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PubMed1995

Distinctive sequence features in protein coding genic non-coding, and intergenic human DNA.

We have studied the behavior of a number of sequence statistics, mostly indicative of protein coding function, in a large set of human clone sequences randomly selected in the course of genome mapping (randomly selected clone sequences), and compared this with the behavior in known sequences containing genes (which we term genic sequences). As expected, given the higher coding density of the genic sequences, the sequence statistics studied behave in a substantially different manner in the randomly selected clone sequences (mostly intergenic DNA) and in the genic sequences. Strong differences in behavior of a number of such statistics are also observed, however when the randomly selected clone sequences are compared with only the non-coding fraction of the genic sequences, suggesting that intergenic and genic non-coding DNA constitute two different classes of non-coding DNA. By studying the behavior of the sequence statistics in simulated DNA of different C+G content, we have observed that a number of them are strongly dependent on C+G content. Thus, most differences between intergenic and genic non-coding DNA can be explained by differences in C+G content. A+T-rich intergenic DNA appears to be at the compositional equilibrium expected under random mutation, while C+G richer non-coding genic DNA is far from this equilibrium. The results obtained in simulated DNA indicate, on the other hand, that a very large fraction of the variation in the coding statistics that underlie gene identification algorithms is due simply to C+G content, and is not directly related to protein coding function. It appears, thus, that the performance of gene-finding algorithms should be improved by carefully distinguishing the effects of protein coding function from those of mere base compositional variation on such coding statistics.

Algorithms↗

PubMed2004

Genetic codes as evolutionary filters: subtle differences in the structure of genetic codes result in significant differences in patterns of nucleotide substitution.

The codon-degeneracy model (CDM) predicts that patterns of nucleotide substitution in protein-coding genes are largely determined by the relative frequencies of four-fold (4f), two-fold, and non-degenerate sites, the attributes of which are determined by the structure of the governing genetic code. The CDM thus further predicts that genetic codes with alternative structures will "filter" molecular evolution differentially. A method, therefore, is presented by which the CDM may be applied to the unique structure of any genetic code. The mathematical relationship between the proportion of transitions at 4f degenerate nucleotide sites and the transition-to-transversion ratio is described. Predictions for five individual genetic codes, relative to the relationship between code structure and expected patterns of nucleotide substitution, are clearly defined. To test this "filter" hypothesis of genetic codes, simulated DNA sequence data sets were generated with a variety of input parameter values to estimate the relationship between patterns of nucleotide substitution and best-fit estimates of transition bias at 4f degenerate sites for both the universal genetic code and the vertebrate mitochondrial genetic code. These analyses confirm the prediction of the CDM that, all else being equal, even small differences in the structure of alternative genetic codes may result in significant shifts in the overall pattern of nucleotide substitution.

Codon↗

PubMed1999

Evolution of the genetic code: the nonsense, antisense, and antinonsense codes make no sense.

According to the molecular recognition theory, the complementarity of the sense and nonsense DNA strands is reflected in a complementarity of polypeptides and the corresponding nonsense polypeptides. A comparison of the sense and nonsense code matrices, and of the antisense and antinonsense code matrices, either by visual inspection or by comparing the corresponding hydrophobicity matrices (e.g. by simply adding them together), revealed no complementarity of these pairs of matrices in terms of possible attractive physical forces. Instead, it was evident that the codes divide the amino acids into two major groups: hydrophilic and hydrophobic, a division which is directly correlated with the folding property of proteins. A simple primordial genetic code distinguishing between these two types of amino acids would have been capable of generating three-dimensionally folded peptides, which could stabilize coding RNAs by forming ribonucleoprotein complexes. This evolutionary scheme is reflected in the present organisation of information processing and storage in essentially all organisms. RNAs are processed and translated into proteins by ribonucleoproteins, while other steps in information retrieval and processing, such as DNA replication, transcription, protein folding and posttranslational processing, are catalyzed by proteins. This shows that the evolution of DNA as an information storage medium was a secondary event, unrelated to the evolution of the genetic code. From the primordial hydrophilic/hydrophobic (f.ex. Leu/Arg) code, evolution proceeded by introduction of a catalytic amino acid (Ser). The further evolution of the code has mainly served to increase the number of functional hydrophilic amino acids, since there has not been a great advantage in increasing the number of structural, hydrophobic amino acids. At some stage during the evolution of the genetic code, double-stranded DNA was introduced as a maximally safe genetic copy of RNA. This required the action of highly specific enzymes, and was therefore preceded by the refinement of the genetic code. As a conclusion of this evolutionary scheme, it can be inferred that, in general only the sense strand encodes proteins.

Codon, Nonsense↗

PubMed2002

No accident: genetic codes freeze in error-correcting patterns of the standard genetic code.

The standard genetic code poses a challenge in understanding the evolution of information processing at a fundamental level of biological organization. Genetic codes are generally coadapted with, or 'frozen' by, the protein-coding genes that they translate, and so cannot easily change by natural selection. Yet the standard code has a significantly non-random pattern that corrects common errors in the transmission of information in protein-coding genes. Because of the freezing effect and for other reasons, this pattern has been proposed not to be due to selection but rather to be incidental to other evolutionary forces or even entirely accidental. We present results from a deterministic population genetic model of code-message coevolution. We explicitly represent the freezing effect of genes on genetic codes and the perturbative effect of changes in genetic codes on genes. We incorporate characteristic patterns of mutation and translational error, namely, transition bias and positional asymmetry, respectively. Repeated selection over small successive changes produces genetic codes that are substantially, but not optimally, error correcting. In particular, our model reproduces the error-correcting patterns of the standard genetic code. Aspects of our model and results may be applicable to the general problem of adaptation to error in other natural information-processing systems.

Animals↗

PubMed1983

Evolution of the amino acid code: inferences from mitochondrial codes.

The amino acid code is usually presented as a table of 64 codons. Actually the code results from the action of tRNA molecules that carry amino acids to codons in mRNA by means of codon-anticodon pairing. The tRNA molecules are transcribed from genes that undergo evolution and the number of anticodons can therefore increase during evolution, but the number of codons is fixed at 64. Mammalian mitochondrial codes contain only 22 anticodons for 20 amino acids as compared with 54 anticodons for 20 amino acids in the universal code. It is proposed that an archetypal code containing 16 anticodons for 15 amino acids evolved into the universal code by gene duplication, followed by mutations that modified the anticodons and amino acid acceptor sites. In substantiation of this proposal, it is noted that the mammalian mitochondrial code is simplified by comparison with the universal code. For example, single anticodons are used for each of eight amino acids in the mammalian mitochondrial code. This simplification may represent an evolutionary retrogression towards the proposed archetypal code.

Amino Acids↗

PubMed1995

Coding medical concepts: a controlled experiment with a computerised coding tool.

In clinical routine there is a growing need to encode medical concepts with available standard coding systems. The coding process can be time consuming and may significantly add to daily paperwork, particularly regarding patients with multiple diagnoses and in busy clinical environments with a high turnover of patients. We have developed a generic computerised encoding tool--the PADS encoder--to ensure rapid, correct and complete coding of diagnoses in daily routine. The tool is integrated into an electronic patient record system (PADS, Patient Archiving & Documentation System) and takes full advantage of the user friendly Macintosh interface. The tool was tested in a controlled experiment by 18 clinicians who encoded a total of 666 medical concepts in each protocol (study protocol vs. control). The following positive findings were significantly associated with the use of the computerised coding tool: the number of correctly encoded medical concepts was higher (99.55% vs. 86.1%), coding errors were lower (0% vs. 10.81%), more modifier codes were encoded correctly (increase by up to 43%), less coding errors were made (decrease by up to 43%), the overall rate of correctly encoded and complete main and modifier codes was increased by 31.27% (97.29% vs. 66.02%), coding time was reduced by 50%. This paper presents data to suggest that a computerised coding tool can produce more complete data of higher quality and can save time compared with the traditional approach to encode medical concepts.

Computer Communication Networks↗

PubMed2003

The ANZPIC registry diagnostic codes: a system for coding reasons for admitting children to intensive care.

OBJECTIVE: To describe the uniform diagnostic coding system used in Australia and New Zealand to code reasons for admitting children to intensive care, and to highlight the benefits of a uniform approach. DESIGN: International, multicentre, observational study. SETTING: A registry of children admitted to intensive care in Australia and New Zealand. PATIENTS: The records of 19249 children admitted to intensive care between 1997 and 2000 were analysed. MEASUREMENTS AND RESULTS: The system was designed empirically using expert consensus. The principal diagnosis or main reason for intensive care admission and up to five associated diagnoses are coded. The system has four levels of coding: non-operative or post-procedural admission, diagnostic group, specific condition, and for injury and infection the aetiological factor. The main reason for intensive care admission was coded in all patient records, however, for 11.1% of records the code was limited to diagnostic group with the specific condition coded as "other diagnosis". Two or more diagnoses were coded in 61% of records. The most frequent reason for admission was asthma. CONCLUSIONS: The major advantage of the system is that units in the region use the same method of coding. A uniform international approach to coding reasons for admitting children to intensive care is needed.

Australia↗

PubMed2002

Comparative analysis of mutation frequency of coding and non coding short mononucleotide repeats in mismatch repair deficient colorectal cancers.

Coding repeats are usually short mononucleotide tracts (SMT) of 10 or less base pairs in size. A number of such sequences contained in genes suspected to play a role in human carcinogenesis have been found to be mutated in mismatch repair deficient tumors (MSI-H cancers). Because of the high background of instability characterizing these cancers and in the absence of functional criteria, the significance of most frameshift gene alterations is unclear. In the present work, we analysed a series of 22 transcribed but non-coding SMT that are thus unlikely to play a tumorigenic role. Their frequency of size alteration in germline DNA and in DNA from MSI-H and microsatellite stable (MSS) tumors were compared to those previously reported in a series of 25 coding SMT of similar size. Non-coding SMT were either monomorphic or polymorphic in germline DNA whereas coding SMT were all monomorphic. In MSI-H tumors, non-coding SMT showed infrequent alterations (0-44%), as opposed to coding SMT which were altered at extremely variable frequencies (0 to 92%). Seven of the 22 non-coding SMT were monomorphic in MSS tumors but presented size alterations in MSI-H tumors with variable frequencies (3-28%). They were thus selected for further comparative statistical analyses for instability in coding SMT in MSI-H colorectal cancers. Only seven out of 25 of the coding SMT showed a significantly higher mutation frequency in these tumors. In the absence of functional criteria, we propose this as a novel and comprehensive approach for distinguishing real target genes amongst the numerous proposed gene mutations. It should allow identification of those that are genuinely selected for during MSI-H tumoral progression from others that play a less important role, if any, in MSI-H carcinogenesis.

Base Pair Mismatch↗

PubMed2006

Discrimination of non-protein-coding transcripts from protein-coding mRNA.

Several recent studies indicate that mammals and other organisms produce large numbers of RNA transcripts that do not correspond to known genes. It has been suggested that these transcripts do not encode proteins, but may instead function as RNAs. However, discrimination of coding and non-coding transcripts is not straightforward, and different laboratories have used different methods, whose ability to perform this discrimination is unclear. In this study, we examine ten bioinformatic methods that assess protein-coding potential and compare their ability and congruency in the discrimination of non-coding from coding sequences, based on four underlying principles: open reading frame size, sequence similarity to known proteins or protein domains, statistical models of protein-coding sequence, and synonymous versus non-synonymous substitution rates. Despite these different approaches, the methods show broad concordance, suggesting that coding and non-coding transcripts can, in general, be reliably discriminated, and that many of the recently discovered extra-genic transcripts are indeed non-coding. Comparison of the methods indicates reasons for unreliable predictions, and approaches to increase confidence further. Conversely and surprisingly, our analyses also provide evidence that as much as approximately 10% of entries in the manually curated protein database Swiss-Prot are erroneous translations of actually non-coding transcripts.

Algorithms↗

PubMed2006

Construction of a semi-automated ICD-10 coding help system to optimize medical and economic coding.

INTRODUCTION: In order to measure the medical activity in hospitals, physicians are required to code manually information concerning a patient's stay using ICD-10. This requires trained staff and a lot of time. We propose to help speed up and facilitate the tedious task of coding patient information. METHODS: we show two methods. First, we propose an automated ICD-10-based coding help system using an automated MeSH-based indexing system and a mapping between MeSH and ICD-10 extracted from the UMLS metathesaurus. Secondly, we propose the use of drug prescriptions to complete the previous coding with the use of a mapping between a given prescription drug and the relevant ICD-10 codes (in compliance with the drug approval). RESULTS: the results of a preliminary experiment indicate that the precision of the indexing system is 40% and the recall is 30% when we compare to an economic rules-based coding and to a descriptive coding. DISCUSSION: moreover, we show that the use of prescription coding is relevant as the recall reaches 68% when the Vidal tool is used. CONCLUSION: Then, it is very interesting to complete the coding obtained automatically by the indexing/mapping system by the coding obtained from the prescriptions.

Automation↗

PubMed1981

Amino acid codes in mitochondria as possible clues to primitive codes.

Differences between mitochondrial codes and the universal code indicate that an evolutionary simplification has taken place, rather than a return to a more primitive code. However, these differences make it evident that the universal code is not the only code possible, and therefore earlier codes may have differed markedly from the previous code. The present universal code is probably a "frozen accident." The change in CUN codons from leucine to threonine (Neurospora vs. yeast mitochondria) indicates that neutral or near-neutral changes occurred in the corresponding proteins when this code change took change took place, caused presumably by a mutation in a tRNA gene.

Amino Acids↗

PubMed2006

Distinguishing protein-coding from non-coding RNAs through support vector machines.

RIKEN's FANTOM project has revealed many previously unknown coding sequences, as well as an unexpected degree of variation in transcripts resulting from alternative promoter usage and splicing. Ever more transcripts that do not code for proteins have been identified by transcriptome studies, in general. Increasing evidence points to the important cellular roles of such non-coding RNAs (ncRNAs). The distinction of protein-coding RNA transcripts from ncRNA transcripts is therefore an important problem in understanding the transcriptome and carrying out its annotation. Very few in silico methods have specifically addressed this problem. Here, we introduce CONC (for "coding or non-coding"), a novel method based on support vector machines that classifies transcripts according to features they would have if they were coding for proteins. These features include peptide length, amino acid composition, predicted secondary structure content, predicted percentage of exposed residues, compositional entropy, number of homologs from database searches, and alignment entropy. Nucleotide frequencies are also incorporated into the method. Confirmed coding cDNAs for eukaryotic proteins from the Swiss-Prot database constituted the set of true positives, ncRNAs from RNAdb and NONCODE the true negatives. Ten-fold cross-validation suggested that CONC distinguished coding RNAs from ncRNAs at about 97% specificity and 98% sensitivity. Applied to 102,801 mouse cDNAs from the FANTOM3 dataset, our method reliably identified over 14,000 ncRNAs and estimated the total number of ncRNAs to be about 28,000.

Animals↗

PubMed2002

JJ1017 committee report: image examination order codes--standardized codes for imaging modality, region, and direction with local expansion: an extension of DICOM.

The digital imaging and communications in medicine (DICOM) standard includes parts regarding nonimage data information, such as image study ordering data and performed procedure data, and is used for sharing information between HIS/RIS and modality systems, which is essential for IHE. To bring such parts of the DICOM standard into force in Japan, a joint committee of JIRA and JAHIS established the JJ1017 management guideline, specifying, for example, which items are legally required in Japan, while remaining optional in the DICOM standard. In Japan, the contents of orders from referring physicians for radiographic examinations include details of the examination. Such details are not used typically by referring physicians requesting radiographic examinations in the United States, because radiologists in the United States often determine the examination protocol. The DICOM standard has code tables for examination type, region, and direction for image examination orders. However, this investigation found that it does not include items that are detailed sufficiently for use in Japan, because of the above-mentioned reason. To overcome these drawbacks, we have generated the JJ1017 code for these 3 codes for use based on the JJ1017 guidelines. This report introduces the JJ1017 code. These codes (the study type codes in particular) must be expandable to keep up with technical advances in equipment. Expansion has 2 directions: width for covering more categories and depth for specifying the information in more detail (finer categories). The JJ1017 code takes these requirements into consideration and clearly distinguishes between the stem part as the common term and the expansion. The stem part of the JJ1017 code partially utilizes the DICOM codes to remain in line with the DICOM standard. This work is an example of how local requirements can be met by using the DICOM standard and extending it.

Diagnostic Imaging↗

PubMedDate not supplied

[Simple and valid ICD9-/10- and IKPM coding using an electronic data-assisted coding system "do it"--experiences after one years use].

UNLABELLED: Question by introducing "Fallpauschalen" and "Sonderentgelte" in German health system the coding of diagnoses and therapies gains a new momentum. Therefore, a new computer based coding-system for ICD- and ICPM- digits is presented. The physician gets enabled for simple and valid classification within his documentation routine. METHODS: Development of a hierarchic menue system, whose first part represents the anatomic region. The second part is reserved for the most common diagnosis rsp. therapies within its special anatomic region. By further sub-menues all other ICD numbers in the orthopedic and traumatologic field may be coded (selection related by frequency). This coding-system has been in clinical use since jan. 1st. 1995. RESULTS: Control of the efficiency of this coding-systems by 1316 patients with 1551 operations within one year. By using ICD-10, the representation of orthopedic-traumatologic diagnosis inhanced by factor 1.8 versus ICD-9. According to ICPM, 3560 therapies were coded, making it 2-3 actions per operation. "Fallpauschalen" were found in 21.9%, in 27.7% there were "Sonderentgelte". Within one year the coding error rate was reduced from 25% to 5%. CONCLUSIONS: Because of its easy handling the coding system "do it" represents a good alternative to conventional coding rsp. clear text analysis.

Data Collection↗

PubMed2001

Development and testing of a hierarchical method to code the reason for admission to intensive care units: the ICNARC Coding Method. Intensive Care National Audit & Research Centre.

A computer-based hierarchical method was developed to code conditions leading to admission to intensive care in the UK. The hierarchy had five tiers: surgical status, body system, anatomical site, physiological or pathological process and medical condition. The hierarchy was populated initially using the free-text descriptions of the reason for admission from 10,806 admissions recorded as part of the Intensive Care Society's UK APACHE II study. After refinement and error-checking, a prospective evaluation was undertaken on 22,059 admissions to 62 UK intensive care units. Individual units coded between 60 and 1610 (mean 356) admissions. All but 50 (0.2%) of the admissions could be coded and 38 units coded every admission. Fifty admissions (0.2%) could not be coded within 24 h of admission but were coded subsequently when more information became available. Of the admissions, 96.1% were coded at all levels of the hierarchy in the coding method. Six hundred and thirty-seven of the 741 unique conditions (85.9%) were used in one of the five reasons for admission and 564 (76.1%) in the primary reason for admission. Five conditions account for 19.4% of all primary reasons for admission. This is the first method to be developed empirically for coding the reason for intensive care admission.

Diagnosis-Related Groups↗

PubMedDate not supplied

Coding medical concepts: a controlled experiment with a computerized coding tool.

In medicine there is a growing need to encode medical concepts with the available standard coding systems. The coding process can be time intensive and may significantly add to daily paperwork. We have developed a generic computerized encoding tool--the PADS (patient archiving and documentation system) encoder--to ensure rapid, correct and complete coding of diagnoses in daily routine. The tool is integrated into an electronic patient record system and takes full advantage of the user friendly Macintosh interface. The tool was tested in a controlled experiment by 18 clinicians who encoded a total of 666 medical concepts in each protocol (study protocol versus control). We present data demonstrating that a computerized coding tool can produce more complete data of higher quality and save time compared with the traditional approach: (a) the number of correctly encoded medical concepts was higher (99.55% versus 86.1%); (b) coding errors were lower (0% versus 10.81%); (c) more modifier codes were encoded correctly (increase by up to 43%); (d) fewer coding errors were made (decrease by up to 43%); (e) the overall rate of correctly encoded and complete main and modifier codes was increased by 31.27% (97.29% versus 66.02%); and (f) coding time was reduced by 50%.

Abstracting and Indexing↗

PubMed1976

A cybernetic approach to the origin of the genetic coding mechanism. II. Formation of the code series.

The sequential fulfillment of the principle of succession necessarily guides the main steps of the genetic code evolution to be reflected in its structure. The general scheme of the code series formation is proposed basing on the idea of "group coding" (Woese, 1970). The genetic code supposedly evolved by means of successive divergence of pra-ARS's loci, accompanied by increasing specification of recognition capacity of amino acids and triplets. The sense of codons had not been changed on any step of stochastic code evolution. The formulated rules for code series formation produce a code version, similar to the contemporary one. Based on these rules the scheme of pra-ARS's divergence is proposed resulting in the grouping of amino acids by their polarity and size. Later steps in the evolution of the genetic code were probably based on more detailed features of the amino acids (for example, on their functional similarities like their interchangeabilities in isofunctional proteins).

Amino Acids↗

PubMed1987

Codon usage in Homo sapiens: evidence for a coding pattern on the non-coding strand and evolutionary implications of dinucleotide discrimination.

This study reports the analysis of codon usage in 35 complete Homo sapiens genes. Both codon frequency and inter-codon interference exhibit patterns of evolutionary interest. There is a significant positive correlation between the frequency with which a given codon is used and the frequency with which its complement is used. Since the frequency of appearance of the complementary codon on the coding strand is equal to the frequency of appearance of the original codon on the non-coding strand, in the same phase, the non-coding strand is found to resemble the coding strand in triplet composition. The same effect has been observed in Escherichia coli. This preference for the use of certain complementary triplets as codons suggests that the evolution of the use of the genetic code depended to some extent upon the double-stranded nature of the coding material. In addition, the effect of discrimination against the use of two dinucleotides, CpG and UpA, is observed in codon usage and also in adjacent codon interference. Codons beginning with G, or A, are unlikely to be preceded by codons ending in C, or U, respectively. Consideration of codon assignment in the genetic code together with the observed CpG infrequency suggests that the evolution of the code may have been influenced by conditions in which the use of CpG dinucleotides was unfavorable. The infrequent use of UpA dinucleotides can be explained as the result of frameshift mutation during gene evolution.

Base Sequence↗