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PubMed2026

Cost-Effectiveness and the Economics of Genomic Testing and Molecularly Matched Therapies.

Cost-effectiveness analysis of precision oncology can help guide value-driven care. Next-generation sequencing is increasingly cost-efficient over single gene testing because diagnostic algorithms require multiple individual gene tests to determine biomarker status. Matched targeted therapy is often not cost-effective due to the high cost associated with drug treatment. However, genomic profiling can promote cost-effective care by identifying patients who are unlikely to benefit from therapy. Additional applications of genomic profiling such as universal testing for hereditary cancer syndromes and germline testing in patients with cancer may represent cost-effective approaches compared with traditional history-based diagnostic methods.

Humans↗
PubMed1991

Stimulation of human peripheral blood lymphocytes with chironomid hemoglobin allergen (Chi t I).

Hemoglobins (Chi t I) of the dipteron species Chironomus thummi thummi are known to cause severe allergic diseases in humans. We tested the allergen-specific stimulation of human peripheral blood lymphocytes (PBL) by Chi t I and its nine main components. Further, we applied fragments of the well-analyzed component III, obtained by cleavage with trypsin as well as arginine protease. In this way, we screened the molecule in order to identify T-cell epitopes. The whole component was found to be immunogenic and to have regions demonstrating varying PBL stimulation. In addition, interindividual patterns of reactivity, probably due to genetic restriction, were found. A T-cell epitope could be shown to be within the site 98-111, as predicted by application of Rothbard's algorithms.

Allergens↗
PubMed1992

Crossmatch prediction of highly sensitized patients.

1. A subset of negative reactions of sera from highly sensitized patients to donor lymphocytes are predicted with high accuracy (96.5% negative correct). 2. The prediction is performed by a hybrid expert system (HES) which uses multiple knowledge of stochastic (SCORES), artificial neural net (ANN), and genetic algorithm (GA) techniques. 3. All knowledge for the T-cell predictions is derived from serological reactions of the investigated sera (93) to a large panel (284). 4. When analyzing 5 HLA Class I typing sera controls, HES performs better than a standard serum analysis method in 3 measurement categories: r value; percent correct; and percent negative correct. 5. SCORES and ANN produce the strongest complementary association. SCORES is the best method with low PRA sera, while ANN is better at predicting high PRA sera. GA performs very poorly with high PRA sera. 6. HES can acquire knowledge from any of the various methods used for serum screening and crossmatch testing. Therefore, there is no need for method standardization as each laboratory will produce its own program incorporating its patients' data. High standardization of HLA Class I typing is necessary. 7. Most recipients for whom donors are never selected by HES are in the PRA range of 97-100%. 8. Certainty level categorization of a crossmatch gives clinical flexibility in judgement of potential donors. 9. All programs are written in the C language and are portable to numerous platforms. HES is implemented on an inexpensive IBM-PC compatible computer and can calculate predictions quickly. 10. HES predicts negative crossmatches with enough accuracy to initiate an organ sharing protocol to increase the chance for highly sensitized patients to obtain a transplant.

Algorithms↗
PubMed1991

The octave approach to EEG analysis.

A "tonal" approach to EEG spectral analysis is presented which is compatible with the concept of physical octaves, thus providing a constant resolution of partial tones over the full frequency range inherent to human brain waves, rather than for equidistant frequency steps in the spectral domain. The specific advantages of the tonal approach, however, mainly pay off in the field of EEG sleep analysis where the interesting information is predominantly located in the lower octaves. In such cases the proposed method reveals a fine structure which displays regular maxima possessing typical properties of "overtones" within the three octaves 1-2 Hz, 2-4 Hz and 4-8 Hz. Accordingly, spectral patterns derived from tonal spectral analyses are particularly suited to measure the fine gradations of mutual differences between individual EEG sleep patterns and will therefore allow a more efficient investigation of the genetically determined proportion of sleep EEGs. On the other hand, we also tested the efficiency of tonal spectral analyses on the basis of our 5-year follow-up data of 30 healthy volunteers. It turned out that 28 persons (93.3%) could be uniquely recognized after five years by means of their EEG spectral patterns. Hence, tonal spectral analysis proved to be a powerful tool also in cases where the main EEG information is typically located in the medium octave 8-16 Hz.

Algorithms↗
PubMed1992

Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2.

Fetal hemoglobin (Hb F) production in sickle cell (SS) disease and in normal individuals varies over a 20-fold range and is under genetic control. Previous studies suggested that variant Hb F levels might be controlled by genetic loci separate from the beta-globin complex on chromosome 11. Using microscopic radial immunodiffusion and flow cytometric immunofluorescent assays to determine the percentage of F reticulocytes and F cells in SS and nonanemic individuals, we observed that F-cell levels were significantly higher in nonanemic females than males (mean +/- SD, 3.8% +/- 3.2% v 2.7% +/- 2.3%). F-cell production as determined by F reticulocyte levels in SS females was also higher than in SS males (17% +/- 10% v 13% +/- 8%). We tested the hypothesis that F-cell production in both normal and anemic SS individuals was controlled by an X-linked locus with two alleles, high (H) and low (L). Using an algorithm to determine the 99.8% confidence interval of a normal distribution in nonanemic individuals, we estimated that males and females with at least one H allele had greater than 3.3% F cells. Comparisons of male-male or female-female SS sib pairs with discordant F reticulocyte levels distinguished two phenotypes in SS males (L, less than 12%; H, greater than 12%) and three phenotypes in SS females (LL, less than 12%; HL, 12% to 24%, HH greater than 24%). Linkage analysis using polymorphic restriction sites along the X chromosome in eight SS and one AA family localized the F-cell production (FCP) locus to Xp22.2, with a maximum lod score (logarithm of odds of linkage v independent assortment) of 4.6 at a recombination fraction of 0.04.

Adult↗
PubMed1976

Age trends in human chiasma frequencies and recombination fractions. II. Method for analyzing recombination fractions and applications to the ABO:nail-patella linkage.

A new method is presented for studying the relationship between human recombination fractions and parental age at the time of conception. Assuming the sex specific recombination fraction to be a linear function of age, a feasible computer algorithm is described whereby the likelihood of multigenerational families can be calculated. Using this method and the likelihood ratio test, it is found that for the ABO:nail-patella linkage age (P= .17)is more significant than sex (p= .23) in its effect on the recombination fraction. The age effect, if it is real, appears to be limited to males: the paternal recombination fraction decreases by .0062(+/- .0036) per year.

ABO Blood-Group System↗
PubMed1992

[Selective screening for amino and organic acid inborn errors].

Aminoacidopathies and organoacidopathies are the most common acute life-threatening inborn errors of metabolism in the neonatal period. In the Federal Republic of Germany approximately 1 out of 5000 newborns is currently diagnosed as having an aminoacidopathy and approximately 1 out of 9000 newborns an organoacidopathy. Especially in the case of organoacidopathies there is substantial evidence that this number represents an underestimation. Many cases of amino- and organoacidopathies are still likely to remain undiagnosed. The incidence figures would warrant neonatal population screening for these disorders; however, the complexity and expense of the current methods prohibit this approach. Instead specialized investigations are carried out in children who develop symptoms indicative of an inborn error of metabolism. This approach is called selective screening. Early diagnosis, therefore, rests on a high degree of suspicion. In this paper clinical and laboratory findings of amino- and organoacidopathies are summarized. They can be nonspecific and misinterpreted. In the neonate and infant the presentation is commonly that of an acute overwhelming disease, whereas in the older child unexplained mental and/or neurological problems are often the leading symptom. We present an algorithm for the quick and comprehensive diagnosis of acutely presenting inborn errors of metabolism using commonly available parameters. However, in many cases the definitive diagnosis is not reached by selective metabolic screening of a single urine specimen of a patient, but requires close cooperation between the referring physician and the metabolic specialist. Multiple analyses, sometimes of different physiological fluids, or even in vivo and in vitro loading tests may be necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1987

Helper T-cell antigenic site identification in the acquired immunodeficiency syndrome virus gp120 envelope protein and induction of immunity in mice to the native protein using a 16-residue synthetic peptide.

Much effort has been devoted to the analysis of antibodies to acquired immunodeficiency syndrome virus antigens, but no studies, to our knowledge, have defined antigenic sites of this virus that elicit T-cell immunity, even though such immunity is important in protection against many other viruses. T cells tend to recognize only a limited number of discrete sites on a protein antigen. Analysis of immunodominant helper T-cell sites has suggested that such sites tend to form amphipathic helices. An algorithm based on this model was used to identify two candidate T-cell sites, env T1 and env T2, in the envelope protein of human T-lymphotropic virus type IIIB that were conserved in other human immunodeficiency virus isolates. Corresponding peptides were synthesized and studied in genetically defined inbred and F1 mice for induction of lymph node proliferation. After immunization with a 426-residue recombinant envelope protein fragment, significant responses to native gp 120, as well as to each peptide, were observed in both F1 combinations studied. Conversely, immunization with env T1 peptide induced T-cell immunity to the native gp 120 envelope protein. The genetics of the response to env T1 peptide were further examined and revealed a significant response in three of four independent major histocompatibility haplotypes tested, an indication of high frequency responsiveness in the population. Identification of helper T-cell sites should facilitate development of a highly immunogenic, carrier-free vaccine that induces T-cell and B-cell immunity. The ability to elicit T-cell immunity to the native viral protein by immunization with a 16-residue peptide suggests that such sites represent potentially important components of an effective vaccine for acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1989

The statistical analysis of mitochondrial DNA polymorphisms: chi 2 and the problem of small samples.

Significance levels obtained from a chi 2 contingency test are suspect when sample sizes are small. Traditionally this has meant that data must be combined. However, such an approach may obscure heterogeneity and hence potentially reduce the power of the statistical test. In this paper, we present a Monte Carlo solution to this problem: by this method, no lumping of data is required, and the accuracy of the estimate of alpha (i.e., a type 1 error) depends only on the number of randomizations of the original data set. We illustrate this technique with data from mtDNA studies, where numerous genotypes are often observed and sample sizes are relatively small.

Algorithms↗
PubMed2024

Algorithms for the identification of prevalent diabetes in the All of Us Research Program validated using polygenic scores.

The All of Us Research Program (AoU) is an initiative designed to gather a comprehensive and diverse dataset from at least one million individuals across the USA. This longitudinal cohort study aims to advance research by providing a rich resource of genetic and phenotypic information, enabling powerful studies on the epidemiology and genetics of human diseases. One critical challenge to maximizing its use is the development of accurate algorithms that can efficiently and accurately identify well-defined disease and disease-free participants for case-control studies. This study aimed to develop and validate type 1 (T1D) and type 2 diabetes (T2D) algorithms in the AoU cohort, using electronic health record (EHR) and survey data. Building on existing algorithms and using diagnosis codes, medications, laboratory results, and survey data, we developed and implemented algorithms for identifying prevalent cases of type 1 and type 2 diabetes. The first set of algorithms used only EHR data (EHR-only), and the second set used a combination of EHR and survey data (EHR+). A universal algorithm was also developed to identify individuals without diabetes. The performance of each algorithm was evaluated by testing its association with polygenic scores (PSs) for type 1 and type 2 diabetes. We demonstrated the feasibility and utility of using AoU EHR and survey data to employ diabetes algorithms. For T1D, the EHR-only algorithm showed a stronger association with T1D-PS compared to the EHR + algorithm (DeLong p-value = 3 × 10-5). For T2D, the EHR + algorithm outperformed both the EHR-only and the existing T2D definition provided in the AoU Phenotyping Library (DeLong p-values = 0.03 and 1 × 10-4, respectively), identifying 25.79% and 22.57% more cases, respectively, and providing an improved association with T2D PS. We provide a new validated type 1 diabetes definition and an improved type 2 diabetes definition in AoU, which are freely available for diabetes research in the AoU. These algorithms ensure consistency of diabetes definitions in the cohort, facilitating high-quality diabetes research.

Humans↗
PubMed1991

"Soft docking": matching of molecular surface cubes.

Molecular recognition is achieved through the complementarity of molecular surface structures and energetics with, most commonly, associated minor conformational changes. This complementarity can take many forms: charge-charge interaction, hydrogen bonding, van der Waals' interaction, and the size and shape of surfaces. We describe a method that exploits these features to predict the sites of interactions between two cognate molecules given their three-dimensional structures. We have developed a "cube representation" of molecular surface and volume which enables us not only to design a simple algorithm for a six-dimensional search but also to allow implicitly the effects of the conformational changes caused by complex formation. The present molecular docking procedure may be divided into two stages. The first is the selection of a population of complexes by geometric "soft docking", in which surface structures of two interacting molecules are matched with each other, allowing minor conformational changes implicitly, on the basis of complementarity in size and shape, close packing, and the absence of steric hindrance. The second is a screening process to identify a subpopulation with many favorable energetic interactions between the buried surface areas. Once the size of the subpopulation is small, one may further screen to find the correct complex based on other criteria or constraints obtained from biochemical, genetic, and theoretical studies, including visual inspection. We have tested the present method in two ways. First is a control test in which we docked the components of a molecular complex of known crystal structure available in the Protein Data Bank (PDB). Two molecular complexes were used: (1) a ternary complex of dihydrofolate reductase, NADPH and methotrexate (3DFR in PDB) and (2) a binary complex of trypsin and trypsin inhibitor (2PTC in PDB). The components of each complex were taken apart at an arbitrary relative orientation and then docked together again. The results show that the geometric docking alone is sufficient to determine the correct docking solutions in these ideal cases, and that the cube representation of the molecules does not degrade the docking process in the search for the correct solution. The second is the more realistic experiment in which we docked the crystal structures of uncomplexed molecules and then compared the structures of docked complexes with the crystal structures of the corresponding complexes. This is to test the capability of our method in accommodating the effects of the conformational changes in the binding sites of the molecules in docking.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigen-Antibody Complex↗
PubMed1988

A numerical classification of the genus Bacillus.

Three hundred and sixty-eight strains of aerobic, endospore-forming bacteria which included type and reference cultures of Bacillus and environmental isolates were studied. Overall similarities of these strains for 118 unit characters were determined by the SSM, SJ and DP coefficients and clustering achieved using the UPGMA algorithm. Test error was within acceptable limits. Six cluster-groups were defined at 70% SSM, which corresponded to 69% SP and 48-57% SJ. Groupings obtained with the three coefficients were generally similar but there were some changes in the definition and membership of cluster-groups and clusters, particularly with the SJ coefficient. The Bacillus strains were distributed among 31 major (4 or more strains), 18 minor (2 or 3 strains) and 30 single-member clusters at the 83% SSM level. Most of these clusters can be regarded as taxospecies. The heterogeneity of several species, including Bacillus brevis, B. circulans, B. coagulans, B. megateriun, B. sphaericus and B. stearothermophilus, has been indicated and the species status of several taxa of hitherto uncertain validity confirmed. Thus on the basis of the numerical phenetic and appropriate (published) molecular genetic data, it is proposed that the following names be recognized; Bacillus flexus (Batchelor) nom. rev., Bacillus fusiformis (Smith et al.) comb. nov., Bacillus kaustophilus (Prickett) nom. rev., Bacillus psychrosaccharolyticus (Larkin & Stokes) nom. rev. and Bacillus simplex (Gottheil) nom. rev. Other phenetically well-defined taxospecies included 'B. aneurinolyticus', 'B. apiarius', 'B. cascainensis', 'B. thiaminolyticus' and three clusters of environmental isolates related to B. firmus and previously described as 'B. firmus-B. lentus intermediates'. Future developments in the light of the numerical phenetic data are discussed.

Bacillus↗
PubMed2026

MULTIPREVENT: Integrated screening for smoking-related multimorbidity using low-dose chest computed tomography.

OBJECTIVES: Tobacco consumption, combined with individual genetic predispositions, contributes to an age-dependent risk not only for lung cancer but also for other non-communicable diseases (NCDs) such as cardiovascular disease (CVD), chronic obstructive pulmonary disease (COPD), osteoporosis, and diabetes. The MULTIPREVENT project aims to validate whether low-dose computed tomography (LDCT) of the chest, combined with simple biomarkers, functional tests, and genomic profiling, can serve as an effective tool for comprehensive health assessment and risk prediction of multimorbidity in adults. STUDY DESIGN: The study is based on a prospective epidemiological design involving 3000 participants from the MOLTEST-BIS lung cancer screening cohort (2016-2018). These participants, aged 50-79 years (during MOLTEST-BIS) and with a smoking history of at least 30 pack-years, will undergo two follow-up assessments in 2025-2027 and 2030-2032. METHODS: Each follow-up includes LDCT, spirometry, standardized blood pressure measurement, anthropometric evaluation, biomarker assessment (lipid profile, lipoprotein(a), glycated haemoglobin), and health-related questionnaires. Genetic profiling will be performed using the Illumina Infinium Global Screening Arrays approach to identify inherited predispositions to major NCDs. All data, clinical, imaging (including radiomics), molecular, and genetic, will be integrated through machine learning algorithms to develop AI-based risk prediction models. RESULTS: The MULTIPREVENT study is expected to generate a wide range of scientific, clinical, and infrastructural results that will serve as a foundation for future public health initiatives in integrated prevention. CONCLUSIONS: By linking imaging and biochemical markers, genetic susceptibility, and clinical parameters within a longitudinal design, MULTIPREVENT will establish data-driven, AI-supported prevention strategies aimed at reducing morbidity and mortality among adults exposed to tobacco. The project will also serve as a model for population-based multimorbidity prevention programs.

Humans↗
PubMed1977

MLC (HLA-D) typing: a family study.

The genetics of five HLA-D specificities (Dw1, Dw2, Dw3, Dw4 and Dw6) have been assessed in 21 normal families with four or more children. The HLA-D traits, as defined by typing response against homozygous typing cells, normally behave as dominant characters. The data support the concept of allelic factors. The locial flaw in the basic algorithm of MLC typing (HLA-D typing), i.e. to draw positive conclusions from negative observations, has been amply reinforced in the following studies. Five assignments could not be verified genetically under the assumption of dominant traits. Homozygous lack of specific response genes is among the mechanisms proposed as a cause for the phenomenon which has not yet been fully explained. The estimated magnitude of the frequency of false assignments is approximately 10%.

Adult↗
PubMed1988

Self-stabilization of neuronal networks. II. Stability conditions for synaptogenesis.

This study is concerned with synaptic reorganization in local neuronal networks. Within networks of 30 neurons, an initial disequilibrium in connectivity has to be compensated by reorganization of synapses. Such plasticity is not a genetically determined process, but depends on results of neuronal interaction. Neurobiological experiments have lead to a model of the behavior of individual neurons during neuroplastic reorganization, formalized as a "synaptogenetic rule" that governs changes in the amount of synaptic elements on each neuron. When this synaptogenetic rule is applied to a system of neurons, there is some freedom left to the choice of further conditions. In this study it is examined, which assumptions additional to the synaptogenetic rule are essential in order to obtain morphogenetic stability. By explicating these assumptions, their plausibility can be tested. It is analysed, in which respect these conditions are important, in which part of the model they exert their influence, and what kind of instability and degeneration happens if the assumptions are violated. Our essentials for reaching morphogenetic stability are: (1) A network structure that guarantees the possibility of oscillations, (2) a compensation algorithm that guarantees a smooth morphogenesis, (3) kinetic parameters that guarantee convergence in the synaptic elements' change, and (4) a synaptic modification rule that prohibits Hebb-like as well as anti-Hebb-like synaptic changes. It is concluded that many structural features of the mammalian cerebral cortex are in accordance with the requirements of the model.

Algorithms↗
PubMed1991

Estimation of genetic parameters using sampled data from populations undergoing selection.

In populations undergoing selection, genetic (co)variances may be altered in amounts dependent on selection intensity among parents and the mating structure. In order to estimate the genetic parameters of the unselected population, all information that led to the current population must be included in the analysis. This is often not possible due to missing information or computer limitations, and, therefore, only samples of data and pedigree information of recent generations are included in analysis, and simplified operational models are used. Biases in genetic parameters, which were estimated by multitrait derivative-free REML method, were investigated in different strategies of sampling data and pedigree. In dual purpose cattle, in which young bulls are selected for growth before being progeny tested for milk yield, heritabilities and additive genetic correlations were all unbiased when all data and all relationships were used in an animal model. Using only recent data but all relationships in an animal model also gave unbiased estimates of heritabilities. Using an animal model for growth but a sire model for milk with all data gave an unbiased estimate of heritability for milk. When only recent data were used, the heritability estimate for milk was biased downward. In single purpose dairy populations, sire models gave biased estimates of genetic parameters even when all data were included in the analysis. Treating sire effects on second crop of daughters as fixed did not overcome selection bias.

Algorithms↗
PubMed1991

A proposed method for assembly and interpretation of short-term test data.

The genetic toxicology databases for chemicals that have been tested extensively are generally composed of inconsistent responses from a diverse set of assays. Consequently, difficulties arise when the data are evaluated for classifying the agent or for assessing the chemical's hazard potential. Several years ago, the International Commission for Protection against Environmental Mutagens and Carcinogens (ICPEMC) established a committee to construct a process for compiling and interpreting diverse data sets. The Committee has developed a weight-of-evidence approach that combines test data into a series of scores for test type, class, family, and a consensus score defining the relative mutagenic activity of the agent compared with other chemicals in the database. This report describes the method and preliminary results from 113 chemicals.

Algorithms↗
PubMed1992

WORDUP: an efficient algorithm for discovering statistically significant patterns in DNA sequences.

We present here a fast and sensitive method designed to isolate short nucleotide sequences which have non-random statistical properties and may thus be biologically active. It is based on a first order Markov analysis and allows us to detect statistically significant sequence motifs from six to ten nucleotides long which are significantly shared (or avoided) in the sequences under investigation. This method has been tested on a set of 521 sequences extracted from the Eukaryotic Promoter Database (2). Our results demonstrate the accuracy and the efficiency of the method in that the sequence motifs which are known to act as eukaryotic promoters, such as the TATA-box and the CAAT-box, were clearly identified. In addition we have found other statistically significant motifs, the biological roles of which are yet to be clarified.

Algorithms↗