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mROC: a computer program for combining tumour markers in predicting disease states.

Receiver operating characteristic (ROC) curves are limited when several diagnostic tests are available, mainly due to the problems of multiplicity and inter-relationships between the different tests. The program presented in this paper uses the generalised ROC criteria, as well as its confidence interval, obtained from the non-central F distribution, as a possible solution to this problem. This criterion corresponds to the best linear combination of the test for which the area under the ROC curve is maximal. Quantified marker values are assumed to follow a multivariate normal distribution but not necessarily with equal variances for two populations. Other options include Box-Cox variable transformations, QQ-plots, interactive graphics associated with changes in sensitivity and specificity as a function of the cut-off. We provide an example to illustrate the usefulness of data transformation and of how linear combination of markers can significantly improve discriminative power. This finding highlights potential difficulties with methods that reject individual markers based on univariate analyses.

Biomarkers, Tumor↗

An interactive computer program for the analysis of growth curves.

An interactive FORTRAN program, MUDIFT, is presented. This program was designed to perform a multivariate distribution-free significance test for the comparison of growth curves. Such a test, not assuming functional forms of individual growth, has proved useful when the variety of observed growth curves was too broad to be represented by the family of growth functions and when there were incomplete observations. A numerical example illustrates the use of MUDIFT to analyze serial data pertaining to the measurable solid tumors in 20 mice treated with liposome incorporated muramyltripeptide phosphatidylethanolamine and a control group of 30 mice. The tumor volumes were recorded weekly for 10 weeks following initial entry into the research protocol. The test hypothesis was whether the tumors grew slower in the treated group than in the control group. The test statistic, an asympotically chi 2 statistic, was 7.312 with df = 2, which was significant at alpha = 0.05.

Animals↗

A computer program for the simulation of colony-like proliferation of fibroblasts and their cell cycle behavior.

Several models have been constructed which describe the population dynamics of fibroblast cultures by means of their collective behavior. In contrast, we present here the first example of a program which also allows a topographical simulation of colony-like growth. Starting with one cell, each clonal population consists of single 'intelligent' cells running through a fictive cell cycle. Within the cycle several parameters (position of daughter cells, duration of cycle, etc.) are randomly chosen within given intervals, thus leading to an extremely large number of different clones which can be simulated. Therefore, an experimental-like procedure is possible. Although not being a true reflection of the cell cycle, the model is in good accordance with the clonal growth of fibroblasts. Our model has several aims, for example the application to prenatal diagnosis and the appearance of aberrant clones (in vivo versus in vitro occurrence of chromosome abnormalities in amniotic fluid cell clones). However, it seems to be well suited to check theories related to cellular senescence in vitro, and in particular the commitment theory.

Cell Cycle↗

The DeltaCrit System (DCS): a computer program for standardized bedside detection of critical oxygen delivery using the Deltatrac II metabolic monitor.

Under resting conditions oxygen consumption (VO2) of the tissues equals their O2 demand. However, when oxygen delivery (DO2) decreases below "a critical" value, the consecutive decline of VO2 reflects a critical restriction of DO2 resulting in the onset of tissue hypoxia. Reliable bedside detection of a significant VO2 decline requires continuous measurement of in- and exspiratory O2 concentrations with a metabolic monitor as well as a standardized online analysis of the data obtained. However, for this purpose no standardized procedure was available yet. Therefore, the DeltaCrit-System (DCS) has been developed enabling online detection of a significant VO2 decline indicating critical restriction of DO2. After a reference period with stable VO2 values the DCS tests whether a subsequently measured VO2 value is significantly lower than the mean baseline VO2. A significant VO2 decrease should indicate the onset of O2 supply dependency of VO2 due to a critical restriction of DO2. The DCS has been validated with nine different, artificially generated data sets and has been tested in one animal experiment. DCS has proven consistency and may therefore be considered a new tool allowing clinicians to recognize restrictions in DO2 at an early time, and to start early therapeutic interventions.

Algorithms↗

Scrutineer: a computer program that flexibly seeks and describes motifs and profiles in protein sequence databases.

Scrutineer is an interactive, user-friendly program designed to search for motifs, patterns and profiles in the Swissprot, Protein Identification Resource (PIR) or SeqDb protein sequence databases. Basic capabilities include (i) searches for strings of amino acids with multiple choices at a given position; (ii) searches for strings including variable-length segments and delocalized constraints; (iii) searches over subsets of a database or particular regions within each sequence (e.g. N-terminal one-third); (iv) searches involving secondary structure predictions, physicochemical characteristics, and the like; and (v) searches using aligned sequences as targets with various optional weighting schemes. The various search criteria and hits can be combined and complex targets located. Once the data are loaded into virtual memory, all occurrences in PIR release 22.0 (3.7 x 10(6) amino acids) of a given short string of amino acids (e.g. a hexamer) are found in approximately 36 s. Scrutineer can also describe the entire database, user-specified hits, user-defined regions of sequence and all hits. The source code and accompanying manual are being freely distributed.

Algorithms↗

Rapid i.v. loading with phenytoin with subsequent dose adaptation using non-steady-state serum levels and a Bayesian forecasting computer program to predict maintenance doses.

OBJECTIVE: To evaluate the suitability of a phenytoin loading dose regimen; to assess whether dose-individualization was necessary and to investigate the reliability of a Bayesian forecasting method for phenytoin dose adaptation using non-steady-state levels in hospital-admitted patients. METHOD: An initial loading dose (15 mg phenytoin acid/kg BW) was given i.v. over 4 h, followed by standardized maintenance doses given i.v. in 12-h intervals from days 1 to 5 (175 mg </= 70 kg; 202 mg > 70 kg BW). The evening dose of day 5 was individualized based on three serum trough levels: L1 (after 16 h), L2 (morning day 4) and L3 (morning day 5). RESULTS: Ninety of 136 consecutive patients were evaluable in a prospective study for the standardized phase; 50 of them had additional serum levels in the individualized phase. There was no exclusion of patients with interacting co-medication. Seventy-seven per cent (L1) and 68% (L3) of patients showed therapeutic values (10-20 mg/L). The prediction error of the forecasting was 3.95 mg/L, the root mean squared error 6.27 mg/L (target trough level 11 mg/L). Seventy per cent of the levels (n=50) were within the 68% confidence interval. CONCLUSION: The effectiveness and safety of the regimen with rapid i.v. loading and the necessity to individualize phenytoin dosing after day 5 were demonstrated.

Adolescent↗

Bilingual telephone-assisted computerized speech-recognition assessment: is a voice-activated computer program a culturally and linguistically appropriate tool for screening depression in English and Spanish?

The purpose of this study was to evaluate an automated voice-interactive program for screening depression in English and Spanish. The Center for Epidemiological Studies-Depression Scale (CES-D) was administered in two interview formats: a speech recognition program presented by cellular telephone, and a face-to-face method. In a single-session counterbalanced design, 32 English speakers and 23 Spanish speakers completed randomly ordered administrations of the two CES-D methods, the Beck Depression Inventory (BDI), and the Short Acculturation Scale (SAS). There was strong evidence that the two CES-D methods were psychometrically equivalent, reliable, and valid in both languages. The two methods were highly rated by both language groups. The Spanish speakers did not display a preference for either method, but the English speakers preferred the face-to-face method. The results also suggested that verbal response latency time was positively correlated with depression scores. Last, the Spanish-speakers' acculturation levels were not correlated with depression scores. Differences in age, education, and income between the language groups were confounded by unequal sample sizes. The findings generally supported the viability of the automated CES-D as a culturally and linguistically appropriate tool for screening depression in English and Spanish. Furthermore, the analyses of respondent voice characteristics show promise as a method for screening depression in both languages.

Acculturation↗

OSP: a computer program for choosing PCR and DNA sequencing primers.

OSP (Oligonucleotide Selection Program) selects oligonucleotide primers for DNA sequencing and the polymerase chain reaction (PCR). The user can specify (or use default) constraints for primer and amplified product lengths, %(G+C), (absolute or relative) melting temperatures, and primer 3' nucleotides. To help minimize nonspecific priming and primer secondary structure, OSP screens candidate primer sequences, using user-specifiable cutoffs, against potential base-pairing with a variety of sequences present in the reaction, including the primer itself, the other primer (for PCR), the amplified product, and any other sequences desired (e.g., repetitive element sequences in genomic templates, vector sequence in cloned templates, or other primer pair sequences in multiplexed PCR reactions). Base-pairing involving the primer 3' end is considered separately from base-pairing involving internal sequences. Primers meeting all constraints are ranked by a "combined score," a user-definable weighted sum of any of the above parameters. OSP is being routinely and extensively used to select sequencing primers for the Caenorhabditis elegans genome sequencing project and human genomic PCR primer pairs for the Washington University Genome Center mapping project, with success rates exceeding 96% and 81%, respectively. It is available for research purposes from the authors, at no cost, in both text output and interactive graphics (X windows) versions.

Animals↗

[Society of Nephrology, Computer Technology Commission. Dialysis computer program. VI. - Survival and risk factors].

The sixth report of the "Diaphane Dialyse Informatique" Program concerns 2,518 adult patients (age 15 and over) treated by chronic hemodialysis or hemofiltration in 33 French dialysis centres between June 1972 and December 1978. 1) The number of centers participating to the program is progressively increasing. Overall duration of follow-up represents 4,192 patient-years, allowing precise evolutive studies of terminal renal failure treated by hemodialysis. 2) Mean age at start of treatment continues to increase. Among 709 patients who started treatment in 1977-1978, 8,8 p. 100 of men and 11 p. 100 of women were over 69 years old. 3) Patients with diabetic nephropathy represent 4,4 p. 100 of all patients dialyzed between 1972 and 1978 and 5,9 p. 100 of the patients starting treatment in 1977-1978. 4) The percentage of patients temporarily treated by peritoneal dialysis before hemodialysis decreases from 32,9 p. 100 in 1973-1974 to 15,9 p. 100 in 1977-1978. 5) In 1978, 65,3 p. 100 of patients are dialyzed 3 times a week with a mean weekly duration of 14,0 h for male and 12,9 for female. 73 p. 100 of the patients are dialyzed during the night. 6) Disposable parallel plate hemodialyzers (71,8 per cent of dialysis sessions in 1978) and hollow fiber hemodialyzers (11,6 per cent) progressively replace disposable coil dialyzers and non disposable Kiil dialyzers. 7) Transient hypotensive episodes during dialysis sessions remain the most frequent complications (21,7 per cent of sessions in 1978). Transient hypotensive episodes are more frequently observed with coils than with parallel plate hemodialyzers or with hollow fiber dialyzers. 8) Mean diastolic blood pressure (DBP) +/- SD is 101,9 +/- 21,7 mmHg at start of dialysis and 81,4 +/- 11,8 mmHg when dialysed. During the course of treatment 28,7 per cent of the patients receive long term antihypertensive treatment. In spite of dialysis and antihypertensive treatments 11 per cent of all patients followed up maintain DBP greater than or equal to 95 mmHg. 9) Viral hepatitis remain the most prominent infectious problem with 30 per cent of patients being chronic Hbs antigen carriers. 10) Annual death rate calculated in the 2,518 patients dialyzed between 1972 and 1978 (78/1000) is 12 times superior to the death rate of the French population, adjusted for sex and age to the dialysis population. 43,1 per cent of deaths are of cardiovascular origin. Risk factors for overall mortality are age, sex (male), existence of a vascular or diabetic nephropathy, twice weekly dialysis strategy, elevation of systolic or diastolic blood pressure during the course of dialysis treatment, hypocholesterolemia and to a lesser extent hypotriglyceridemia. On the contrary, hypercholesterolemia, hypertriglyceridemia and hyperuricemia do not appear as risk factors for overall mortality or cardiovascular mortality. These results plead for a perfect control of hypertension and to the extension of thrice weekly dialysis for the whole population of patients treated by maintenance hemodialysis.

Adolescent↗

[Dialysis-computer program. IV. Summary report. Epidemiology of complications].

The Diaphane-program instituted under the authority of the French Society of Nephrology has been steadily expanding since 1972. By December 1977, about 1500 patients treated in 30 public and private Dialysis Centres were followed up by this system. Full coverage of expenses is provided by the participating Centres. The statistical work presented in this report involves 1572 adult patients treated between June 1972 and December 1976 in 24 dialysis centres. The amount of collected data and the duration of the observation period permit to build up evolutive profiles of the population of patients treated in France by maintenance hemodialysis, of the various techniques and strategies used and of the main complications recorded in the patients. 1. Mean age of patients at start of dialysis is steadily increasing, from 40.1 years in 1972 to 48.2 years in 1976. 2. The predominance of male patients, constant over each year, may be explained by an increased proportion in man of chronic glomerulonephritis and renal vascular diseases. The sex-ratio in patients with chronic pyelonephritis is close to the one recorded in the French population. 3. The regular decrease of the mean plasma creatinine level at time of first dialysis recorded since 1972, is probably related to an earlier start of treatment. However, 10.6 per cent of the patients taken on treatment in 1975-1976 still had a plasma creatinine greater than or equal to 200 mg/100ml. 18.7 per cent had a diastolic blood pressure greater than or equal to 120 mmHg, and exsudative lesions at eye fundi examination were found in 33.5 per cent. The delay in initiating dialysis treatment may account for the frequency of early acute cardiopulmonary complications such as pulmonary oedema and pericarditis and also for the increase in the mortality rate recorded during the first year of treatment: 12.1 per cent instead of 6.2 per cent during the second year. This particularly relevant for the younger age group of patients. 4. There seems to be some social disparity concerning the detection of renal disease and the conditions under which dialysis treatment is started: chronic renal disease is detected at an earlier stage and dialysis treatment initiated for lower values of plasma creatinine and of diastolic blood pressure in patients belonging to the "higher income" group of population. 5. The percentage of patients dialysed twice a week is steadily increasing, whereas the average weekly dialysis time decreases, being about 15 hours in 1976. Day and evening dialysis replace overnight dialysis. Disposable flat-plate dialysers are used increasingly. 6. Episodes of hypotension and cramps are the incidents most frequently recorded during the dialysis sessions. Risk factors evidenced in the occurrence of hypotensive accidents are: the female sex, age greater than or equal to 55 years in males, orthostatic blood pressure drop at the end of previous dialysis, weight loss of more than 4 per cent of total body weight during dialysis...

Adult↗

Computer program (SEQPEP) to aid in the interpretation of high-energy collision tandem mass spectra of peptides.

An algorithm (SEQPEP) that aids in the interpretation of high-energy (greater than 1 kV) collision-induced dissociation mass spectra of peptide ions generated by fast atom bombardment (FAB) ionization is described. The only required input is a list of product ion masses and relative abundances generated by the mass spectrometer data system, the mass of the precursor [M + H]+ ion, and the mass of any C-terminal modification, if present (e.g., amide). Possible N-terminal modifications and amino acid compositions are not required as input. In the output, sequences are ranked according to the fraction of total product ion current that can be accounted for as either sequence-specific or non-sequence-specific fragment ions. These are listed by ion type. One of the major advantages of this program over algorithms described earlier is the incorporation of ion types more recently discovered. Also, this program is much faster, requiring less than 5 min of central processing unit time for an input of as many as 100 product ions. The results obtained from 50 peptides, including some generated when sequencing a protein of previously unknown structure, are discussed.

Amino Acid Sequence↗

Computer program for analyzing donor photobleaching FRET image series.

BACKGROUND: The photobleaching fluorescence resonance energy transfer (pbFRET) technique is a spectroscopic method to measure proximity relations between fluorescently labeled macromolecules using digital imaging microscopy. To calculate the energy transfer values one has to determine the bleaching time constants in pixel-by-pixel fashion from the image series recorded on the donor-only and donor and acceptor double-labeled samples. Because of the large number of pixels and the time-consuming calculations, this procedure should be assisted by powerful image data processing software. There is no commercially available software that is able to fulfill these requirements. METHODS: New evaluation software was developed to analyze pbFRET data for Windows platform in National Instrument LabVIEW 6.1. This development environment contains a mathematical virtual instrument package, in which the Levenberg-Marquardt routine is also included. As a reference experiment, FRET efficiency between the two chains (beta2-microglobulin and heavy chain) of major histocompatibility complex (MHC) class I glycoproteins and FRET between MHC I and MHC II molecules were determined in the plasma membrane of JY, human B lymphoma cells. RESULTS: The bleaching time constants calculated on pixel-by-pixel basis can be displayed as a color-coded map or as a histogram from raw image format. CONCLUSION: In this report we introduce a new version of pbFRET analysis and data processing software that is able to generate a full analysis pattern of donor photobleaching image series under various conditions. .

Algorithms↗

Exclusion map of Salla disease: attempts to localize the disease gene using a computer program.

Salla disease is a lysosomal storage disorder due to impaired transport of free sialic acid across the lysosomal membrane. The clinical presentation of this autosomal recessive trait is severe psychomotor retardation from early infancy on. In order to determine the gene locus for the disease we have initiated a genetic linkage study using polymorphic gene markers in representative family material comprising about 60% of all families known to be affected with Salla disease. Here we present an exclusion map based on combined linkage data from 64 informative loci on 19 autosomes. Theoretically, at least 55% of the genome has been excluded as a locus for the disease gene, while some chromosome areas, particularly the long arm of chromosome 2, are highlighted as possible sites for the gene locus.

Chromosome Mapping↗