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PubMed2006

Predicting population coverage of T-cell epitope-based diagnostics and vaccines.

BACKGROUND: T cells recognize a complex between a specific major histocompatibility complex (MHC) molecule and a particular pathogen-derived epitope. A given epitope will elicit a response only in individuals that express an MHC molecule capable of binding that particular epitope. MHC molecules are extremely polymorphic and over a thousand different human MHC (HLA) alleles are known. A disproportionate amount of MHC polymorphism occurs in positions constituting the peptide-binding region, and as a result, MHC molecules exhibit a widely varying binding specificity. In the design of peptide-based vaccines and diagnostics, the issue of population coverage in relation to MHC polymorphism is further complicated by the fact that different HLA types are expressed at dramatically different frequencies in different ethnicities. Thus, without careful consideration, a vaccine or diagnostic with ethnically biased population coverage could result. RESULTS: To address this issue, an algorithm was developed to calculate, on the basis of HLA genotypic frequencies, the fraction of individuals expected to respond to a given epitope set, diagnostic or vaccine. The population coverage estimates are based on MHC binding and/or T cell restriction data, although the tool can be utilized in a more general fashion. The algorithm was implemented as a web-application available at http://epitope.liai.org:8080/tools/population. CONCLUSION: We have developed a web-based tool to predict population coverage of T-cell epitope-based diagnostics and vaccines based on MHC binding and/or T cell restriction data. Accordingly, epitope-based vaccines or diagnostics can be designed to maximize population coverage, while minimizing complexity (that is, the number of different epitopes included in the diagnostic or vaccine), and also minimizing the variability of coverage obtained or projected in different ethnic groups.

Algorithms↗

PubMed2006

Selecting normalization genes for small diagnostic microarrays.

BACKGROUND: Normalization of gene expression microarrays carrying thousands of genes is based on assumptions that do not hold for diagnostic microarrays carrying only few genes. Thus, applying standard microarray normalization strategies to diagnostic microarrays causes new normalization problems. RESULTS: In this paper we point out the differences of normalizing large microarrays and small diagnostic microarrays. We suggest to include additional normalization genes on the small diagnostic microarrays and propose two strategies for selecting them from genomewide microarray studies. The first is a data driven univariate selection of normalization genes. The second is multivariate and based on finding a balanced diagnostic signature. Finally, we compare both methods to standard normalization protocols known from large microarrays. CONCLUSION: Not including additional genes for normalization on small microarrays leads to a loss of diagnostic information. Using house keeping genes from the literature for normalization fails to work for certain datasets. While a data driven selection of additional normalization genes works well, the best results were obtained using a balanced signature.

Algorithms↗

PubMed2003

The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews.

BACKGROUND: In the era of evidence based medicine, with systematic reviews as its cornerstone, adequate quality assessment tools should be available. There is currently a lack of a systematically developed and evaluated tool for the assessment of diagnostic accuracy studies. The aim of this project was to combine empirical evidence and expert opinion in a formal consensus method to develop a tool to be used in systematic reviews to assess the quality of primary studies of diagnostic accuracy. METHODS: We conducted a Delphi procedure to develop the quality assessment tool by refining an initial list of items. Members of the Delphi panel were experts in the area of diagnostic research. The results of three previously conducted reviews of the diagnostic literature were used to generate a list of potential items for inclusion in the tool and to provide an evidence base upon which to develop the tool. RESULTS: A total of nine experts in the field of diagnostics took part in the Delphi procedure. The Delphi procedure consisted of four rounds, after which agreement was reached on the items to be included in the tool which we have called QUADAS. The initial list of 28 items was reduced to fourteen items in the final tool. Items included covered patient spectrum, reference standard, disease progression bias, verification bias, review bias, clinical review bias, incorporation bias, test execution, study withdrawals, and indeterminate results. The QUADAS tool is presented together with guidelines for scoring each of the items included in the tool. CONCLUSIONS: This project has produced an evidence based quality assessment tool to be used in systematic reviews of diagnostic accuracy studies. Further work to determine the usability and validity of the tool continues.

Bias↗

PubMed2006

The added value of C-reactive protein to clinical signs and symptoms in patients with obstructive airway disease: results of a diagnostic study in primary care.

BACKGROUND: To evaluate the diagnostic accuracy of clinical signs and symptoms, C-reactive protein (CRP) and spirometric parameters and determine their interrelation in patients suspected to have an obstructive airway disease (OAD) in primary care. METHODS: In a cross sectional diagnostic study, 60 adult patients coming to the general practitioner (GP) for the first-time with complaints suspicious for obstructive airway disease (OAD) underwent spirometry. Peak expiratory flow (PEF)-variability within two weeks was determined in patients with inconspicuous spirometry. Structured medical histories were documented and CRP was measured. The reference standard was the Tiffeneau ratio (FEV1/VC) in spirometry and the PEF-variability. OAD was diagnosed when FEV1/VC < or = 70% or PEF-variability > 20%. RESULTS: 37 (62%) patients had OAD. The best cut-off value for CRP was found at 2 mg/l with a diagnostic odds ratio (OR) of 4.4 (95% CI 1.4-13.8). Self-reported wheezing was significantly related with OAD (OR 3.4; CI 1.1-10.3), whereas coughing was inversely related (OR 0.2; CI 0.1-0.7). The diagnostic OR of CRP increased when combined with dyspnea (OR 8.5; 95% CI 1.7-42.3) or smoking history (OR 8.4; 95% CI 1.5-48.9). CRP (p = 0.004), FEV1 (p = 0.001) and FIV1 (p = 0.023) were related with the severity of dyspnea. CRP increased with the number of cigarettes, expressed in pack years (p = 0.001). CONCLUSION: The diagnostic accuracy of clinical signs and symptoms was low. The diagnostic accuracy of CRP improved in combination with dyspnea and smoking history. Due to their coherence with the severity of dyspnea and number of cigarettes respectively, CRP and spirometry might allow risk stratification of patients with OAD in primary care. Further studies need to be done to confirm these findings.

Adult↗

PubMed1990

The validity of 3 clinical diagnostic criteria for Alzheimer's disease.

To examine the validity of criteria-based (clinical) diagnosis of Alzheimer's disease (AD), 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients based on standardized medical record information. Diagnostic outcome was validated by neuropathologic examination (completed previously) for all (43) demented patients and 4 nondemented patients and by follow-up in the remainder (15) with no dementia. Raters were blind to the composition of the study group as well as to the clinical and pathologic diagnoses. We evaluated 3 diagnostic criteria sets for AD: the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the NINCDS-ADRDA Work Group criteria for the diagnosis of Alzheimer's disease (NINCDS), and the Eisdorfer and Cohen research diagnostic criteria for primary neuronal degeneration (ECRDC). ECRDC had the highest specificity (0.88) but also the greatest odds of false-negative diagnosis (LRneg = 0.61, sensitivity = 0.46). NINCDS had the best sensitivity (0.92, specificity = 0.65), and DSM-III showed intermediate values (sensitivity = 0.76, specificity = 0.80). We conclude that the investigator or clinician who wishes to ensure that patients classified as AD are more likely to be AD should choose DSM-III, whereas the investigator who wishes to include the greatest number of AD cases, seldom assigning a diagnosis of no AD to a true case, should choose NINCDS.

Aged↗

PubMed2005

Diagnostic utility of bone marrow sampling in HIV-infected patients since the advent of highly active antiretroviral therapy.

We investigated the diagnostic value of bone marrow (BM) sampling in investigation of HIV-infected patients presenting to a major London HIV treatment centre between 1999 and 2004. One hundred and fourteen consecutive patients underwent 130 BM samplings. The majority of BM aspirates were normal or showed non-diagnostic changes; microscopy revealed lymphoma in one and mycobacterial infection in two. Subsequent culture identified mycobacterial infection in nine samples. BM trephine had a diagnostic yield of 26% in patients with fever and cytopaenia (including mycobacteriosis in 14%, lymphoma in 6%, Castleman disease in 3% and "drug effect" in 3%), a yield of 20% in patients with fever, but no cytopaenia (mycobacteriosis in each case), and a yield of 19% in patients with cytopaenia in the absence of fever (lymphoma in 5% and "drug effect" in 14%). In investigation/staging of lymphoma, the diagnostic yield was 36%. The overall yield from BM sampling was 30% in patients receiving highly active antiretroviral therapy (HAART) and 23% in those not receiving HAART. In this study, BM sampling was of most diagnostic value in HIV-infected patients where fever and cytopaenia coexisted in the absence of localizing signs of infection, and in the staging/investigation of lymphoma. BM sampling had less diagnostic value in the investigation of fever without cytopaenia or cytopaenia without fever.

AIDS-Related Opportunistic Infections↗

PubMed2004

Clarity and diagnostic quality of digitized conventional intraoral radiographs.

OBJECTIVES: To compare digital images of conventional radiographs with the original radiographs for perceived clarity of endodontic files, periapical lesions and carious lesions, and to establish the diagnostic value of the digital images. METHODS: Four groups of ten radiographs were used: standardized bitewings demonstrating carious lesions, periapical radiographs of apical lesions, periapical radiographs showing endodontic files of various sizes at working length, and standardized periapical radiographs with size 08 files at working length. Radiographs were photographed using an Olympus C 2500-L digital camera and a Nikon D1X digital camera and were scanned using a Nikon Supercoolscan 4000 ED film/slide scanner. The digital images were then transferred to a Toshiba Satellite 2210 laptop. Three general dental practitioners compared each conventional radiograph with the three matching digital images. Images were ranked for clarity and were assessed for diagnostic quality. Data were analysed using General Estimating Equations. RESULTS: The clarity and diagnostic quality of the conventional radiographs were superior to the digital images produced by the three techniques (P < 0.001). No significant difference was found between the Nikon D1X and Camedia 2500-L cameras for clarity or diagnostic quality. The scanner was equivalent to the Camedia 2500-L camera for diagnostic quality, but was otherwise inferior to both cameras. CONCLUSIONS: Digitizing conventional radiographs using current high-grade digital cameras or scanners does not produce images of diagnostic quality. Improved resolution of viewing monitors is necessary to fully harness the potential of digital technology.

Computer Terminals↗

PubMed2000

Diagnostic yield of fiberoptic bronchoscopy in evaluating solitary pulmonary nodules.

STUDY OBJECTIVES: To evaluate factors affecting the diagnostic yield of flexible fiberoptic bronchoscopy in evaluating solitary pulmonary nodules (SPNs). DESIGN: Retrospective analysis of bronchoscopies performed over a 4-year period. SETTING: A tertiary teaching hospital. PATIENTS: One hundred seventy-seven patients with pulmonary nodules without endobronchial lesions who underwent bronchoscopy with brushing, washing, and transbronchial biopsy. RESULTS: There were 151 malignant and 26 benign lesions. The diagnostic accuracy of bronchoscopy in malignant and benign lesions were 64% (97 of 151) and 35% (9 of 26), respectively. The yield of bronchoscopy was directly related to lesion size (p < 0.001, chi(2)). When lesions were grouped according to distance from the hilum, yields of bronchoscopy in central, intermediate, and peripherally located lesions were 82, 61, and 53%, respectively (p = 0.05, chi(2)). When we stratified distance from the hilum by lesion size, the difference in yield was not significant. However, lesions </= 2 cm had a diagnostic yield of 14% (2 of 14) when located in the peripheral third vs 31% (5 of 16) when located in the inner two thirds of the lung. There was a trend toward higher combined diagnostic yield in right middle and lingular lobes when compared to all other segments (p = 0.09, chi(2)). Transbronchial biopsy, washing, and brushing were complementary in improving the yield of bronchoscopy. CONCLUSIONS: Size is the strongest determinant of diagnostic yield in bronchoscopy when evaluating SPNs. The yield of bronchoscopy is particularly low in lesions </= 2 cm that are located in the outer third of the lung. Thus, alternative diagnostic approaches may be preferable in this situation.

Adult↗

PubMed2002

Applying sputum as a diagnostic tool in pneumonia: limited yield, minimal impact on treatment decisions.

STUDY OBJECTIVES: We evaluated the role of sputum examination in the management of patients with community-acquired pneumonia (CAP) in a primary-care hospital without microbiologic laboratory facilities. DESIGN AND INTERVENTIONS: A diagnostic strategy using regular collection of sputum samples, Gram staining in a local laboratory, and mailing of samples to a commercial laboratory for culture analysis. SETTING: A 200-bed primary-care hospital without subspeciality physicians. PATIENTS: One hundred sixteen consecutive patients with a diagnosis of CAP were prospectively evaluated during a 12-month period. RESULTS: Of 116 patients, 42 patients (36%) were capable of producing a sputum sample. Age > or = 75 years (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.18 to 0.93) and prior ambulatory antimicrobial treatment (OR, 3.2; 95% CI, 1.2 to 8.4) were independent predictors of sputum production. A delay in collection and processing of sputum samples of > 24 h was present in 31% and 39%, respectively. A delay in collection yielded an increased number of Gram-negative enteric bacilli and nonfermenters (44% vs. 7%, p = 0.056). A delay in processing was associated with an increased number of Candida spp isolates (33% vs. 9%, p = 0.16). The overall diagnostic yield was low (10 of 116 patients, 9%) due to a limited number of valid samples (n = 23 of 42 patients, 55%) and a limited number of definitely or probably positive samples on Gram's stain and culture (n = 10 of 42 patients, 24%). Prior ambulatory antimicrobial treatment was associated with a reduction in diagnostic yield (14% vs. 56%, p = 0.09). The impact of diagnostic results on antimicrobial treatment decisions was minimal, with antimicrobial treatment directed to diagnostic results in only one patient. CONCLUSIONS: We conclude that in this setting representative of primary-care hospitals in Germany, sputum had a low diagnostic yield and did not contribute significantly to patient management.

Adult↗

PubMed2003

Diagnostic accuracy and safety of flexible bronchoscopy with multiplanar reconstruction images and ultrafast Papanicolaou stain: evaluating solitary pulmonary nodules.

STUDY OBJECTIVES: To assess the diagnostic accuracy and safety of flexible bronchoscopy with multiplanar reconstruction (MPR) images and ultrafast Papanicolaou (UFP) stain in evaluating solitary pulmonary nodules (SPNs). DESIGN: Prospective study of bronchoscopies performed between June 2000 and June 2002. PATIENTS: One hundred consecutive patients with SPNs underwent bronchoscopy with MPR and UFP (MPR and UFP group). The data on historical control were collected in a retrospective fashion, between July 1997 and June 2000. METHOD: All information obtained from MPR regarding the leading bronchus of the SPNs was used to guide biopsy. Samples obtained by curette biopsies were stained with UFP and evaluated by a cytopathologist during the bronchoscopy procedure. RESULTS: There were 88 malignant and 12 benign lesions in the MPR and UFP group, and 97 malignant and 3 benign lesions in the historical control group. The total diagnostic accuracy of bronchoscopy in the MPR and UFP group (91%) was significantly higher compared with the historical control group (58%) [p < 0.05]. Although the yield of bronchoscopy was significantly related to the lesion size in the historical control group (p < 0.05), there was no significant association between the diagnostic yield and lesion size in the MPR and UFP group. The diagnostic yield for SPNs < 4.0 cm in the MPR and UFP group was significantly higher compared with the historical control group (p < 0.05). In addition, the diagnostic yield in both upper lobes in the MPR and UFP group was significantly higher compared with the historical control group (p < 0.05). On the contrary, the complication rate was significantly lower in the MPR and UFP group (2%) compared with the historical control group (13%) [p < 0.05]. CONCLUSION: Combined use of the MPR image and UFP during flexible bronchoscopy improved diagnostic accuracy and safety in evaluating SPNs using a double-hinged curette.

Adult↗

PubMed1999

A prospective multicenter trial evaluating diagnostic validity of multivariate analysis and individual serum marker in differential diagnosis of pancreatic cancer from benign pancreatic diseases.

CONCLUSION: A multivariate analysis of CAMPAS-PX2 can increase its diagnostic accuracy in differential diagnosis of pancreatic cancer from benign pancreatic or extrapancreatic disease, when compared with CA19-9 alone. However, the improvement in diagnostic accuracy is still not satisfactory in spite of an elaborate combination of serum markers in diagnosis for pancreatic cancer. Optimal combination of a sensitive serum marker and another diagnostic modality, such as ultrasonography, can be a practical way to improve important diagnostic and cost-effectiveness in diagnosis for pancreatic cancer. BACKGROUND: No specific biological test has yet been developed for diagnosis of pancreatic cancer, although increasing numbers of tumor markers become available. For improvement in the diagnostic and cost effectiveness, it is important to select optimal combination of several serum markers relatively independent of each other. METHODS: A new model of discriminant function, computer-aided multivariate and pattern analysis system for pancreatic cancer examination 2 (CAMPAS-PX2), was developed based on the data of the 23 serum tumor markers from the first prospective trial (1) to differentiate between pancreatic cancer and benign pancreatobiliary disease by logistic regression analysis using a stepwise selection method. In 243 patients suspected of having pancreatic pancreatic cancer by a multicenter prospective study, the diagnostic value of the multivariate analysis, CAMPAS-PX2, was compared with the 23 markers. RESULTS: Pancreatic cancer was subsequently identified in 27 patients. Positive in disease, negative in health, and area under receiver operating characteristic curve were significantly higher by CAMPAS-PX2 (89, 87, 91%) than by CA 19-9 (78, 82, 84%), the most sensitive marker among the 23 markers.

Biomarkers, Tumor↗

PubMed1980

The NCA diagnostic criteria: critique, assessment, alternatives.

This analysis of the NCA diagnostic criteria has noted the relative lack of use and lack of research pertinent to the instrument. A critique and assessment of the criteria reveal major conceptual, methodological, psychometric and utilitarian problems. This may well explain why the instrument has received relatively little attention. Although the document (1) presents a legitimate diagnostic approach, it is narrow in scope and severely limited in applicability. Other diagnostic instruments exist which accomplish the same diagnostic task as the NCA diagnostic criteria, but in addition have more desirable psychometric qualities and are more utilitarian. Finally, more sophisticated methodologies, with the requisite psychometric and conceptual flexibility to deal with the data, have been developed, which render the NCA diagnostic criteria obsolete.

Alcoholism↗

PubMed1999

Minimum incidence and diagnostic rate of first urinary tract infection.

OBJECTIVE: To study awareness of urinary tract infections (UTIs) by determining the diagnostic rate of first UTI in children <2 years of age and to estimate the minimum incidence. METHODS: Twenty-six of a total of 43 pediatric centers participated in the study. Sixty-four percent of the total childhood population <2 years of age was covered. The number of all children included in the study was used to calculate the diagnostic rate. Only UTI confirmed by either suprapubic aspiration (any growth) or midstream or bag samples with >/=100 000 bacteria/mL, together with a positive nitrite reaction, was used to estimate the minimum incidence. RESULTS: The mean diagnostic rate was 1.5% for boys (range, 0.7%-3.0%) and 1.7% for girls (range, 0.7%-2.9%). The diagnostic rate was significantly higher in June than in December. The mean incidence was 1.0% for both boys and girls (range, 0.3%-3.0% and 0.4%-2.9%, respectively). The minimum cumulative incidence at 2 years of age was estimated to be 2.2% for boys and 2.1% for girls. CONCLUSION: This study suggests a high UTI awareness in Sweden as indicated by a higher diagnostic rate and, despite stricter diagnostic criteria, a higher incidence of UTI in children <2 years of age than previously reported. It is suggested that a high UTI awareness may reduce chronic renal failure because of pyelonephritic renal scarring.

Female↗

PubMed2000

Identifying insecticide-resistant greenbugs (Homoptera: Aphididae) with diagnostic assay tests.

Laboratory bioassays were used to develop a diagnostic assay test for identifying greenburg, Schizaphis graminum (Rondani), populations that are insecticide-resistant. Petri dish assays with chlorpyrifos showed greenbug mortality should be monitored after 2 h of exposure. One-hour exposure did not kill a high percentage of susceptible greenbugs, and a 3-h exposure killed too many resistant greenbugs. Ethanol and methanol were both good solvents for mixing with chlorpyrifos in the petri dish assay. From the laboratory bioassays, four diagnostic concentrations of chlorpyrifos (3, 10, 30, and 100 ppm) were evaluated in the field by Texas A&M University agricultural research and extension entomologists across the Texas High Plains. Results from the diagnostic assay tests were compared with gel-electrophoresis resistance tests to validate resistance detection. The diagnostic assay tests gave the same greenbug resistance identification as the gel-electrophoresis analysis in 21 of 22 field bioassays in 1994 and 35 of 39 field bioassays in 1995. Diagnostic concentrations of 30 and 100 ppm chlorpyrifos killed > or = 85 and > or = 90%, respectively, of greenbugs identified by gel-electrophoresis as susceptible and < 40% and < 55%, respectively, of resistant greenbugs. The diagnostic assay technique is a quick, reliable, and inexpensive method for detecting insecticide resistance in greenbug populations.

Animals↗

PubMed1998

International standards for test methods and reference sera for diagnostic tests for antibody detection.

International standards are necessary to ensure that the diagnostic tests used by trading partners meet a minimum standard of diagnostic performance. The tests that are used to qualify animals for international movement must provide a degree of confidence that those animals which give negative test results (and therefore qualify for movement) are free of a particular infectious disease agent. Without the development of standards for diagnostic tests, no level of international harmonisation can ever be achieved. International standards for both test methods and sera serve to establish a baseline on which inferences can be made with respect to the diagnostic performance of a given test in a given laboratory. International standard test methods set baseline analytical and diagnostic performance requirements for new reagents or methodologies. International standard sera are primary reference standards and serve as both reference materials for the calibration of test methods and reagents and prototypes for the production of national and working standards. For most serological test methods, three standard sera should be established: a strong positive, a weak positive and a negative standard. These standards are used to calibrate the detection range and analytical sensitivity of the test method. Assays calibrated in this way are more likely to exhibit a diagnostic sensitivity and specificity which parallels that of the standard test method, thus resulting in a higher degree of international harmonisation.

Animals↗

PubMed2005

Diagnostic accuracy of a new clinical test (the Thessaly test) for early detection of meniscal tears.

BACKGROUND: Clinical tests used for the detection of meniscal tears in the knee do not present acceptable diagnostic sensitivity and specificity values. Diagnostic accuracy is improved by arthroscopic evaluation or magnetic resonance imaging studies. The objective of this study was to evaluate the diagnostic accuracy of a new dynamic clinical examination test for the detection of meniscal tears. METHODS: Two hundred and thirteen symptomatic patients with knee injuries who were examined clinically, had magnetic resonance imaging studies performed, and underwent arthroscopic surgery and 197 asymptomatic volunteers who were examined clinically and had magnetic resonance imaging studies done of their normal knees were included in this study. For clinical examination, the medial and lateral joint-line tenderness test, the McMurray test, the Apley compression and distraction test, the Thessaly test at 5 degrees of knee flexion, and the Thessaly test at 20 degrees of knee flexion were used. For all clinical tests, the sensitivity, specificity, false-positive, false-negative, and diagnostic accuracy rates were calculated and compared with the arthroscopic and magnetic resonance imaging data for the test subjects and the magnetic resonance imaging data for the control population. RESULTS: The Thessaly test at 20 degrees of knee flexion had a high diagnostic accuracy rate of 94% in the detection of tears of the medial meniscus and 96% in the detection of tears of the lateral meniscus, and it had a low rate of false-positive and false-negative recordings. Other traditional clinical examination tests, with the exception of joint-line tenderness, which presented a diagnostic accuracy rate of 89% in the detection of lateral meniscal tears, showed inferior rates. CONCLUSIONS: The Thessaly test at 20 degrees of knee flexion can be used effectively as a first-line clinical screening test for meniscal tears, reducing the need for and the cost of modern magnetic resonance imaging methods.

Adolescent↗

PubMed2025

Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention. FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster.

Journal Article↗

PubMed2006

Diagnostic and therapeutic strategy for acute pulmonary thromboembolism.

BACKGROUND: The diagnostic and therapeutic strategy for acute pulmonary thromboembolism (APTE) was published by the Japanese Circulation Society. But in Japan, there has been no report on how to improve the pre-test probability in APTE-suspected cases, to determine a practically available diagnostic strategy, nor has been a report that compares diagnostic methods and therapies for APTE by decision analysis. METHODS AND RESULTS: APTE was found in 66.7% before using diagnostic imaging techniques. Compared with the absence of APTE, prolonged immobilization, cancer, tachycardia, unilateral leg swelling and inverted T-wave in V(1-3) were found more often in the presence of APTE. The rate of obtaining the result on the day of ordering the examination test was 100% with arterial blood gas analysis, trans-thoracic echocardiography and computed tomography (CT), 78.2% in D-dimer, 85.5% in pulmonary angiography, and 54.5% in perfusion lung scan. Decision analysis showed that the highest expected utility was anticoagulant over 0.51 in pre-test probability, with CT between 0.13 and 0.51. CONCLUSIONS: The pre-test probability of APTE has already been high before using specific diagnostic imaging techniques in Japan. Our results showed that the diagnostic strategy for APTE made by the Japanese Circulation Society was available in most hospitals in Japan.

Acute Disease↗