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PubMed2000

Clinical tests of the sacroiliac joint.

In the literature many tests are described which are designed to provoke pain or detect joint mobility in the sacroiliac joint (SIJ). However, in part 1 of this review, the authors stated that there is little evidence of reliability of these tests. In this article, the authors describe the methodological review of 11 studies, which have dealt with the validity of SIJ tests. The methodological quality of the studies was tested by using a list of criteria that consisted of three categories: 1) study population, 2) test procedure and 3) test results. A weighting for each criterion was developed. The methodological score for the studies was, in general, disappointing and looked promising for only two out of 11 studies (58 and 64 points). Four authors drew conclusions of positive validity from the tests they studied but other authors did not confirm these results. The conclusion of this methodological review is that there is no evidence to support the inclusion of mobility and pain provocation tests for the SIJ in clinical practice. Three major problems have been identified in validating SIJ dysfunction tests. Firstly, poor reliability of SIJ dysfunction tests exists, which may be improved by multiple test scores as postulated in part 1 of this review. Secondly, the methodological quality of validity studies needs to be developed to a much higher level with special consideration paid to sensitivity, specificity, confidence intervals and likelihood ratio values. And finally, there is a need for the proper use of a gold standard in assessing the validity of SIJ tests.

Humans↗

PubMed1996

The reliability of aerobic capacity (VO2max) testing in adolescent girls.

Despite the fact that our subjects were naive regarding the test procedures, it appears that aerobic fitness testing using an incremental treadmill protocol is extremely reliable in adolescent girls. In addition, day-to-day variability of VO2max in our subjects averaged less than 5%, which is similar to results obtained with adults (Katch, Sady, & Freedson, 1982). Finally, it was most encouraging to find that a single VO2max test trial resulted in high reliability coefficients. This finding should provide a great deal of confidence to investigators who are performing aerobic fitness tests on large numbers of subjects where multiple testing is neither practical nor cost-effective.

Adolescent↗

PubMed2006

Single nucleotide polymorphisms in DNA repair genes and basal cell carcinoma of skin.

In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P = 0.0007, multiple testing corrected P = 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in non-carriers (P = 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and gender-specific effect by E185Q polymorphism in NBS1.

Adolescent↗

PubMedDate not supplied

Spirometry and obstructive lung disease in Manitoba.

BACKGROUND: Spirometry, the measurement of forced expiratory volume in 1 s and forced vital capacity, is recommended in the diagnosis and management of the obstructive lung diseases asthma and chronic obstructive pulmonary disease (COPD). The present report describes spirometry use in Manitoba and tests the hypothesis that regional spirometry use correlates with the prevalence of physician-diagnosed obstructive lung diseases. METHODS: Spirometry is renumerated on a fee-for-service basis by Manitoba Health. Like other physician services, billing data include a diagnosis, patient identifiers, as well as the patient's sex, date of birth and residential postal code. Physician billings for spirometry for 1991 to 1998 were analyzed, comparing data with billings for physician visits for obstructive diseases. Four age groups were examined, as were income quintiles in Winnipeg, Manitoba. In addition, the prevalence of physician-diagnosed obstructive diseases were compared with spirometry rates in 49 service use areas of the province. RESULTS: Annually, about 3% of the Manitoba population underwent spirometry, and in aggregate, about 14% underwent spirometry during the eight years of the study. Rates in Winnipeg were higher than in the remainder of the province. Spirometry rates did not increase with time, and people who underwent spirometry had 1.4 to 1.7 tests/year. In children, higher income quintiles were tested more than lower income quintiles, while in adults, income quintiles were tested with equal frequency. People with obstructive lung disease accounted for about 75% of those tested, and in people with these diagnoses, the likelihood of testing increased approximately linearly with the number of physician visits for asthma or COPD. Children with asthma were tested less often than adults, and adults with asthma or both asthma and COPD were tested more often than those with COPD alone. In adults with asthma or asthma and COPD who had more than 10 physician visits for these diagnoses, testing rates were more than 70%, and multiple tests were common. In patients labelled with COPD only and with more than 20 physician visits, about one-third did not undergo spirometry. In children aged five to 14 years and in adults 15 to 44 years old, regional spirometry rates correlated well with regional asthma rates. Regional spirometry rates also correlated significantly with regional rates of asthma and/or COPD in people older than 34 years old. INTERPRETATION: Spirometry use is considerably higher in patients with asthma than in patients with COPD, suggesting that guidelines are followed more closely in patients with asthma, and that many patients are labelled with COPD without appropriate documentation. Spirometry use is apparently indicative of physician interest in the problem of obstructive lung diseases.

Adolescent↗

PubMed1983

Interactive microcomputer-based graphical tools for physician decision support. Aids to test selection and interpretation and use of Bayes' theorem.

Three microcomputer programs have been developed to give the practicing physician graphic aid in assessing the usefulness of obtaining a diagnostic test, to assist in interpreting the result after a test has been obtained, and to facilitate exploration of, and familiarity with, the use of Bayes' theorem in clinical practice. Each program uses a different representation for depicting the transformation of pretest to post-test probability produced by the various results of the test. Choice of representation depends on whether multiple tests or results are evaluated concurrently, on the probability range of interest, and on which model the user finds most intuitively appealing. A library of data on sensitivities and specificities of various tests and procedures can be used to select tests of interest from a menu, or data may be entered by the user.

Bayes Theorem↗

PubMed2003

Linkage and association analysis of radiation damage repair genes XRCC3 and XRCC5 with nevus density in adolescent twins.

Previous studies have shown that a deficiency in DNA damage repair is associated with increased cancer risk, and exposure to UV radiation is a major risk factor for the development of malignant melanoma. High density of common nevi (moles) is a major risk factor for cutaneous melanoma. A nevus may result from a mutation in a single UV-exposed melanocyte which failed to repair DNA damage in one or more critical genes. XRCC3 and XRCC5 may have an effect on nevus count through their function as components of DNA repair processes that may be involved directly or indirectly in the repair of DNA damage due to UV radiation. This study aims to test the hypothesis that the frequency of flat or raised moles is associated with polymorphism at or near these DNA repair genes, and that certain alleles are associated with less efficient DNA repair, and greater nevus density. Twins were recruited from schools in south eastern Queensland and were examined close to their 12th birthday. Nurses examined each individual and counted all moles on the entire body surface. A 10cM genome scan of 274 families (642 individuals) was performed and microsatellite polymorphisms in XRCC3 and adjacent to XRCC5 were also typed. Linkage and association of nevus count to these loci were tested simultaneously using a structural-equation modeling approach implemented in MX. There is weak evidence for linkage of XRCC5 to a QTL influencing raised mole count, and also weak association. There is also weak evidence for association between flat mole count and XRCC3. No tests were significant after correction for testing multiple alleles, nor were any of the tests for total association significant. If variation in XRCC3 or XRCC5 influences UV sensitivity, and indirectly affects nevus density, then the effects are small.

Adolescent↗

PubMed1982

Neuropsychological deficits among patients with chronic obstructive pulmonary disease.

Sixty-six patients with chronic obstructive pulmonary disease (COPD) were evaluated for neuropsychological functioning. While the patients showed normal skills on broad intellectual tasks, they displayed mild cerebral deficits on several neuropsychological tests. Multiple regression analyses revealed that the neuropsychological test battery scores were significantly related to partial pressure of arterial oxygen (PaO2), and to degree of pulmonary impairment. Although the cognitive deficits were real, they were generally small. This result may explain why the widely assumed link between chronic lung disorders and cognitive deficit has been difficult to demonstrate. The general pattern was similar to deficits produced by chronic alcoholism and childhood asthma, with complex skills suffering the greatest insult. Because the cognitive deficits among COPD patients in stable condition are small, it is uncertain whether they have importance clinically or for accomplishing daily activities.

Aged↗

PubMed1999

Evaluation of the MicroScan system for identification of staphylococci.

Conventional biochemical tests were compared with reactions in a multiple test system, MicroScan Walkaway (Dade Diagnostic Inc. MicroScan Divison, West Sacramento, California) in conjugation with the Combo Pos ID Panels (Dade Diagnostic Inc. MicroScan Divison, West Sacramento, California), in order to evaluate the accuracy for the identification of 99 clinical isolates of Staphylococcus spp. and five reference strains. False-negative or positive reactions were detected from Voges-Proskauer, urease and mannose tests. A good correlation was found among the two identification systems for the fermentation of trehalose, lactose, raffinose, as well as for arginine dyhydrolase, esculin hydrolisis and nitrate reduction. From the results of the present study, it is concluded that the MicroScan Walkaway system is a reliable method for identification of staphylococci (94.23%), although 8.2% could be identified to the species level only after use of additional test.

Bacterial Typing Techniques↗

PubMed2001

Tree models for dependent copy number changes in bladder cancer.

We analyzed comparative genomic hybridization data on a collection of 237 bladder cancer tumors with the aim of identifying sets of copy number aberrations (CNAs) that tend to occur together. A test based on Fisher's exact test for pairs, but taking into account multiple testing, showed strong dependencies amongst several pairs of aberrations including (+1q, -11p), (+17q, +20q), (+10p, -17p), (-8p, -17p), (+5p, +10p). To determine whether co-occurrence of CNAs may characterize tumor subtypes, we used two recently proposed methods to construct tree models of tumor progression. We constructed tree models for all the tumors, the tumors of stage pT1, and the tumors of stages pT2-4. The tree models confirmed that most of the non-random events and the associations are the same for different stages. We conclude that the combination of large data sets and tree models provide a useful approach to systematically identifying tumor subgroups characterized by more than a single chromosomal aberration.

Algorithms↗

PubMed2005

Integrating genomics and transcriptomics with geo-ethnicity and the environment for the resolution of complex cardiovascular diseases.

One of the crucial steps on the way to individualized medicine to treat cardiovascular disease (CVD) is to better understand the identities, roles, extent and at least the major patterns of interaction between influential genomic and environmental factors. It is clear that such a bold goal can hardly be achieved without a major upgrade of our conceptualization of the phenomena studied, taking advantage of recent developments of novel technological and computational tools. Firstly, the search for the genomic components of the most common multifactorial CVDs is no longer restricted to protein-coding genes; truly genome-wide investigations should replace them in both humans and animal models. Secondly, the 'environment' has also undergone semantic expansion, incorporating such remote constituents as developmental plasticity and epigenetics on one side, and socioeconomic status on the other. To elucidate and analyze the resulting complex picture, appropriate statistical models and approaches need to be designed to tackle issues such as population stratification and admixture, multiple testing, and multidimensionality reduction in models involving multiple genes and environmental factors. Eventually, an integrated platform bringing together all of the above will probably be necessary to secure relevant information specific to a particular combination of conditions and settings (age, geo-ethnicity and exposure), which may perhaps become visible only after a step back, through systems (network) biology.

Animals↗

PubMed1998

Expression of prostate-specific antigen and prostate-specific membrane antigen transcripts in blood cells: implications for the detection of hematogenous prostate cells and standardization.

Circulating prostate cells can be detected in cancer patients by using reverse transcriptase-PCR (RT-PCR) assay for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) mRNA. A quality-control study involving a conventional RT-PCR assay was performed and, surprisingly, detected both transcripts in many negative control cell lines and in normal blood samples. The existence of an illegitimate transcription of the PSA and PSM genes was evidenced by sequence analysis of several PSM and PSA-PCR products. Sequencing indeed demonstrated the presence of a PSA or PSM polymorphism in some but not all the cell lines and patient samples, as well as a heterozygous mutation (G to A; Asp to Asn) in the Jurkat cell line. Moreover, the amount of PSA transcript in MCF-7, a PSA-negative breast line, increased after incubation with cycloheximide. Interestingly, the frequency of positivity was as high as 12% in male samples if only tested once, but dropped to 3% upon multiple testing of the same cDNA. This highlights the stochastic effects in RT-PCR results at high sensitivity, hence the importance of repetitive testing in clinical samples. Decreasing the number of cycles avoided the amplification of illegitimate transcripts but also affected the limit of detection, as evidenced with PSA and PSM cDNA containing plasmids, mixing of LNCap with normal blood samples, and the PSA-PSM-negative K562 cell line. The current data raise the need for a multicentric standardization of the RT-PCR methodology used to amplify PSA and PSM transcripts.

Adult↗

PubMed1987

Comparison of a multiple puncture tuberculin test, 'Imotest', and the Mantoux test in an Australian population.

The new multiple puncture tuberculin testing device, 'Imotest', was compared to the Mantoux test (10 I.U.) in an Australian population. The tests were applied simultaneously to opposite forearms of 105 volunteers. Sixty-eight per cent of the Mantoux tests were positive compared to 39% of the 'Imotests', resulting in a false negative rate of 44% and the difference was highly significant. A further 30 volunteers were tested with a different batch of 'Imotest' and similar results were obtained. When multiple 'Imotests' were applied simultaneously to each of two subjects in a separate study, there was a wide variation of response within each subject, and positive and negative reactions occurred side by side. These results indicate that the 'Imotest' is significantly less sensitive than the Mantoux test and is unsuitable for use as a diagnostic or screening test.

Australia↗

PubMed2004

Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections.

OBJECTIVES: Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (DeltaF508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders. The objective of this study was to evaluate technical feasibility and practical implications of 2-tiered CF newborn screening that uses testing for multiple mutations (multiple-CFTR-mutation testing). METHODS: We implemented statewide CF newborn screening using a 2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT then had multiple-CFTR-mutation testing. Infants who screened positive by detection of 1 or 2 mutations or extremely elevated IRT (>99.8%; failsafe protocol) were then referred for definitive diagnosis by sweat testing. We compared the number of sweat-test referrals using single- with multiple-CFTR-mutation testing. Initial physician assessments and diagnostic outcomes of these screened-positive infants and any affected infants missed by the screen were analyzed. We evaluated compliance with our screening and follow-up protocols. All Massachusetts delivery units, the Newborn Screening Program, pediatric health care providers who evaluate and refer screened-positive infants, and the 5 Massachusetts CF Centers and their affiliated genetic services participated. A 4-year cohort of 323 506 infants who were born in Massachusetts between February 1, 1999, and February 1, 2003, and screened for CF at approximately 2 days of age was studied. RESULTS: A total of 110 of 112 CF-affected infants screened (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation screening; 2 false-negative screens did not show elevated IRT. A total of 107 (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation screen, and 3 had positive screens on the basis of the failsafe protocol. In contrast, had we used single-mutation testing, only 96 (87%) of the 110 would have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had positive screens on the basis of the failsafe protocol, and an additional 6 infants would have had false-negative screens. Among 110 CF-affected screened-positive infants, a likely "genetic diagnosis" was made by the multiple-CFTR-mutation screen in 82 (75%) versus 55 (50%) with DeltaF508 alone. Increased sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals for sweat testing and carrier identifications than testing with DeltaF508 alone. CONCLUSIONS: Use of multiple-CFTR-mutation testing improved sensitivity and postscreening prediction of CF at the cost of increased referrals and carrier identification.

Algorithms↗

PubMed2005

Computer based safety training: an investigation of methods.

BACKGROUND: Computer based methods are increasingly being used for training workers, although our understanding of how to structure this training has not kept pace with the changing abilities of computers. Information on a computer can be presented in many different ways and the style of presentation can greatly affect learning outcomes and the effectiveness of the learning intervention. Many questions about how adults learn from different types of presentations and which methods best support learning remain unanswered. AIMS: To determine if computer based methods, which have been shown to be effective on younger students, can also be an effective method for older workers in occupational health and safety training. METHODS: Three versions of a computer based respirator training module were developed and presented to manufacturing workers: one consisting of text only; one with text, pictures, and animation; and one with narration, pictures, and animation. After instruction, participants were given two tests: a multiple choice test measuring low level, rote learning; and a transfer test measuring higher level learning. RESULTS: Participants receiving the concurrent narration with pictures and animation scored significantly higher on the transfer test than did workers receiving the other two types of instruction. There were no significant differences between groups on the multiple choice test. CONCLUSIONS: Narration with pictures and text may be a more effective method for training workers about respirator safety than other popular methods of computer based training. Further study is needed to determine the conditions for the effective use of this technology.

Adult↗

PubMed2004

Vegetable, fruit and meat consumption and potential risk modifying genes in relation to colorectal cancer.

Epidemiological evidence shows high red meat consumption to increase the risk of colorectal cancer, while the consumption of fruit and vegetables has been shown to be protective. Many genes have been identified that encode for enzymes involved in the metabolism of dietary carcinogens or anti-carcinogens. A study of 500 incident colorectal cancer cases and population controls, matched for age, sex and general practitioner, was conducted in the United Kingdom to investigate whether 6 such genes (CYP1A1, GSTT1, GSTM1, GSTP1, EPHX1 and NQO1) modify the relationship between diet and disease risk. Usual diet was estimated using a detailed questionnaire administered by interview. Fruit and vegetable consumption were both found to protect against colorectal cancer, while overall meat and red meat consumption were found to increase risk. There was some evidence of interaction between GSTT1 and vegetable consumption (p=0.006, not adjusted for multiple tests) but no evidence of interaction with GSTM1. The protective effect of vegetables was only seen in those with deficient or intermediate GSTT1 predicted phenotype [OR 0.3, 95% confidence interval (0.1, 0.6), and OR 0.6 (0.4, 0.96), OR 1.4 (0.3, 2.4) for those with fast phenotype], and a similar result was observed for cruciferous vegetables. There was also weak evidence of interaction between red meat intake and GSTT1 (p=0.06), GSTP1 (p=0.16, with p=0.02 after adjustment for potential confounders) and NQO1 predicted phenotype (p=0.01). Because of the multiple hypotheses tested in our study, these findings require independent confirmation.

Aged↗

PubMed2025

Causal Inference for Genomic Data with Multiple Heterogeneous Outcomes.

With the evolution of single-cell RNA sequencing techniques into a standard approach in genomics, it has become possible to conduct cohort-level causal inferences based on single-cell-level measurements. However, the individual gene expression levels of interest are not directly observable; instead, only repeated proxy measurements from each individual's cells are available, providing a derived outcome to estimate the underlying outcome for each of many genes. In this paper, we propose a generic semiparametric inference framework for doubly robust estimation with multiple derived outcomes, which also encompasses the usual setting of multiple outcomes when the response of each unit is available. To reliably quantify the causal effects of heterogeneous outcomes, we specialize the analysis to standardized average treatment effects and quantile treatment effects. Through this, we demonstrate the use of the semiparametric inferential results for doubly robust estimators derived from both Von Mises expansions and estimating equations. A multiple testing procedure based on Gaussian multiplier bootstrap is tailored for doubly robust estimators to control the false discovery exceedance rate. Applications in single-cell CRISPR perturbation analysis and individual-level differential expression analysis demonstrate the utility of the proposed methods and offer insights into the usage of different estimands for causal inference in genomics.

Derived outcomes↗

PubMed1997

Significance of a false-positive trisomy 18 multiple-marker screening test.

OBJECTIVE: To determine if a false-positive trisomy 18 multiple-marker screening test (all three analytes low: maternal serum alpha-fetoprotein [AFP] at most 0.75 multiples of the median [MoM], unconjugated estriol at most 0.60 MoM, and hCG at most 0.55 MoM) indicates increased risk for obstetric complications or is related to maternal weight. METHODS: We accessed our genetic database to obtain multiple-marker screening test results, fetal karyotypes, and pregnancy outcomes from all patients with a normal multiple-marker screening test (n = 3900) and from all patients with a positive trisomy 18 screening test (n = 103) seen in the prenatal diagnosis clinic from 1992 to 1996. During this period, only maternal serum AFP was adjusted for maternal weight. RESULTS: A positive trisomy 18 screen identified five of 12 trisomy 18 fetuses. Women with a false-positive trisomy 18 screen were heavier (175.6 +/- 43.8 lb versus 159.9 +/- 37.9 lb, P < .001) and younger (29.7 +/- 6.5 years versus 32.3 +/- 6.5 years, P < .001) than women with a normal multiple-marker screening test, but were not at increased risk for pregnancy complications. Weight-adjusting all three analytes reduced the false-positive trisomy 18 screen rate by 42% (from 1.9% to 1.1%) but did not change the trisomy 18 detection rate. CONCLUSION: A false-positive trisomy 18 screening test does not indicate increased risk to develop pregnancy complications and may be related to inadequate correction for increased maternal weight.

Adult↗

PubMed1998

Quantitative evaluation of multiplicity in epidemiology and public health research.

Epidemiologic and public health researchers frequently include several dependent variables, repeated assessments, or subgroup analyses in their investigations. These factors result in multiple tests of statistical significance and may produce type 1 experimental errors. This study examined the type 1 error rate in a sample of public health and epidemiologic research. A total of 173 articles chosen at random from 1996 issues of the American Journal of Public Health and the American Journal of Epidemiology were examined to determine the incidence of type 1 errors. Three different methods of computing type 1 error rates were used: experiment-wise error rate, error rate per experiment, and percent error rate. The results indicate a type 1 error rate substantially higher than the traditionally assumed level of 5% (p < 0.05). No practical or statistically significant difference was found between type 1 error rates across the two journals. Methods to determine and correct type 1 errors should be reported in epidemiologic and public health research investigations that include multiple statistical tests.

Bias↗