on indicating requested angles. Before training, the subjects perceived in the aircraft and centrifuge, respectively: 37 (17)°, 38 (14)° during 60° turns and 19 (12)°, 20 (10)° during 30° turns. Training improved the perception of angle during the 60° [to 60 (7)°, 55 (10)°; P ≤ 0.04] but not the 30° [21 (10)°, 15 (9)°; P ≥ 0.30] turns; the improvement disappeared within 2 yr after training. Angle assessments did not change in the untrained group. The results suggest that it is possible to, in a centrifuge, train a pilot's ability to perceive large but not discrete-to-moderate roll-angular displacements. The transient training effect is attributable to improved capacity to perceive and translate G load into roll angle and/or to increased reliance on semicircular canal signals.NEW & NOTEWORTHY Spatial disorientation is a major problem in aviation. When performing coordinated flight turns without external visual cues (e.g., flying in clouds or darkness), the pilot underestimates the aircraft bank angle because the vestibular system provides unreliable information of roll tilt. The present study demonstrates that it is possible to, in a long-arm centrifuge, train a pilot's ability to perceive large but not discrete-to-moderate roll-angular displacements.

Medial positioning of the hippocampus and hippocampal fissure volume in developmental topographical disorientation.

Developmental topographical disorientation (DTD) refers to the lifelong inability to orient by means of cognitive maps in familiar surroundings despite otherwise well-preserved general cognitive functions, and the absence of any acquired brain injury or neurological condition. While reduced functional connectivity between the hippocampus and other brain regions has been reported in DTD individuals, no structural differences in gray matter tissue for the whole brain neither for the hippocampus were detected. Considering that the human hippocampus is the main structure associated with cognitive map-based navigation, here, we investigated differences in morphological and morphometric hippocampal features between individuals affected by DTD (N = 20) and healthy controls (N = 238). Specifically, we focused on a developmental anomaly of the hippocampus that is characterized by the incomplete infolding of hippocampal subfields during fetal development, giving the hippocampus a more round or pyramidal shape, called incomplete hippocampal inversion (IHI). We rated IHI according to standard criteria and extracted hippocampal subfield volumes after FreeSurfer's automatic segmentation. We observed similar IHI prevalence in the group of individuals with DTD with respect to the control population. Neither differences in whole hippocampal nor major hippocampal subfield volumes have been observed between groups. However, when assessing the IHI independent criteria, we observed that the hippocampus in the DTD group is more medially positioned comparing to the control group. In addition, we observed bigger hippocampal fissure volume for the DTD comparing to the control group. Both of these findings were stronger for the right hippocampus comparing to the left. Our results provide new insights regarding the hippocampal morphology of individuals affected by DTD, highlighting the role of structural anomalies during early prenatal development in line with the developmental nature of the spatial disorientation deficit.

A computational model of motion sickness dynamics during passive self-motion in the dark.

Predicting the time course of motion sickness symptoms enables the evaluation of provocative stimuli and the development of countermeasures for reducing symptom severity. In pursuit of this goal, we present an Observer-driven model of motion sickness for passive motions in the dark. Constructed in two stages, this model predicts motion sickness symptoms by bridging sensory conflict (i.e., differences between actual and expected sensory signals) arising from the Observer model of spatial orientation perception (stage 1) to Oman's model of motion sickness symptom dynamics (stage 2; presented in 1982 and 1990) through a proposed "Normalized Innovation Squared" statistic. The model outputs the expected temporal development of human motion sickness symptom magnitudes (mapped to the Misery Scale) at a population level, due to arbitrary, 6-degree-of-freedom, self-motion stimuli. We trained model parameters using individual subject responses collected during fore-aft translations and off-vertical axis of rotation motions. Improving on prior efforts, we only used datasets with experimental conditions congruent with the perceptual stage (i.e., adequately provided passive motions without visual cues) to inform the model. We assessed model performance by predicting an unseen validation dataset, producing a Q2 value of 0.91. Demonstrating this model's broad applicability, we formulate predictions for a host of stimuli, including translations, earth-vertical rotations, and altered gravity, and we provide our implementation for other users. Finally, to guide future research efforts, we suggest how to rigorously advance this model (e.g., incorporating visual cues, active motion, responses to motion of different frequency, etc.).

Factors of significance for the ability of fighter pilots to visually indicate the magnitude of roll tilt during simulated turns in a centrifuge.

During coordinated flight and centrifugation, pilots show interindividual variability in perceived roll tilt. The study explored how this variability is related to perceptual and cognitive functions. Twelve pilots underwent three 6-min centrifugations on two occasions (G levels: 1.1G, 1.8G, and 2.5G; gondola tilts: 25°, 56°, and 66°). The subjective visual horizontal (SVH) was measured with an adjustable luminous line and the pilots gave estimates of experienced G level. Afterward, they were interrogated regarding the relationship between G level and roll tilt and adjusted the line to numerically mentioned angles. Generally, the roll tilt during centrifugation was underestimated, and there was a large interindividual variability. Both knowledge on the relationship between G level and bank angle, and ability to adjust the line according to given angles contributed to the prediction of SVH in a multiple regression model. However, in most cases, SVH was substantial smaller than predictions based on specific abilities.

Attentional Tunneling in Pilots During a Visual Tracking Task With a Head Mounted Display.

OBJECTIVE: We examined whether active head aiming with a Helmet Mounted Display (HMD) can draw the pilot's attention away from a primary flight task. Furthermore, we examined whether visual clutter increases this effect. BACKGROUND: Head up display symbology can result in attentional tunneling, and clutter makes it difficult to identify objects. METHOD: Eighteen military pilots had to simultaneously perform an attitude control task while flying in clouds and a head aiming task in a fixed-base flight simulator. The former consisted of manual compensation for roll disturbances of the aircraft, while the latter consisted of keeping a moving visual target inside a small or large head-referenced circle. A "no head aiming" condition served as a baseline. Furthermore, all conditions were performed with or without visual clutter. RESULTS: Head aiming led to deterioration of the attitude control task performance and an increase of the amount of roll-reversal errors (RREs). This was even the case when head aiming required minimal effort. Head aiming accuracy was significantly lower when the roll disturbances in the attitude control task were large compared to when they were small. Visual clutter had no effect on both tasks. CONCLUSION: We suggest that active head aiming of HMD symbology can cause attentional tunneling, as expressed by an increased number of RREs and less accuracy on a simultaneously performed attitude control task. APPLICATION: This study improves our understanding in the perceptual and cognitive effects of (military) HMDs, and has implications for operational use and possibly (re)design of HMDs.

A computational model of motion sickness dynamics during passive self-motion in the dark.

Predicting the time course of motion sickness symptoms enables the evaluation of provocative stimuli and the development of countermeasures for reducing symptom severity. In pursuit of this goal, we present an observer-driven model of motion sickness for passive motions in the dark. Constructed in two stages, this model predicts motion sickness symptoms by bridging sensory conflict (i.e., differences between actual and expected sensory signals) arising from the observer model of spatial orientation perception (stage 1) to Oman's model of motion sickness symptom dynamics (stage 2; presented in 1982 and 1990) through a proposed "Normalized innovation squared" statistic. The model outputs the expected temporal development of human motion sickness symptom magnitudes (mapped to the Misery Scale) at a population level, due to arbitrary, 6-degree-of-freedom, self-motion stimuli. We trained model parameters using individual subject responses collected during fore-aft translations and off-vertical axis of rotation motions. Improving on prior efforts, we only used datasets with experimental conditions congruent with the perceptual stage (i.e., adequately provided passive motions without visual cues) to inform the model. We assessed model performance by predicting an unseen validation dataset, producing a Q2 value of 0.86. Demonstrating this model's broad applicability, we formulate predictions for a host of stimuli, including translations, earth-vertical rotations, and altered gravity, and we provide our implementation for other users. Finally, to guide future research efforts, we suggest how to rigorously advance this model (e.g., incorporating visual cues, active motion, responses to motion of different frequency, etc.).

At Crossroads in a Virtual City: Effect of Spatial Disorientation on Gait Variability and Psychophysiological Response among Healthy Older Adults.

INTRODUCTION: Aging has been associated with a decline in cognitive and motor performance, often expressed in multitasking situations, which could include wayfinding. A major challenge to successful wayfinding is spatial disorientation, occurring mostly at crossings. Although gait changes have been observed in various dual-task conditions, little is known about the effect of disorientation on gait and psychophysiological response among older adults during wayfinding. The study aimed at identifying the effect of spatial disorientation on gait variability and psychophysiological response among healthy older adults during wayfinding in a controlled environment. METHOD: We analyzed data of 28 participants (age 70.8 ± 4.6, 18 female), 14 experimental and 14 controls. Participants performed a wayfinding task consisting of 14 major decision points (7 intersections) within a virtual environment (VE) projected on a 180° screen while walking on a self-paced treadmill equipped with a marker-based optical motion-capture system. The VE was held constant for the controls and manipulated for the experimental participants. Disorientation was identified based on a customized annotation scheme. Variability in gait, including the coefficient of variation (CV), was measured as the primary endpoint. Psychophysiological response measures, including heart rate variability (RMSSD) and skin conductance response (SCR), were continuously monitored as secondary endpoints and estimates of cognitive effort. Linear Mixed Effects models were applied to hypothesis-driven outcome measures extracted from decision points. RESULTS: Walking speed and step length decreased when disoriented (p < 0.05), while stride time, stance time, walking speed CV, stance time CV, SCR amplitude, and SCR count increased when disoriented (p < 0.05). A higher RMSSD was associated with being disoriented at crossings (p < 0.05). SCR count was greater in the older experimental group (p < 0.001), including when disoriented (p < 0.001). DISCUSSION/CONCLUSION: The results provide evidence for the impact of spatial disorientation on changes in gait pattern and psychophysiological response among older adults during wayfinding. Location also had implications for the effect of disorientation on gait and cognitive effort. This gives further insight into the substrates of real-world navigation challenges among older adults, with an emphasis on viable features for designing situation-adaptive interventional devices aiding independent mobility.

Galvanic vestibular stimulation to counteract leans illusion: comparing step and ramped waveforms.

Leans is a common type of Spatial Disorientation (SD) illusion that causes pilots to be confused about the position of the aircraft during a flight. This illusion could lead to serious adverse effects and even flight mishaps. Therefore, an effective means to deal with leans is crucial for flight safety. This study aims to investigate the effects of Galvanic Vestibular Stimulation (GVS) technology with different waveforms as a tool to mitigate the negative effects of leans. 20 Air Force pilots participated in leans-induced flight simulation experiment with three GVS conditions (without-GVS, step-GVS, ramped-GVS). Bank angle error, subjective SD, perceived strength, and annoyance were measured as the dependent variables. Analysis revealed that step-GVS and ramped-GVS yielded lower bank angle errors and subjective SD than without-GVS. In addition, annoyance ratings were lower for ramped-GVS than step-GVS. This study suggests that GVS has the potential to be utilised as a counteracting tool to cope with leans.Practitioner summary: Galvanic Vestibular Stimulation (GVS) can be utilised as a tool to counteract the detrimental effects of leans illusion, specifically the ramped style GVS, considering that it is less annoying and distracting for the pilots. In general, GVS induces a roll sensation that can offset the false sensation caused by the leans, which can potentially help maintain flight safety and avoid spatial disorientation-related accidents.Abbreviations: SD: spatial disorientation; GVS: galvanic vestibular stimulation; MSSQ: motion sickness susceptibility questionniare; SSQ: simulator sickness questionnaire; BLE: bluetooth low energy; PCB: printed circuit board; RPM: revolution per minute.

Induction of spatial anxiety in a virtual navigation environment.

Spatial anxiety (i.e., feelings of apprehension and fear about navigating everyday environments) can adversely impact people's ability to reach desired locations and explore unfamiliar places. Prior research has either assessed spatial anxiety as an individual-difference variable or measured it as an outcome, but there are currently no experimental inductions to investigate its causal effects. To address this lacuna, we developed a novel protocol for inducing spatial anxiety within a virtual environment. Participants first learnt a route using directional arrows. Next, we removed the directional arrows and randomly assigned participants to navigate either the same route (n = 22; control condition) or a variation of this route in which we surreptitiously introduced unfamiliar paths and landmarks (n = 22; spatial-anxiety condition). The manipulation successfully induced transient (i.e., state-level) spatial anxiety and task stress but did not significantly reduce task enjoyment. Our findings lay the foundation for an experimental paradigm that will facilitate future work on the causal effects of spatial anxiety in navigational contexts. The experimental task is freely available via the Open Science Framework ( https://osf.io/uq4v7/ ).

The role of spatial acuity in a dynamic balancing task without gravitational cues.

In earlier studies, blindfolded participants used a joystick to orient themselves to the direction of balance in the horizontal roll plane while in a device programmed to behave like an inverted pendulum. In this spaceflight analog situation, position relevant gravitational cues are absent. Most participants show minimal learning, positional drifting, and failure of path integration. However, individual differences are substantial, some participants show learning and others become progressively worse. In Experiment 1, our goal was to determine whether spatial acuity could explain these individual differences in active balancing. We exposed blindfolded participants to passive movement profiles, with different frequency components, in the vertical and horizontal roll planes. They pressed a joystick trigger to indicate every time they passed the start point. We found greater spatial acuity for higher frequencies but no relation between passive spatial accuracy and active balance control in the horizontal roll plane, suggesting that spatial acuity in the horizontal roll plane does not predict performance in a disorienting spaceflight condition. In Experiment 2, we found significant correlations between passive spatial acuity in the vertical roll plane, where participants have task relevant gravitational cues, and early active balancing in the horizontal roll plane. These correlations appeared after participants underwent brief provocative vestibular stimulation by making a pitch head movement during vertical yaw rotation. Our findings suggest that vestibular stimulation may be a valuable part of assessments of individual differences in performance during initial exposure to disorienting spaceflight conditions where there are no reliable gravity dependent positional cues.

"Split-day syndrome", a patient with frontotemporal dementia who lives two days in the span of one: a case report and review of articles.

Frontotemporal dementia (FTD) is among the most prevalent causes of young-onset dementia  . Along with the frontotemporal and striate atrophy, dopamine dysregulation is also present in FTD. The dopamine system controls mechanisms of time perception. Its depletion can cause miscalculations in the perception of time. We present a 72-year-old man with a unique profile of disorientation in time, such that he split each day into two, 12-h intervals. Although through each 12-h period, he went by his daily activities as if a complete day had passed, e.g., he had two sets of breakfast, lunch, and dinner  , hence the designated "split-day syndrome."

Fat embolism syndrome in a patient with a right undisplaced femoral neck fracture.

Fat embolism syndrome (FES) is a rare condition characterised by the classic triad of respiratory distress, neurologic symptoms and petechial rash. Here, we encountered a case of FES in a patient with an asymptomatic right undisplaced femoral neck fracture (Garden Stage II). FES was diagnosed based on the Gurd and Willson's diagnostic criteria and brain magnetic resonance imaging features. To the best of our knowledge, this is the first case of FES in a patient with an undisplaced femoral neck fracture. This study highlights the importance of considering the possibility of FES even in patients with undisplaced femoral neck fractures.

Congenital lack and extraordinary ability in object and spatial imagery: An investigation on sub-types of aphantasia and hyperphantasia.

Studies that have shown a distinction between object and spatial imagery suggest more than one type of aphantasia and hyperphantasia, yet this has not been systematically investigated in studies on imagery ability extremes. Also, if the involuntary imagery is preserved in aphantasia and how this condition affects other skills is not fully clear. We collected data on spatial and object imagery, retrospective, and prospective memory, face recognition, and sense of direction (SOD), suggesting a distinction between two subtypes of aphantasia/hyperphantasia. Spatial aphantasia is associated with difficulties in visuo-spatial mental imagery and SOD. Instead, in object aphantasia there are difficulties in imaging single items and events - with no mental visualization of objects, out-of-focus, and black-and-white mental images more frequent than expected - in SOD and face recognition. Furthermore, associative involuntary imagery can be spared in aphantasia. The opposite pattern of performance was found in spatial and object hyperphantasia.

Navigation ability in patients with acquired brain injury: A population-wide online study.

The ability to travel independently is a vital part of an autonomous life. It is important to investigate to what degree people with acquired brain injuries (ABI) suffer from navigation impairments. The aim of this study was to investigate the prevalence and characteristics of objective and subjective navigation impairments in the population of ABI patients. A large-scale online navigation study was conducted with 435 ABI patients and 7474 healthy controls. Participants studied a route through a virtual environment and completed 5 navigation tasks that assessed distinct functional components of navigation ability. Subjective navigation abilities were assessed using the Wayfinding questionnaire. Patients were matched to controls using propensity score matching. Overall, performance on objective navigation tasks was significantly lower in the ABI population compared to the healthy controls. The landmark recognition, route continuation and allocentric location knowledge tasks were most vulnerable to brain injury. The prevalence of subjective navigation impairments was higher in the ABI population compared to the healthy controls. In conclusion, a substantial proportion (39.1%) of the ABI population reports navigation impairments. We advocate the evaluation of objective and subjective navigation ability in neuropsychological assessments of ABI patients.

Orientation Comes First: Becoming Aware of Spatial Disorientation Interferes with Cognitive Performance.

BACKGROUND: Previous research has shown that experiencing motion stimuli negatively impacts cognitive performance. OBJECTIVE: In the current study, we investigate whether this impact relates to Type-II spatial disorientation (SD), to motion stimulus magnitude, or to an interaction of these factors. METHOD: Stimuli for participants (n = 23) consisted of Earth-vertical yaw rotations on a rotating chair in a completely darkened room. In the surprise condition, the stimulus started with subthreshold acceleration, followed by suprathreshold deceleration to a non-zero velocity, inducing a sensation of rotation that is opposite to the actual rotation revealed when the lights were switched on. In the no-surprise condition, the same changes in velocity were used, but starting from (almost) zero velocity, which induced a sensation of rotation in the same direction as the actual rotation. Participants performed a self-paced arithmetic task and measurement of their cognitive performance started after the environment was revealed. Stimulus magnitude was operationalized through higher or lower peak suprathreshold deceleration. RESULTS: The results revealed that counting speed decreased significantly when participants were surprised, constituting a large effect size. The proportion of counting errors likewise increased significantly when participants were surprised, but only in the high-magnitude condition. APPLICATION: The findings suggest that surprise caused by the recognition of SD has an involuntary disruptive effect on cognition, which may impact performance of piloting tasks. These results are relevant when modeling motion stimuli effects on performance, and when developing SD awareness training for pilots.

Leans Illusion in Hexapod Simulator Facilitates Erroneous Responses to Artificial Horizon in Airline Pilots.

OBJECTIVE: We tested whether a procedure in a hexapod simulator can cause incorrect assumptions of the bank angle (i.e., the "leans") in airline pilots as well as incorrect interpretations of the attitude indicator (AI). BACKGROUND: The effect of the leans on interpretation errors has previously been demonstrated in nonpilots. In-flight, incorrect assumptions can arise due to misleading roll cues (spatial disorientation). METHOD: Pilots (n = 18) performed 36 runs, in which they were asked to roll to wings level using only the AI. They received roll cues before the AI was shown, which matched with the AI bank angle direction in most runs, but which were toward the opposite direction in a leans-opposite condition (four runs). In a baseline condition (four runs), they received no roll cues. To test whether pilots responded to the AI, the AI sometimes showed wings level following roll cues in a leans-level condition (four runs). RESULTS: Overall, pilots made significantly more errors in the leans-opposite (19.4%) compared to the baseline (6.9%) or leans-level condition (0.0%). There was a pronounced learning effect in the leans-opposite condition, as 38.9% of pilots made an error in the first exposure to this condition. Experience (i.e., flight hours) had no significant effects. CONCLUSION: The leans procedure was effective in inducing AI misinterpretations and control input errors in pilots. APPLICATION: The procedure can be used in spatial disorientation demonstrations. The results underline the importance of unambiguous displays that should be able to quickly correct incorrect assumptions due to spatial disorientation.

How the design and complexity of concept maps influence cognitive learning processes.

Concept maps are assumed to enhance learning as their inherent structure makes relations between information more salient. Nevertheless, research on how to design concept maps as conducive to learning as possible is still rare. In particular, the salience of spatial arrangement of thematically related concepts within the map as well as the complexity of the map were found to be central design elements that influence learning. This study aimed to examine how the structure (i.e., the salience of the spatial relationship between individual concepts) and the complexity (i.e., number of nodes per sub concept) influence learning. Accordingly, a 2 (low vs. high salience of map structure) × 2 (few vs. many nodes) between-subject design was used (N = 122) to examine cognitive processes while learning with a concept map. No significant learning performance differences were found. Concepts maps with a low salience of map structure increased perceptions of disorientation. A serial mediation with learning performances as dependent variable revealed that the salience of the map structure is significantly associated with disorientation and extraneous cognitive load perceptions. By this, current attempts to measure extraneous cognitive load are questioned.

Phenotypes and subphenotypes of delirium: a review of current categorisations and suggestions for progression.

Delirium is a clinical syndrome occurring in heterogeneous patient populations. It affects 45-87% of critical care patients and is often associated with adverse outcomes including acquired dementia, institutionalisation, and death. Despite an exponential increase in delirium research in recent years, the pathophysiological mechanisms resulting in the clinical presentation of delirium are still hypotheses. Efforts have been made to categorise the delirium spectrum into clinically meaningful subgroups (subphenotypes), using psychomotor subtypes such as hypoactive, hyperactive, and mixed, for example, and also inflammatory and non-inflammatory delirium. Delirium remains, however, a constellation of symptoms resulting from a variety of risk factors and precipitants with currently no successful targeted pharmacological treatment. Identifying specific clinical and biological subphenotypes will greatly improve understanding of the relationship between the clinical symptoms and the putative pathways and thus risk factors, precipitants, natural history, and biological mechanism. This will facilitate risk factor mitigation, identification of potential methods for interventional studies, and informed patient and family counselling. Here, we review evidence to date and propose a framework to identify subphenotypes. Endotype identification may be done by clustering symptoms with their biological mechanism, which will facilitate research of targeted treatments. In order to achieve identification of delirium subphenotypes, the following steps must be taken: (1) robust records of symptoms must be kept at a clinical level. (2) Global collaboration must facilitate large, heterogeneous research cohorts. (3) Patients must be clustered for identification, validation, and mapping of subphenotype stability.