DECO: decompose heterogeneous population cohorts for patient stratification and discovery of sample biomarkers using omic data profiling.

MOTIVATION: Patient and sample diversity is one of the main challenges when dealing with clinical cohorts in biomedical genomics studies. During last decade, several methods have been developed to identify biomarkers assigned to specific individuals or subtypes of samples. However, current methods still fail to discover markers in complex scenarios where heterogeneity or hidden phenotypical factors are present. Here, we propose a method to analyze and understand heterogeneous data avoiding classical normalization approaches of reducing or removing variation. RESULTS: DEcomposing heterogeneous Cohorts using Omic data profiling (DECO) is a method to find significant association among biological features (biomarkers) and samples (individuals) analyzing large-scale omic data. The method identifies and categorizes biomarkers of specific phenotypic conditions based on a recurrent differential analysis integrated with a non-symmetrical correspondence analysis. DECO integrates both omic data dispersion and predictor-response relationship from non-symmetrical correspondence analysis in a unique statistic (called h-statistic), allowing the identification of closely related sample categories within complex cohorts. The performance is demonstrated using simulated data and five experimental transcriptomic datasets, and comparing to seven other methods. We show DECO greatly enhances the discovery and subtle identification of biomarkers, making it especially suited for deep and accurate patient stratification. AVAILABILITY AND IMPLEMENTATION: DECO is freely available as an R package (including a practical vignette) at Bioconductor repository (http://bioconductor.org/packages/deco/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Experimental pain measurement in patients with asymptomatic myocardial ischemia.

Men with substantial coronary heart disease determined angiographically and with reproducible myocardial ischemia were studied. During exercise electrocardiography, 22 patients exhibited significant ST segment depression with concomitant angina pectoris (that is, symptomatic myocardial ischemia) and 20 patients demonstrated significant ST segment depression without any symptoms (that is, asymptomatic myocardial ischemia). No significant differences were found between the patient groups in functional variables, coronary angiographic data or coronary risk factors. In contrast, various experimental pain measures (for example, electrical pain threshold, according to Notermans' method, cold pressor test and tourniquet pain test) yielded significant differences between groups. Results indicate that patients with asymptomatic myocardial ischemia demonstrated significantly higher electrical pain thresholds and ischemic pain thresholds, as well as more tolerance to cold and ischemia, so that individual differences in sensibility to pain may partly explain lack of pain in patients with asymptomatic myocardial ischemia.

Reduced pain during baroreceptor stimulation in patients with symptomatic and silent myocardial ischaemia.

OBJECTIVE: Baroreceptor activation has been shown to reduce pain, and the accumulation of such pain reduction has been implicated in the operant learning (under certain circumstances) of hypertension. The current study is an examination of differences in the pain dampening effects of baroreceptor activity in patients with symptomatic and asymptomatic myocardial ischaemia. The objective was to determine whether there are differences between patients with symptomatic and silent myocardial ischaemia with respect to their antinociceptive response to baroreceptor stimulation, and, if so, whether these differences could be related to the absence of angina pectoris pain in patients with silent myocardial ischaemia. METHODS: Sensory detection and electrical pain thresholds were compared in nine symptomatic and 10 asymptomatic patients with replicable myocardial ischaemia during PRES (phase related external suction) carotid baroreceptor manipulation in which the pressure inside a neck cuff was phase locked in time to the R wave of the ECG and negative pressure was applied during either systole or diastole. Tourniquet pain thresholds were also determined. RESULTS: It was found that (1) external baroreceptor manipulation had no effect on detection thresholds; (2) painful stimuli were judged by both symptomatic and asymptomatic patients as less intense when delivered during maximum baroreceptor activity; (3) symptomatic and asymptomatic patients did not differ in their sensory detection thresholds; and (4) asymptomatic patients had significantly higher ischaemic (tourniquet) pain thresholds than symptomatic patients. CONCLUSIONS: The results indicate that baroreceptor activity can modify the intensity of painful stimuli. The degree to which baroreceptor manipulation affects pain does not appear to differ between patients with painful and silent myocardial ischaemia. Thus the baroreceptor dependent pain inhibition effects seems not to be responsible for the higher ischaemic pain threshold found in the silent myocardial ischaemia group.

Development of angina pectoris pain and cardiac events in asymptomatic patients with myocardial ischemia.

A total of 389 patients with angiographically determined coronary artery disease, who exhibited a complete absence of angina pectoris in the presence of reproducible myocardial ischemia, were studied in a follow-up investigation. After an initial coronary angiogram, anti-ischemic medication was prescribed as treatment. After a mean follow-up time of 4.9 years (maximum 13.4 years) patients were sent a questionnaire that assessed any new development of angina pectoris pain and cardiac events. In 48 of these patients a second angiogram was recorded after a mean period of 4.2 years. Asymptomatic patients had a worse prognosis than an age-adjusted normal population. After 5 and 10 years, 9 and 26% of the patients, respectively, had died, nonfatal cardiac events (myocardial infarction, bypass surgery or percutaneous transluminal coronary angioplasty) occurred after 5 and 10 years in 19 and 46%, respectively. A large number of initially asymptomatic patients developed angina pectoris pain over the follow-up period (34% after 5 years, 58% after 10 years). Novel angina pectoris pain often preceded cardiac events by months to years. Multivariate analysis indicated that vessel disease (p = 0.0001) and degree of ischemia (defined by ST-segment depression free exercise tolerance, p = 0.04) proved to have independent predictive value with respect to mortality rate. Newly developed angina pectoris was associated with an increase in objective signs of myocardial ischemia and a progression in coronary stenosis. The results indicate that patients who originally had myocardial ischemia with a marked absence of pain can develop angina pectoris over the course of years and that newly developed pain often precedes cardiac events.

Verbal memory after three months of intranasal vasopressin in healthy old humans.

In animals, evidence has been accumulated that vasopressin (VP) improves learning and memory. In humans, this effect was not consistently demonstrated, and attempts to restore age-related memory deficits by VP also remained inconsistent. Assuming that in old subjects a beneficial effect on memory occurs only after prolonged treatment with VP, we conducted a study in 26 healthy elderly persons receiving 40 IU of VP for three months through the intranasal route. The trial was randomized, placebo-controlled and held double-blind. Memory was assessed by the Auditory Verbal Learning Test (AVLT) requiring the subject to learn repeatedly presented lists of 15 words. Results demonstrated no general effect of long-term treatment with VP on memory in aged humans. However, recall of an interfering word list was improved, indicating a diminished proactive interference by the peptide. Additionally, VP influenced recall depending on the serial position of an item: it improved the primacy effect (i.e. recall of the first words of a list) and impaired the recency effect. This result may indicate an improved semantic encoding (i.e. a primary effect on processes of attention) after long-term administration of VP.

Ambulatory electrocardiography evaluation of the post-coronary artery bypass graft and post-percutaneous transluminal coronary angioplasty patient. Diagnostic and prognostic value.

Investigations carried out in recent years have shown that patients with coronary heart disease display partial to considerable extent transient ST-segment changes that can be determined with ambulatory ECG. An interesting question is how often transient ST-segment changes are present in patients in whom the indication for an aortocoronary bypass operation or percutaneous transluminal coronary angioplasty (PTCA) has already been determined. In the patients who are waiting for a bypass operation or PTCA, the proof of myocardial ischemia has been determined, and which subgroups of patients display ST changes in the ambulatory ECG must be tested. It is interesting to ask what happens to such transient ischemic episodes as a result of surgical or catheter intervention, how often such episodes are present even after these interventions, and whether the latter has a clinical significance in view of the success of the intervention (graft patency in coronary artery bypass graft patients or reocclusion in PTCA patients). Furthermore, it is to be tested whether transient ST-segment changes take on a prognostic significance in the long-term follow-up after bypass operation or PTCA.

Experimental pain thresholds and plasma beta-endorphin levels during exercise.

Experimental pain thresholds (electrical intracutaneous finger and dental pulp stimulation) and plasma hormone levels (beta-endorphin, cortisol, and catecholamines) were measured in ten healthy sportive men before, during, and after progressively more strenuous physical exercise. In a double-blind study conducted on two different days, 20 mg of the opioid-antagonist naloxone or placebo was administered prior to exercise. A significant pain threshold elevation was found during exercise for finger (ANOVA, P less than 0.004) and dental pulp stimulation (P less than 0.01). Pain threshold elevation was most pronounced during maximal exertion, at which time the subjects reported the greatest subjective fatigue. Thresholds remained elevated 10-15 min after the end of exercise, and, 60 min after exercise, thresholds returned to baseline values. The subjective magnitude estimation of suprathreshold stimuli was significantly reduced (P less than 0.0001) 5-10 min after exercise. Plasma beta-endorphin, cortisol, and catecholamines increased significantly (P less than 0.0005, all values) during exercise. Plasma beta-endorphin levels did not correlate significantly with pain thresholds (r = -0.37, NS). Naloxone failed to affect pain thresholds, although beta-endorphin and cortisol increased significantly more (P less than 0.02) during exercise after naloxone. It is concluded that short-term, exhaustive physical exercise can evoke a transient elevation in pain thresholds. This exercise-induced elevation in pain threshold does not, however, appear to be directly related to plasma endorphin levels.

Baroreceptor stimulation: pain perception and sensory thresholds.

Baroreceptor activity has been implicated in the modulation of pain. Sensory detection thresholds and pain ratings were measured in a group of 28 men during carotid baroreceptor manipulation with the PRES (phase-related external suction) neck suction technique. Brief, cardiac phase-related electrical impulses were delivered intracutaneously to the finger. The results indicate that minimum baroreceptor activity was associated with more severe pain, but had no effect on sensory detection threshold. The results are discussed in terms of the learned model of hypertension.

Symptomatic myocardial ischemia and everyday life: implications for clinical use of interactive monitoring.

In coronary heart disease (CHD), pathological myocardial ischemic changes do not always occur with the symptom of heart pain. Methodological problems make it difficult to examine the factors that influence silent and symptomatic myocardial ischemia in everyday life. This study uses a computer-assisted monitoring system with an interactive Holter ECG, an actometer, and an electronic diary. Self-report measurements indicate that symptomatic patients tend toward increased neuroticism, whereas asymptomatic patients engage in beneficial and active coping skills more frequently. The results of the monitoring study demonstrate the same degree of ischemia in silent and symptomatic episodes. However, these episodes show differences in certain psychological context variables. Symptomatic episodes are linked to high subjective strain and severe tension. Because angina pectoris is not a reliable warning signal of myocardial ischemia, the use of the interactive monitoring system is recommended for educating CHD patients on how to cope with excessive strain in everyday life.

Transient hypoalgesia under physical exercise--relation to silent ischaemia and implications for cardiac rehabilitation.

A series of studies with humans as well as experiments carried out on animals could show that physical exercise leads to temporary hypoalgesia. Reduced sensitivity to pain is not only demonstrable after long-distance exercise (such as marathon run) but also after intensive physical exercise on a laboratory ergometer. Pain threshold elevation is most pronounced during maximal exertion, but hypoalgesia remains present also after exercise is stopped demonstrating that a systemic analgetic effect is induced by the exercise process. Pre-exercise pain threshold level is returned to approximately 60 minutes after the exercise. The cause of the exercise-induced hypoalgesia is probably an activation of central pain inhibitory mechanisms by the "stimulus" of physical exercise (stimulation- or stress-induced analgesia). Central pain inhibitory systems are thereby triggered by the stimulation of afferent nerve endings (group III and IV) in the skeletal muscle. The same trigger mechanism also plays a role as a release stimulus for hormones such for beta-endorphin which is increased under physical exercise. Plasma-beta-endorphin is probably not directly involved in the exercise-induced hypoalgesia but is rather a "marker" for the activating of central analgesia mechanisms. Stress-induced hypoalgesia plays also a role in the coronary heart disease. The activation of endogenous analgetic mechanisms leads to a part of the myocardial ischaemia provoked by exercise being silent under exercise. Completely asymptomatic myocardial ischaemia patients display a generalized hypoalgesia which is demonstrable independent of an exertion stimulus and which indicates a central set-point change in the antinociceptive system.

[Physical exercise, endogenous opiates and pain regulation.]. / Körperliche Belastung, endogene Opiate und Schmerz.

A series of studies with humans as well as experiments carried out on animals have shown that physical exercise leads to temporary hypoalgesia. Reduced sensitivity to pain is not only demonstrable after long-distance exercise (such as a marathon run) but also during and after intensive physical exercise on a laboratory ergometer. In a double blind study (20 mg naloxone versus placebo) experimental pain thresholds (electrical intracutaneous finger and dental pulp stimulation) and plasma hormone levels (beta-endorphin, cortisol, and catecholamines) were measured in ten healthy athletic men before, during, and after physical exercise on a cycle ergometer. A significant pain threshold elevation during exercise was found for finger (Anova,p<0.004) and dental pulp stimulation (p<0.01). Hypoalgesia remained present after exercise was stopped and the initial pain threshold level was returned to approximately 60 minutes after the exercise. The subjective magnitude estimation of suprathreshold stimuli was significantly reduced (p<0.001) after exercise. Naloxone failed to affect pain thresholds and plasma beta-endorphin did not correlate significantly with pain thresholds. The cause of the exercise-induced hypoalgesia is probably an activation of central pain inhibitory mechanisms by the "stimulus" of physical exercise (stimulation-induced analgesia). Central pain inhibitory systems are probably thereby activated by the stimulation of afferent nerves endings (group III and IV) in the skeletal muscle. The same trigger mechanism also plays a role as a release stimulus for hormones which are secreted in increased measure during physical exercise (catecholamines, pituitary hormones). Plasma beta-endorphin is probably not directly involved in the exercise-induced hypoalgesia but is rather a "marker" for the activating of central analgesia mechanisms.

[Pain perception and peripheral pain localization in angina pectoris]. / Schmerzperzeption und periphere Schmerzlokalisation bei Angina pectoris.

Cardiac nociceptive afferences are mainly transmitted by sympathetic nervous tracts. After passing the ganglion stellatum and neighbouring ganglia, the nerves enter the dorsal horn of the spinal cord at C8-Th9 (especially Th2-Th6). Here the nerve synapses for the first time, mainly to neurons which run up to the thalamus contralaterally by the tractus spinothalamicus. Apart from atypically localised pain (jaw, head, neck), the nervus vagus is rarely involved in transmitting angina pectoris pain. There is no close relation between peripheral pain localisation and localisation of coronary stenosis or myocardial ischemia areas. The localisation of angina pectoris is decided by viscero-somatic summation (convergence-projection-theory). Almost all the ascending tracts of the tractus spinothalamicus with visceral inflow also receive inflow from somatic afferences, from skin areas of the dermatome from the same segment level, and especially from deep somatic structures such as muscle and ligaments (Head's zones). Additional reflex mechanisms, where the efferent part is probably sympathetic, explain transferred effects in the matching dermatome such as hypothermic skin zones, cutaneous hyperalgesia, higher pressure sensitivity of the muscles and occasionally even dystrophic changes. The amount of spinal visceral afferences is relatively small (only 1.5-2.5% of all somatic spinal afferences). The low amount, the pronounced divergence and, compared to converging somatic afferences, the larger receptive fields in the organ explain the diffuse, barely localisable character of angina pectoris pain. Cardiac afferences are tonically and phasically inhibited at spinal and supraspinal levels, especially by descending tracts. This explains why angina pectoris can be missing in spite of pronounced peripheral nociceptive impulse rates. Patients with silent myocardial ischemia have a higher central pain threshold than patients with symptomatic myocardial ischemia. Endogenous opioids are involved in the body's own analgesia system. The beta-endorphin level in the serum rises significantly in many patients during exercise diagnostic tests. Patients with silent myocardial ischemia have higher beta-endorphin levels compared to symptomatic patients at the same exercise level. This can be interpreted as expressing quantitative differences in a superior pain regulation system. Myocardial ischemia is experienced as angina pectoris pain when the peripheral nociceptive impulse rate is so pronounced that the prevailing inhibitory pain threshold can be overcome and when the pain pathways are intact.

[Pathophysiology of painful and silent myocardial ischemia]. / Pathophysiologie schmerzhafter und stummer Myokardischämie.

Regardless of the factor assumed responsible for precipitation of myocardial ischemia - varying from coronary occlusion in acute myocardial infarction to increased oxygen demand in exertional angina pectoris and reduced myocardial oxygen supply due to plaque rupture or changes in vasomotor tone in unstable angina - its incurrence may or may not be associated with pain. In the vast majority of cases, silent myocardial ischemia is observed in patients with established symptomatic coronary artery disease. Interindividual comparisons have not enabled reliable differentiation between those with painful and those with silent ischemia based on the anatomic extent of coronary artery disease, left ventricular function or previous myocardial infarction. Similarly, functional parameters such as exercise capacity, exercise duration, time to onset of ST-segment depression during exercise as well as heart rate and blood pressure both at rest and during exercise have failed to reveal differences between the symptomatic and the asymptomatic patients. Intraindividual differences have also been noted, but not consistently corroborated, and postulated as responsible for the fact that ischemia in a given patient alternates in its presence with and without pain. Since most patients with silent ischemia either have, or at some time in the past have experienced, painful ischemia, the integrity of the appropriate nervous system function can be assumed to be intact and neurocardiologic factors seem most likely to account for apparent discrepancies in pain perception. Prior to precipitation of pain, myocardial ischemia must elicit an adequate stimulus. According to some investigators, the adequate stimulus is that associated with a duration of the ischemic episode of at least three minutes and with increase in left ventricular filling pressure of more than 7 mm Hg. This threshold, consequently, represents a prerequisite but not invariably sufficient criteria for the occurrence of pain. The next step in the sequence of pain is generation of an action potential, that is, transduction by means of chemical or mechanical stimuli. During this process, a latency of 20 to 40 seconds is incurred such that the appearance of pain usually has its onset after derangement of relaxation and contraction, increased filling pressure and the observation of ECG changes. Through conduction, the information is forwarded to the central nervous system after coding of the details with regard to intensity. The intensity, in turn, is determined by the number of receptors (free nerve endings) in the field activated by the ischemic event.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of opiate systems in pain transmission during angina pectoris.

The situation of absent pain with silent myocardial ischemia is highly difficult to define. There are probably several reasons for the lack of pain. Partly, nerve ways may be destroyed, partly, myocardial ischemia as peripheral pain stimulus may be to weak and beyond threshold, however, additionally, there are a lot of clues for the participation of endogenous pain modification systems therein. A certain amount of myocardial ischemia is a necessary, but not sufficient precondition for anginal pain. Myocardial ischemia is only felt painfully if the peripheral nociceptive impulse rate is high enough to pass the actual inhibitory pain threshold, and if the nerve ways are intact. It is generally accepted that the endogenous opiate system, to some extent, takes part in the endogenous analgesia system. A range of examinations in recent years hinted at the fact that endorphins are in relation to the absence of pain in silent ischemia. Patients with symptomatic and asymptomatic myocardial ischemia are significantly different in plasma beta-endorphin levels at rest and during physical exercise. A relation between peripheral endogenous opiates and suffering behavior can, at present, only be indicated correlatively. It is likely that the intensive overlaying of the cardiovascular and pain regulating systems is related to the absence of pain in silent myocardial ischemia.

Psychophysiological mechanisms in silent myocardial ischaemia.

Six levels of coronary pain are defined and for each of them explanations for absence of pain in asymptomatic myocardial ischaemia are given: Level I: Myocardial ischaemia which can be less pronounced in amount during asymptomatic episodes. Level II: Adequate stimulus (chemical, mechanical) where biosynthesis of algogesic substances, degree of local mechanical involvement and spatial distribution may be different. Level III: For neuronal encoding the intensity theory is mainly for coronary pain, presupposing a central pain threshold which is higher in asymptomatic patients. Level IV: Conduction of painful information may be interrupted by destruction of afferent nerve ways. Level V: Spinal transmission: resting tone and ability to activate neural and humoral (endorphinergic) pain inhibition systems are stronger in asymptomatic patients. Level VI: Central processing: cognitive mechanisms (coping style) affect perception of coronary pain with differences in symptomatic and silent myocardial ischaemia.

Silent myocardial ischemia.

Myocardial ischemia can manifest itself as strictly silent or a combination of symptomatic and silent episodes. We have demonstrated that most asymptomatic patients have a higher threshold for pain than did symptomatic patients. Low sensitivity to pain in patients with silent ischemia may be related to both a neural pain inhibitory system and the release of endogenous opiates, the endorphins. beta-Endorphin release occurs during and after exercise; patients with asymptomatic ischemia had higher plasma beta-endorphin levels than did patients with symptomatic ischemia, especially during exercise. With naloxone treatment, the pain threshold of patients with silent myocardial ischemia (SMI) can be reduced to the same values as those of symptomatic patients. This supports the possibility of a role for endorphins in SMI. Patients who experience both asymptomatic and symptomatic ischemic episodes do so because their pain threshold and endorphin regulatory system varies throughout the day and because severity and duration of ischemic episodes are different. Although there is controversy over the appropriate therapy for SMI, it is more likely that this should simply be treated in the same way as painful ischemia.