Metabolomic networks in plants: Transitions from pattern recognition to biological interpretation.

Nowadays techniques for non-targeted metabolite profiling allow for the generation of huge amounts of relevant data essential for the construction of dynamic metabolomic networks. Thus, metabolomics, besides transcriptomics or proteomics, provides a major tool for the characterization of postgenomic processes. In this work, we introduce comparative correlation analysis as a complementary approach to characterize the physiological states of various organs of diverse plant species with focus on specific participation of metabolites in different reaction networks. The correlations observed are induced by diminutive fluctuations in environmental conditions, which propagate through the system and induce specific patterns depending on the genomic background. In order to examine this hypothesis, numeric examples of such fluctuations are computed and compared with experimentally obtained metabolite data.

Interpreting correlations in metabolomic networks.

Correlations, as observed between the concentrations of metabolites in a biological sample, may be used to gain additional information about the physiological state of a given tissue. In this mini-review, we discuss the integration of these observed correlations into metabolomic networks and their relationships with the underlying biochemical pathways.

Observing and interpreting correlations in metabolomic networks.

MOTIVATION: Metabolite profiling aims at an unbiased identification and quantification of all the metabolites present in a biological sample. Based on their pair-wise correlations, the data obtained from metabolomic experiments are organized into metabolic correlation networks and the key challenge is to deduce unknown pathways based on the observed correlations. However, the data generated is fundamentally different from traditional biological measurements and thus the analysis is often restricted to rather pragmatic approaches, such as data mining tools, to discriminate between different metabolic phenotypes. METHODS AND RESULTS: We investigate to what extent the data generated networks reflect the structure of the underlying biochemical pathways. The purpose of this work is 2-fold: Based on the theory of stochastic systems, we first introduce a framework which shows that the emergent correlations can be interpreted as a 'fingerprint' of the underlying biophysical system. This result leads to a systematic relationship between observed correlation networks and the underlying biochemical pathways. In a second step, we investigate to what extent our result is applicable to the problem of reverse engineering, i.e. to recover the underlying enzymatic reaction network from data. The implications of our findings for other bioinformatics approaches are discussed.

The mutual information: detecting and evaluating dependencies between variables.

MOTIVATION: Clustering co-expressed genes usually requires the definition of 'distance' or 'similarity' between measured datasets, the most common choices being Pearson correlation or Euclidean distance. With the size of available datasets steadily increasing, it has become feasible to consider other, more general, definitions as well. One alternative, based on information theory, is the mutual information, providing a general measure of dependencies between variables. While the use of mutual information in cluster analysis and visualization of large-scale gene expression data has been suggested previously, the earlier studies did not focus on comparing different algorithms to estimate the mutual information from finite data. RESULTS: Here we describe and review several approaches to estimate the mutual information from finite datasets. Our findings show that the algorithms used so far may be quite substantially improved upon. In particular when dealing with small datasets, finite sample effects and other sources of potentially misleading results have to be taken into account.

Entropy and local uncertainty of data from sensory neurons.

We present an empirical comparison between neural interspike interval sequences obtained from two different kinds of sensory receptors. Both differ in their internal structure as well as in the strength of correlations and the degree of predictability found in the respective spike trains. As a further tool in this context, we suggest the local uncertainty, assigning a well-defined predictability to individual spikes. The local uncertainty is demonstrated to reveal significant patterns within the interspike interval sequences, even when its overall structure is (almost) random. Our approach is based on the concept of symbolic dynamics and information theory.

Noninvasive transcutaneous determination of access blood flow rate.

BACKGROUND: Current indicator dilution techniques for determining the vascular access blood flow rate (Qa) require reversal of the dialysis blood lines and are time consuming. We have recently described an indicator dilution technique for determining Qa using a novel optical transcutaneous hematocrit (Hct) sensor that does not require reversal of the dialysis lines, and have validated the accuracy of this method (TQa) in vitro. METHODS: This study compared results using the TQa method with those obtained using a similar indicator dilution technique but which required reversal of the dialysis lines (HD01 Monitor, Transonic Systems, Ithaca, NY, USA) during routine hemodialysis in 59 patients (25 native fistulas and 34 synthetic grafts). The sensor for the TQa method was placed on the skin directly over the access to measure changes in Hct approximately 25 mm downstream of the venous needle. A single 30 mL bolus of saline was infused into the dialyzer venous line over approximately six seconds without reversal of the dialysis blood lines, and the vascular access flow rate was calculated using indicator dilution methods from the time-dependent decrease in the Hct downstream of the venous needle. Two additional small-scale studies were performed to assess the effect skin pigmentation and to evaluate further the reproducibility of the TQa method. RESULTS: Qa values determined by the TQa method were highly correlated with those determined by the HD01 method (N = 72, R2 = 0.948, P < 0.001) over the range of 153 to 2,042 mL/min. There was no significant difference between vascular access flow rates determined by the TQa method and those determined by the HD01 METHOD: Results from one small-scale study showed that the relationship between Qa values determined by the TQa and the HD01 methods was similar when tested only among black patients (N = 12), suggesting that skin pigmentation is not an important determinant of the accuracy of the TQa METHOD: The second small-scale study showed that the intratreatment coefficient of variation for the TQa method was 7.8 +/- 5.6% (N = 14). CONCLUSIONS: : These results show that transcutaneous measurement of Qa is an accurate, simple, and fast technique for determining Qa without requiring the reversal of the dialysis blood lines.

Ultrafiltration method for measuring vascular access flow rates during hemodialysis.

BACKGROUND: The vascular access blood flow rate (QA) has been shown to be an important predictor of vascular access failure; therefore, the routine measurement of QA may prove to be a useful clinical method of vascular access assessment. METHODS: We have developed a new ultrafiltration (UF) method for determining QA during HD from changes in arterial hematocrit (H) after abrupt changes in the UF rate with the dialysis blood lines in the normal (DeltaHn) and reverse (DeltaHr) configurations. This method accounts for cardiopulmonary recirculation and requires neither intravenous saline injections nor accurate knowledge of the dialyzer blood flow rate. Clinical studies were conducted in 65 chronic HD patients from three different dialysis programs to compare QA determined by the UF method with that determined by saline dilution using an ultrasound flow sensor. RESULTS: Arterial H increased (P<0.0001) after abrupt increases in the UF rate when the lines were in the normal and reverse configurations. An increase in the UF rate from the minimum setting to 1.8 liter/hr resulted in a DeltaHn of 0.3+/-0.2 (mean +/- SD) H units and a DeltaHr of 1.6+/-1.0 H units. Q(A) values determined by the UF method (1050+/-460 ml/min) were 16+/-25% higher (P<0.001) than those determined by saline dilution (950+/-440 ml/min); the calculated QA values by the UF and saline dilution methods correlated highly with each other (R = 0.92, P<0.0001). The average coefficient of variation for duplicate measurements of QA determined by the UF method in a subset of these patients (N = 21) was approximately 10% when assessed in either the same dialysis session or consecutive sessions. CONCLUSIONS: The results from this study show that changes in arterial H after abrupt changes in the UF rate can be used to assess Q(A).

Optical measurement of hematocrit and other biological constituents in renal therapy.

Optical sensors have advanced significantly over the past 2 decades leading to today's noninvasive optical measurement capabilities and their widespread applications in renal therapy. These measurements provide significant advantages to the clinician. For example, a given blood constituent can be monitored in real time (continuously, nondestructively), which facilitates the ability to optimally "titrate" the therapy with immediate visual feedback. Optical methods have another intrinsic advantage in that each biologic constituent has its own unique spectral "signature" allowing for simultaneous, multiple, and specific measurements of biologic analytes. Use of this budding spectral technology in renal therapy today provides for increased patient safety (by measuring plasma-free hemoglobin, microemboli, clots, oxygen saturation, blood leaks, and hematocrit), measurements of dialysis dose (dialysate urea levels), dry weight (tissue water monitoring), access viability (recirculation, access blood flow), cardiac status (absolute blood volume, cardiac output), and enhanced continuous fluid management (fluid overload, critical blood volume). As microelectronics and signal processing capabilities continue to advance, so will the future of optical diagnosis and treatment. These capabilities translate directly to improved patient quality of life.

Enhanced fluid removal guided by blood volume monitoring during chronic hemodialysis.

Fluid overload predisposes chronic hemodialysis patients to cardiovascular disease, a significant cause of morbidity and mortality in these patients. We evaluated the efficacy of monitoring changes in blood volume during routine hemodialysis to detect fluid overload. Intradialytic changes in blood volume were monitored by continuously measuring hematocrit in all 56 patients in a single dialysis unit over 7 weeks. After Week 1, patients were categorized into 2 separate groups depending on their maximum intradialytic decreases in blood volume. In Group 1, 46 of 56 or 82% had greater than a 5% decrease in blood volume while in Group 2, 10 of 56 or 18% had less than a 5% decrease in blood volume. During Weeks 2-7, dialytic fluid removal was intentionally increased in Group 2 patients by 0.80 +/- 0.62 L (mean +/- SD) or 47 +/- 43%. This intervention resulted in a larger (p < 0.02) intradialytic decrease in body weight (2.7 +/- 0.9 kg versus 2.0 +/- 0.8 kg) and a larger (p < 0.02) intradialytic decrease in blood volume (15 +/- 5% versus 4 +/- 1%) than experienced during Week 1 with a low incidence of symptoms. We conclude that there is a significant percentage of chronic hemodialysis patients who can tolerate additional fluid removal without hypovolemic symptoms even though they are considered to be at dry weight by routine physical examination and that the identification of these patients can be facilitated by intradialytic blood volume monitoring.

Reducing symptoms during hemodialysis by continuously monitoring the hematocrit.

Previous studies have demonstrated that patients on hemodialysis develop intradialytic symptoms when the blood volume decreases to a critical level. Using a continuous monitor (CRIT-LINE; In-Line Diagnostics, Riverdale, UT) to determine the instantaneous hematocrit and blood volume, we observed that certain intradialytic symptoms occurred at a patient-specific hematocrit. In the present study, we exploited this hematocrit threshold concept to decrease the occurrence of lightheadedness, cramping, and nausea, regardless of blood pressure changes. In the first phase of the study, hematocrit threshold was established in six hypotension-prone patients. Five patients entered into the second phase in which ultrafiltration rates were increased 25 percent above prescribed values at the beginning of the experimental sessions. Subsequently during the experimental sessions, ultrafiltration rates were manipulated to maintain the instantaneous hematocrit value 2 units below the established hematocrit threshold. Sessions without ultrafiltration rate adjustments based on hematocrit served as controls. There were no differences between experimental (n = 27) and control (n = 28) sessions with respect to treatment time (230 minutes v 229 minutes), fluid volume removed (3,351 mL v 3,383 mL), and maximum percentage change in systemic blood pressure (-26 percent v -24 percent). However, there were less symptoms during the experimental sessions (26 percent v 57 percent; P = 0.038). These data suggest that a twofold reduction in intradialytic symptoms can be achieved using continuous hematocrit monitoring without altering treatment times or volume removed in hypotension-prone patients.

Determination of circulating blood volume by continuously monitoring hematocrit during hemodialysis.

Dialysis-induced hypovolemia occurs because the rate of extracorporeal ultrafiltration exceeds the rate of refilling of the blood compartment. The purpose of this study was to evaluate a method for calculating circulating blood volume (BV) during hemodialysis (HD) from changes in hematocrit (Hct) shortly (2 to 10 min) before and after ultrafiltration (UF) was abruptly stopped. Hct was monitored continuously during 93 HD treatment sessions in 16 patients by an optical technique and at selected times by centrifugation of blood samples. Total plasma protein and albumin concentrations were also measured at selected times. Continuously monitored Hct correlated with Hct determined by centrifugation (R = 0.89, N = 579). Relative changes in BV determined by continuously monitored Hct were not different from those determined by total plasma protein concentration (P = 0.05; N = 273). Calculated BV at the start of dialysis (4.1 +/- 1.3 L) was not different (P = 0.18, N = 12) from that derived anthropometrically from the patient's dry weight (4.6 +/- 0.8 L), and calculated BV when UF was stopped was 3.2 +/- 0.5 L (46 +/- 7 ml/kg body wt). These latter estimates of BV are consistent with those determined previously by dilution techniques in HD patients. It was concluded that (1) relative changes in BV assessed by continuously monitored Hct were unbiased and (2) BV can be determined noninvasively during HD by continuously monitoring Hct and temporarily stopping UF.

Factors affecting satisfaction among community-based hospice volunteer visitors.

Trained volunteers are an essential component in the delivery of care to clients and families facing a terminal and/or life-threatening illness. As the need for hospice care increases, so does the need to increase the number of volunteers available for visiting. Hospice of London, which is a community based hospice, proposed that volunteers who felt satisfied would remain with the organization longer, thereby, decreasing the costs associated with training new volunteers and enhancing the ability of the agency to provide high-quality volunteer client matches. Accordingly, a survey was conducted in August 1992 to determine which factors were related to hospice volunteer satisfaction. One hundred and five volunteer were surveyed over the telephone. Results demonstrated a positive correlation between satisfaction and feeling like a team member, receiving feedback from staff, feeling valuable and having the volunteer's expectations match the position. Differences in the factors related to satisfaction were noted when the groups were divided by age and gender.

Hematocrit as an indicator of blood volume and a predictor of intradialytic morbid events.

Hematocrit (H) levels can change during hemodialysis, and these changes in H are inversely related to changes in blood volume (BV). The objectives of this study were to determine whether mean arterial pressure (MAP) decreases with decreasing BV and rising H during hemodialysis, and to determine the relationship between dialysis induced intravascular volume depletion and intradialytic morbid events (IME), defined as hypotension, cramping, or lightheadedness that led to dialysis staff intervention. We monitored H continuously using a noninvasive optical technique in 93 hemodialysis sessions in 16 patients. IME occurred in 48 sessions. MAP decreased with increasing H in 10 of 16 patients (P < 0.05), but the relationship between MAP and H varied among the patients. The rate of BV change during sessions without morbidity (5.6 +/- 3.6 [SD] %/hr) was lower (P < 0.001) than that preceding IME in the other sessions (12.2 +/- 5.5 [SD] %/hr). Twelve of 16 patients who exhibited recurrent IME during this study experienced these events when H reached a patient specific threshold. It is concluded that MAP decreases with decreasing BV and increasing H in many patients on hemodialysis, and that a high rate of BV change often indicates that IME are forthcoming. It is further hypothesized that a patient specific H threshold is indicative of a critical BV level below which certain patients experience IME.

Production-economic effects of delegation and practice size in a private dental office.

Practicing dentists, researchers, and a computer analyzed data from phases of use of expanded function dental auxiliaries in a private dental office. Increases in production and net income were related to the delegation of more complex functions in the expanded practice.