Using virtual reality to investigate psychological processes and mechanisms associated with the onset and maintenance of psychosis: a systematic review.

PURPOSE: In the last decade researchers have embraced virtual reality to explore the psychological processes and mechanisms that are involved in the onset and maintenance of psychosis. A systematic review was conducted to synthesise the evidence of using virtual reality to investigate these mechanisms. METHODS: Web of Science, PsycINFO, Embase, and Medline were searched. Reference lists of collected papers were also visually inspected to locate any relevant cited journal articles. In total 6001 articles were potentially eligible for inclusion; of these, 16 studies were included in the review. RESULTS: The review identified studies investigating the effect of interpersonal sensitivity, childhood bullying victimisation, physical assault, perceived ethnic discrimination, social defeat, population density and ethnic density on the real-time appraisal of VR social situations. Further studies demonstrated the potential of VR to investigate paranoid ideation, anomalous experiences, self-confidence, self-comparison, physiological activation and behavioural response. CONCLUSIONS: The reviewed studies suggest that VR can be used to investigate psychological processes and mechanisms associated with psychosis. Implications for further experimental research, as well as for assessment and clinical practise are discussed. The present review has been registered in the PROSPERO register: CRD42016038085.

Duration of untreated psychosis and need for admission in patients who engage with mental health services in the prodromal phase.

BACKGROUND: It is unknown whether prodromal services improve outcomes in those who go on to develop psychosis, and whether these patients are demographically different from the overall first-episode population. AIMS: To compare sociodemographic features, duration of untreated psychosis, hospital admission and frequency of compulsory treatment in the first year after the onset of psychosis in patients who present to prodromal services with patients who did not present to services until the first episode of psychosis. METHOD: We compared two groups of patients with first-episode psychosis: one who made transition after presenting in the prodromal phase and the other who had presented with a first episode. RESULTS: The patients who had presented before the first episode were more likely to be employed and less likely to belong to an ethnic minority group. They had a shorter duration of untreated psychosis, and were less likely to have been admitted to hospital and to have required compulsory treatment. CONCLUSIONS: Patients who develop psychosis after being engaged in the prodromal phase have a better short-term clinical outcome than patients who do not present until the first episode. Patients who present during first episodes may be more likely to have sociodemographic features associated with relatively poor outcomes.

Key demographics and psychological skills associated with adjustment to progressive Multiple Sclerosis early in the diagnosis.

Background/purpose: Being diagnosed with a progressive type of multiple sclerosis (MS) has been associated with worse psychological outcomes compared to relapsing-remitting type. Previous studies of adjustment to MS have primarily focused on relapsing-remitting type MS. The present study aims to examine psychological adjustment for people newly diagnosed with progressive multiple sclerosis. Methods: This was a multicenter cross-sectional survey of 189 people newly diagnosed with progressive MS. A composite measure of psychological adjustment was created from questionnaires measuring psychological distress, positive affect, perceived-stress, life satisfaction and self-concept. Predictor variables included coping strategies, social support, relationship with partner, psychological vulnerability, MS-related beliefs, and responses to symptoms. Data were analysed using a regularised regression model to indicate which group of all variables are associated with adjustment. Results: People who were older (b = 0.17(0.07), p = 0.02), in employment (b = 0.40 (0.17), p = 0.01), and with lower illness severity (b = -0.24 (0.08), p = 0.001) showed better adjustment. Based on a Lasso regression, the most important psychological and demographic variables associated with lower adjustment (out-of-sample cross-validation R 2 = 62.6%) were lower MS self-efficacy and higher avoidance, cognitive vulnerability, embarrassment avoidance, conflict, helplessness, and secondary progressive MS type. Conclusions and implications: Helping newly diagnosed people to find ways to tolerate anxiety-causing situations by encouraging acceptance may help people adjust to progressive MS by lowering their avoidance. Further, building confidence in managing the illness and addressing relationship issues are key focus areas in psychological interventions for people with progressive multiple sclerosis.

Lower speech connectedness linked to incidence of psychosis in people at clinical high risk.

BACKGROUND: Formal thought disorder is a cardinal feature of psychotic disorders, and is also evident in subtle forms before psychosis onset in individuals at clinical high-risk for psychosis (CHR-P). Assessing speech output or assessing expressive language with speech as the medium at this stage may be particularly useful in predicting later transition to psychosis. METHOD: Speech samples were acquired through administration of the Thought and Language Index (TLI) in 24 CHR-P participants, 16 people with first-episode psychosis (FEP) and 13 healthy controls. The CHR-P individuals were then followed clinically for a mean of 7 years (s.d. = 1.5) to determine if they transitioned to psychosis. Non-semantic speech graph analysis was used to assess the connectedness of transcribed speech in all groups. RESULTS: Speech was significantly more disconnected in the FEP group than in both healthy controls (p < .01) and the CHR-P group (p < .05). Results remained significant when IQ was included as a covariate. Significant correlations were found between speech connectedness measures and scores on the TLI, a manual assessment of formal thought disorder. In the CHR-P group, lower scores on two measures of speech connectedness were associated with subsequent transition to psychosis (8 transitions, 16 non-transitions; p < .05). CONCLUSION: These findings support the utility and validity of speech graph analysis methods in characterizing speech connectedness in the early phases of psychosis. This approach has the potential to be developed into an automated, objective and time-efficient way of stratifying individuals at CHR-P according to level of psychosis risk.

Cingulate activity and fronto-temporal connectivity in people with prodromal signs of psychosis.

Schizophrenia is associated with fronto-temporal dysconnectivity, but it is not clear whether this is a risk factor for the disorder or is a consequence of the established illness. The aim of the present study was to use fMRI to investigate fronto-temporal connectivity in subjects with prodromal signs of schizophrenia using the Hayling Sentence Completion Task (HSCT). Thirty participants, 15 with an at risk mental state (ARMS) and 15 healthy controls were scanned whilst completing 80 sentence stems. The congruency and constraint of sentences varied across trials. Dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to compare alternative models of connectivity in a task related network. During the HSCT ARMS subjects did not differ from Healthy Controls in terms of fronto-temporal activation, i.e. there was neither a main effect of group nor a group-by-task interaction. However, there was both a significant main effect of group and a significant interaction in the anterior cingulate cortex (ACC), with greater ACC activity in the ARMS subjects. A systematic BMS procedure among 14 alternative DCMs including the ACC, middle frontal, and middle temporal gyri revealed intact task-dependent modulation of fronto-temporal effective connectivity in the ARMS group. However, ARMS subjects showed increased endogenous connection strength between the ACC and the middle temporal gyrus relative to healthy controls. Although task related fronto-temporal integration in the ARMS was intact, this may depend on increased engagement of the ACC which was not observed in healthy control subjects.

The relationship between ethnicity and service access, treatment uptake and the incidence of psychosis among people at ultra high risk for psychosis.

Black ethnicity is associated with increased risk for psychosis in South London. This study explored the distribution of ethnicity among services users at ultra high risk for psychosis (UHR) and examined the influence of ethnicity on service access, treatment uptake and incidence of psychosis. The ethnic distribution of 228 people at UHR for psychosis, seen in an early detection clinical service over 10 years, was compared with 146 people with first episode psychosis from the same geographic region and census figures for the local population. Black service users were significantly over-represented in the UHR group compared to the background population (34% vs 21%; p < 0.05); but less so than in the first episode sample (58% vs 19%; p < 0.05). Within the UHR sample, there was no strong evidence of differences between ethnic groups in the types of treatment provided, nor in the rate of transition to psychosis over 2 years. The absence of differences between ethnic groups in rates of transition to psychosis raises the possibility that access to mental health care at the high risk stage might have reduced the influence of ethnicity on the incidence of psychosis in this sample. This would need to be replicated in a larger sample.

Data-Gathering, Belief Flexibility, and Reasoning Across the Psychosis Continuum.

Background: There is evidence for a group of nonclinical individuals with full-blown, persistent psychotic experiences (PEs) but no need-for-care: they are of particular importance in identifying risk and protective factors for clinical psychosis. The aim of this study was to investigate whether reasoning biases are related to PEs or need-for-care. Method: Two groups with persistent PEs (clinical; n = 74; nonclinical; n = 92) and a control group without PEs (n = 83) were compared on jumping-to-conclusions (JTC) and belief flexibility. A randomly selected subset of interviews (n = 104) was analyzed to examine differences in experiential and rational reasoning. Results: As predicted JTC was more common in the clinical than the other 2 groups. Unexpectedly no group differences were observed between clinical and nonclinical groups on measures of belief flexibility. However, the clinical group was less likely to employ rational reasoning, while the nonclinical group was more likely to use experiential reasoning plus a combination of both types of reasoning processes, compared to the other 2 groups. Conclusions: Reasoning biases differ in groups with PEs with and without need-for-care. JTC is associated with need-for-care rather than with PEs. The ability to invoke rational reasoning processes, together with an absence of JTC, may protect against pathological outcomes of persistent PEs. However, marked use of experiential reasoning is associated with the occurrence of PEs in both clinical and nonclinical groups. Implications for theory development, intervention and further research are discussed.

Adjustment modes in the trajectory of progressive multiple sclerosis: a qualitative study and conceptual model.

OBJECTIVE: We examined cognitive and behavioural challenges and adaptations for people with progressive multiple sclerosis (MS) and developed a preliminary conceptual model of changes in adjustment over time. DESIGN: Using theoretical sampling, 34 semi-structured interviews were conducted with people with MS. Participants were between 41 and 77 years of age. Thirteen were diagnosed with primary progressive MS and 21 with secondary progressive MS. Data were analysed using a grounded theory approach. RESULTS: Participants described initially bracketing the illness off and carrying on their usual activities but this became problematic as the condition progressed and they employed different adjustment modes to cope with increased disabilities. Some scaled back their activities to live a more comfortable life, others identified new activities or adapted old ones, whereas at times, people disengaged from the adjustment process altogether and resigned to their condition. Relationships with partners, emotional reactions, environment and perception of the environment influenced adjustment, while people were often flexible and shifted among modes. CONCLUSIONS: Adjusting to a progressive condition is a fluid process. Future interventions can be tailored to address modifiable factors at different stages of the condition and may involve addressing emotional reactions concealing/revealing the condition and perceptions of the environment.

Impact of crime victimization on initial presentation to an early intervention for psychosis service and 18-month outcomes.

AIM: To investigate the clinical and social correlates of a lifetime history of crime victimization among first-episode psychosis patients at entry to an Early Intervention Service and following 18 months of specialist care. METHODS: Face-to-face interviews were conducted with 149 individuals who presented to an Early Intervention Service for the first time with psychosis in the London borough of Lambeth, UK. A range of demographic and clinical measures were completed including self-reported history of victimization along with the type of crime and its subjective effect on the patient. Clinical and functional outcomes at 18-month follow up were ascertained from clinical case notes by a psychiatrist. RESULTS: A large proportion of patients (n = 64, 43%) reported a history of crime victimization. This was associated with significantly higher levels of depression and substance misuse at initial presentation. Being a victim of a crime was not significantly associated with poorer clinical or functional outcomes after 18 months of specialist care. However, non-significant differences were found for those who reported crime victimization in terms of their increased use of illegal substances or having assaulted someone else during the follow-up period. CONCLUSION: Past experience of being a victim of crime appears to be common in patients presenting for the first time with psychosis and is associated with increased likelihood of comorbidity. Thus, Early Intervention Services should consider screening for past victimization and be prepared to deal with comorbid problems. The impact of crime victimization on clinical and functional outcomes requires investigation over a longer period of time.

Formal thought disorder in people at ultra-high risk of psychosis.

BACKGROUND: Formal thought disorder is a cardinal feature of psychosis. However, the extent to which formal thought disorder is evident in ultra-high-risk individuals and whether it is linked to the progression to psychosis remains unclear. AIMS: Examine the severity of formal thought disorder in ultra-high-risk participants and its association with future psychosis. METHOD: The Thought and Language Index (TLI) was used to assess 24 ultra-high-risk participants, 16 people with first-episode psychosis and 13 healthy controls. Ultra-high-risk individuals were followed up for a mean duration of 7 years (s.d.=1.5) to determine the relationship between formal thought disorder at baseline and transition to psychosis. RESULTS: TLI scores were significantly greater in the ultra-high-risk group compared with the healthy control group (effect size (ES)=1.2), but lower than in people with first-episode psychosis (ES=0.8). Total and negative TLI scores were higher in ultra-high-risk individuals who developed psychosis, but this was not significant. Combining negative TLI scores with attenuated psychotic symptoms and basic symptoms predicted transition to psychosis (P=0.04; ES=1.04). CONCLUSIONS: TLI is beneficial in evaluating formal thought disorder in ultra-high-risk participants, and complements existing instruments for the evaluation of psychopathology in this group. DECLARATION OF INTERESTS: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Perceived ethnic discrimination and persecutory paranoia in individuals at ultra-high risk for psychosis.

Despite a consensus that psychosocial adversity plays a role in the onset of psychosis, the nature of this role in relation to persecutory paranoia remains unclear. This study examined the complex relationship between perceived ethnic discrimination and paranoid ideation in individuals at Ultra High Risk (UHR) for psychosis using a virtual reality paradigm to objectively measure paranoia. Data from 64 UHR participants and 43 healthy volunteers were analysed to investigate the relationship between perceived ethnic discrimination and persecutory ideation in a virtual reality environment. Perceived ethnic discrimination was higher in young adults at UHR in comparison to healthy controls. A positive correlation was observed between perceived ethnic discrimination and paranoid persecutory ideation in the whole sample. Perceived ethnic discrimination was not a significant predictor of paranoid persecutory ideation in the VR environment. Elevated levels of perceived ethnic discrimination are present in individuals at UHR and are consistent with current biopsychosocial models in which psychosocial adversity plays a key role in the development of psychosis and attenuated symptomatology.

Adversity in childhood linked to elevated striatal dopamine function in adulthood.

Childhood adversity increases the risk of psychosis in adulthood. Theoretical and animal models suggest that this effect may be mediated by increased striatal dopamine neurotransmission. The primary objective of this study was to examine the relationship between adversity in childhood and striatal dopamine function in early adulthood. Secondary objectives were to compare exposure to childhood adversity and striatal dopamine function in young people at ultra high risk (UHR) of psychosis and healthy volunteers. Sixty-seven young adults, comprising 47 individuals at UHR for psychosis and 20 healthy volunteers were recruited from the same geographic area and were matched for age, gender and substance use. Presynaptic dopamine function in the associative striatum was assessed using 18F-DOPA positron emission tomography. Childhood adversity was assessed using the Childhood Experience of Care and Abuse questionnaire. Within the sample as a whole, both severe physical or sexual abuse (T63=2.92; P=0.005), and unstable family arrangements (T57=2.80; P=0.007) in childhood were associated with elevated dopamine function in the associative striatum in adulthood. Comparison of the UHR and volunteer subgroups revealed similar incidence of childhood adverse experiences, and there was no significant group difference in dopamine function. This study provides evidence that childhood adversity is linked to elevated striatal dopamine function in adulthood.

Social defeat predicts paranoid appraisals in people at high risk for psychosis.

BACKGROUND: The experience of social defeat may increase the risk of developing psychotic symptoms and psychotic disorders. We studied the relationship between social defeat and paranoid appraisal in people at high risk for psychosis in an experimental social environment created using Virtual Reality (VR). METHOD: We recruited UHR (N=64) participants and healthy volunteers (N=43). Regression analysis was used to investigate which baseline measures predicted paranoid appraisals during the VR experience. RESULTS: At baseline, UHR subjects reported significantly higher levels of social defeat than controls (OR=.957, (CI) .941-.973, p<.000). Following exposure to the VR social environment, the UHR group reported significantly more paranoid appraisals than the controls (p<.000). Within the UHR sample, paranoid appraisals were predicted by the level of social defeat at baseline, as well as by the severity of positive psychotic and disorganised symptoms. CONCLUSION: In people who are at high risk of psychosis, a history of social defeat is associated with an increased likelihood of making paranoid appraisals of social interactions. This is consistent with the notion that social defeat increases the risk of developing psychosis.

Blunted cortisol awakening response in people at ultra high risk of developing psychosis.

BACKGROUND: There is a consensus that stress plays a role in the onset of psychosis but the precise underlying mechanism remains unclear. The hypothalamic-pituitary-adrenal (HPA) axis is hypothesised to mediate the relationship between stress and psychosis and evidence indicates a potential role for the stress hormone cortisol as a biomarker of psychosis risk. OBJECTIVE: We explored this hypothesis by examining the HPA axis in people at ultra-high risk (UHR) for psychosis and its relationship to symptoms. METHOD: UHR (n=52) and healthy control (HC; n=42) participants were compared on two measures of HPA axis function: cortisol response to awakening and daytime cortisol release. RESULTS: UHR participants displayed a blunted cortisol awakening response compared with HC participants. No group difference in daytime cortisol levels was found, nor were any associations between cortisol measures and symptoms. CONCLUSIONS: These findings are broadly consistent with previous studies and neurobiological models which propose that stress and the HPA axis are involved in the onset of psychosis, although they raise further questions regarding the precise nature of this involvement.

Abnormal relationship between medial temporal lobe and subcortical dopamine function in people with an ultra high risk for psychosis.

BACKGROUND: Neuroimaging studies in humans have implicated both dysfunction of the medial temporal lobe (MTL) and the dopamine system in psychosis, but the relationship between them is unclear. We addressed this issue by measuring MTL activation and striatal dopaminergic function in individuals with an At Risk Mental State (ARMS) for psychosis, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), respectively. METHODS: Thirty-four subjects (20 ARMS and 14 Controls), matched for age, gender, digit span performance, and premorbid IQ, were scanned using fMRI, while performing a verbal encoding and recognition task, and using 18F-DOPA PET. All participants were naïve to antipsychotic medication. RESULTS: ARMS subjects showed reduced MTL activation when encoding words and made more false alarm responses for Novel words than controls. The relationship between striatal dopamine function and MTL activation during both verbal encoding and verbal recognition was significantly different in ARMS subjects compared with controls. CONCLUSION: An altered relationship between MTL function and dopamine storage/synthesis capacity exists in the ARMS and may be related to psychosis vulnerability.

Reduced mismatch negativity predates the onset of psychosis.

BACKGROUND: Individuals with an "At Risk Mental State" have a 20-30% chance of developing a psychotic disorder within two years; however it is difficult to predict which individuals will become ill on the basis of their clinical symptoms alone. We examined whether mismatch negativity (MMN) could help to identify those who are particularly likely to make a transition to psychosis. METHOD: 41 cases meeting PACE criteria for the At Risk Mental State (ARMS) and 50 controls performed a duration-deviant passive auditory oddball task whilst their electroencephalogram was recorded. The amplitude of the MMN wave was compared between groups using linear regression. The ARMS subjects were then followed for 2 years to determine their clinical outcome. RESULTS: The MMN amplitude was significantly reduced in the ARMS group compared to controls. Of the at-risk subjects who completed followed up (n=41), ten (24% of baseline sample) subsequently developed psychosis. The MMN amplitude in this subgroup was significantly smaller across all three recording sites (FZ, F3 and F4) than in the ARMS individuals who did not become psychotic. CONCLUSION: Among those with the ARMS, MMN amplitude reduction is associated with an increased likelihood of developing frank psychosis.

Altered prefrontal and hippocampal function during verbal encoding and recognition in people with prodromal symptoms of psychosis.

Despite robust evidence of hippocampal abnormalities in schizophrenia, it is unclear whether hippocampal dysfunction predates the onset of psychosis. We used functional magnetic resonance imaging to investigate hippocampal function in subjects with an at-risk mental state (ARMS). Eighteen subjects meeting criteria for an ARMS and 22 healthy controls, matched for age, gender, and premorbid IQ, were scanned while performing a version of the Deese-Roediger-McDermott false memory task. During an encoding phase, subjects read lists of words aloud. Following a delay, they were presented with 24 target words, 24 semantically related lure words, and 24 novel words and required to indicate if each had been presented before. Behaviorally, the ARMS group made more false alarm responses for novel words than controls (P = .04) and had a lower discrimination accuracy for target words (P = .02). During encoding, ARMS subjects showed less activation than healthy controls in the left middle frontal gyrus, the bilateral medial frontal gyri, and the left parahippocampal gyrus. Correct recognition relative to false alarms was associated with differential engagement of the hippocampus bilaterally in healthy controls, but this difference was absent in the ARMS group. The ARMS was associated with altered function in the medial temporal cortex, as well as in the prefrontal regions, during both verbal encoding and recognition. These neurofunctional differences were associated with diminished recognition performance and may reflect the greatly increased risk of psychosis associated with the ARMS.

Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume.

BACKGROUND: The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic changes in schizophrenia. Here we determine whether changes in brain glutamate are present in subjects at ultra high risk of developing psychosis and whether these changes are related to reductions in cortical gray matter volume. METHODS: Twenty-seven individuals with an at-risk mental state and a group of 27 healthy volunteers underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance imaging using a 3-Tesla scanner. Glutamate and glutamine levels were measured in anterior cingulate, left hippocampus, and left thalamus. These measures were then related to cortical gray matter volume. RESULTS: At-risk mental state (ARMS) subjects had significantly lower levels of glutamate than control subjects in the thalamus (p < .05) but higher glutamine in the anterior cingulate (p < .05). Within the ARMS group, the level of thalamic glutamate was directly correlated with gray matter volume in the medial temporal cortex and insula (p < .01). CONCLUSIONS: This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder. These findings support the hypothesis that drugs affecting the glutamate system may be of benefit in the early stages of psychotic illness.

Fronto-temporal interactions during overt verbal initiation and suppression.

The Hayling Sentence Completion Task (HSCT) is known to activate left hemisphere frontal and temporal language regions. However, the effective connectivity between frontal and temporal language regions associated with the task has yet to be examined. The aims of the study were to examine activation and effective connectivity during the HSCT using a functional magnetic resonance imaging (fMRI) paradigm in which participants made overt verbal responses. We predicted that producing an incongruent response (response suppression), compared to a congruent one (response initiation), would be associated with greater activation in the left prefrontal cortex and an increase in the effective connectivity between temporal and frontal regions. Fifteen participants were scanned while completing 80 sentence stems. The congruency and constraint of sentences varied across trials. Dynamic Causal Modeling (DCM) and Bayesian Model Selection (BMS) were used to compare a set of alternative DCMs of fronto-temporal connectivity. The HSCT activated regions in the left temporal and prefrontal cortices, and the cuneus. Response suppression was associated with greater activation in the left middle and orbital frontal gyri and the bilateral precuneus than response initiation. Left middle temporal and frontal regions identified by the conventional fMRI analyses were entered into the DCM analysis. Using a systematic BMS procedure, the optimal DCM showed that the connection from the left middle temporal gyrus, which was driven by verbal stimuli per se, was significantly increased in strength during response suppression compared to initiation. Greater effective connectivity between left temporal and prefrontal regions during response suppression may reflect the transfer of information from posterior temporal regions where semantic and lexical information is stored to prefrontal regions where it is manipulated in preparation for an appropriate response.

Abnormal P300 in people with high risk of developing psychosis.

BACKGROUND: Individuals with an "at-risk mental state" (or "prodromal" symptoms) have a 20-40% chance of developing psychosis; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether neurophysiological markers could help to identify those who are particularly vulnerable. METHOD: 35 cases meeting PACE criteria for the at-risk mental state (ARMS) and 57 controls performed an auditory oddball task whilst their electroencephalogram was recorded. The latency and amplitude of the P300 and N100 waves were compared between groups using linear regression. RESULTS: The P300 amplitude was significantly reduced in the ARMS group [8.6+/-6.4 microvolt] compared to controls [12.7+/-5.8 microvolt] (p<0.01). There were no group differences in P300 latency or in the amplitude and latency of the N100. Of the at-risk subjects that were followed up, seven (21%) developed psychosis. CONCLUSION: Reduction in the amplitude of the P300 is associated with an increased vulnerability to psychosis. Neurophysiological and other biological markers may be of use to predict clinical outcomes in populations at high risk.