Making quality measurement work

Minnesota's medical groups and health plans are working together to continue the tradition of health care excellence in Minnesota. The collaborative approach of the Minnesota Community Measurement Project will provide Minnesota medical practices with better quality-of-care information than has previously been available.     

Summary report: Missing data and pedigree and genotyping errors

Genetic epidemiology is faced with mapping complex traits to genes with relatively small effects whose phenotypes may be modulated by temporal factors. To do this, detailed and accurate data must be available on families, perhaps collected over time. The Framingham Heart Study data supplied to Genetic Analysis Workshop 13 (GAW13), along with its simulated counterpart, contain longitudinal measurements and genomic scan data on 2,885 individuals in 330 families, and offer an opportunity to examine data quality and completeness issues as they affect analytical conclusions. Six GAW13 contributions applied methods to deal with missing data, both phenotypic and genotypic, at a single time point and longitudinally, and with possible errors in pedigree structure and genotypes. The methods included missing phenotypic data imputation by Markov chain Monte Carlo sampling, propensity scoring, regression, and adjusted mean values, as well as the assessment of transmission-disequilibrium tests when missing marker data may be allele-specific. Pedigree structural errors were found by genome-wide allele-sharing probabilities, while Mendelian consistent genotype errors were evaluated through likelihoods of double-recombination events. Each of the methods reviewed here offered insights into how to better take advantage of large, time-dependent, familial data sets. However, no one of them dealt with the longitudinal and familial aspects simultaneously. Overall, more consideration needs to be given to the effects that missing data and data errors have on our ability to map complex traits efficiently and accurately.     

Reciprocal obligations: managing policy responses to prenatal substance exposure

Substance use during pregnancy poses substantial risks to the developing fetus and continues to generate considerable policy debate. Public policy responses to prenatal substance exposure (PSE) have varied depending in part on whether the substances in question are licit (e.g., tobacco and alcohol) or illicit (e.g., cocaine and heroin). The policy responses also have ranged from warning labels on the dangers to the developing fetus of using alcohol, to treating a pregnant woman's illicit substance use as child abuse. The most controversial case was Cornelia Whitner's criminal conviction in South Carolina for PSE after her newborn baby tested positive for cocaine metabolites. Although the conviction was upheld by the South Carolina Supreme Court, it is, to date, an isolated example (Whitner v. State of South Carolina, 492 S.E.2d 777 [S.C. 1997], cert denied, 523 U.S. 1145 [1998], but see Ferguson v. City of Charleston, 532 U.S. 67 [2001], and Ferguson v. City of Charleston, 308 F.3d 380 [4th Cir. 2002], ruling that PSE detection policies require the woman's informed consent).     

Effect of supplementing a high-fat,low-carbohydrate enteral formula in COPD patients

OBJECTIVE: One of the goals in treating patients with chronic obstructive pulmonary disease (COPD) who suffer from hypoxemia, hypercapnia, and malnutrition is to correct the malnutrition without increasing the respiratory quotient and minimize the production of carbon dioxide. This 3-wk study evaluated the efficacy of feeding a high-fat, low-carbohydrate (CHO) nutritional supplement as opposed to a high-carbohydrate diet in COPD patients on parameters of pulmonary function.S METHODS: Sixty COPD patients with low body weight (<90% ideal body weight) were randomized to the control group, which received dietary counseling for a high-CHO diet (15% protein, 20% to 30% fat, and 60% to 70% CHO), or the experimental group, which received two to three cans (237 mL/can) of a high-fat, low-CHO oral supplement (16.7% protein, 55.1% fat, and 28.2% CHO) in the evening as part of the diet. Measurements of lung function (forced expiratory volume in 1 s or volume of air exhaled in 1 s of maximal expiration, minute ventilation, oxygen consumption per unit time, carbon dioxide production in unit time, and respiratory quotient) and blood gases (pH, arterial carbon dioxide tension, and arterial oxygen tension) were taken at baseline and after 3 wk. RESULTS: Lung function measurements decreased significantly and forced expiratory volume increased significantly in the experimental group. CONCLUSION: This study demonstrates that pulmonary function in COPD patients can be significantly improved with a high-fat, low-CHO oral supplement as compared with the traditional high-CHO diet.     

Di-alkyl phosphate biomonitoring data: assessing cumulative exposure to organophosphate pesticides

The 1996 Food Quality Protection Act (FQPA) requires the evaluation of both aggregate and cumulative health risks from pesticides (FFDCA 408(b)(2)(D)(v) and (vi).) Organophosphate (OP) pesticides are the first class of chemicals to undergo FQPA mandated aggregate and cumulative assessments. In this report, summary data on biomonitoring for urinary levels of six alkyl phosphate (AP) metabolites of OPs, as reported in the initial, March 2001, U.S. Centers for Disease Control and Prevention's (CDC) "National Report on Human Exposure to Environmental Chemicals," are compared to EPA modeled estimates of OP exposure reported in Registration Eligibility Decision documents (REDs), Interim REDs and to currently reported cumulative exposure estimates in the EPA's Cumulative Risk Assessment of the Organophosphate Pesticides. This comparison indicates that EPA's aggregate exposure estimates (dietary, drinking water, and non-dietary residential exposures) for many individual OPs were greater than the cumulative estimate for all OPs combined based on the CDC AP biomonitoring data. The results also suggest that EPA's screening level assessments of OPs, while being qualitative indicators of the relative importance of various exposure sources, are not good quantitative indicators of actual exposures. However, the mean biomonitoring estimate of cumulative OP exposure appears to exceed the EPA's subsequent preliminary estimate of cumulative OP exposure by as much as the REDs appear to overestimate the biomonitoring results. While the conservatism, tendency to overestimate exposure, in the individual REDs is readily acknowledged, the conservatism and limitations of applying currently available CDC AP biomonitoring data to evaluate human exposure to OPs are not as readily apparent. We postulate that oral absorption of non-anti cholinergic, pre-hydrolyzed OPs, sources of APs other than pesticides, and the conservative result of summing exposure from each AP at the geometric mean contribute to non-quantified overestimates of absorbed dosage from the CDC biomonitoring data reported in March 2001. CDC AP biomonitoring data may serve a useful purpose in providing an upper bound estimate of absorbed dosage for "ground truthing" aggregate exposure estimated from first tier models used in REDs, but at best may provide only a credible "target" for the complex cumulative exposure assessment models currently under development. The reliability of quantitative estimates of OP exposure levels will improve as cumulative risk exposure models are validated over time and under use conditions prevalent at the time the AP biomonitoring samples are collected. Analyses contained herein should be revisited and compared to the CDC Second National Report on Human Exposure to Environmental Chemicals ( http://www.cdc.gov/exposurereport), released to the public on January 31, 2003, and the final EPA OP Cumulative Risk Assessment.     

Rotator cuff repair. A biomechanical comparison of three techniques

BACKGROUND: The most common complication of rotator cuff repair is structural failure at the repair site. A single-layer repair does not adequately reproduce the anatomic insertion and may not optimize fixation strength. HYPOTHESIS: A double-layer rotator cuff repair will have greater initial fixation strength than a single-layer repair. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve fresh-frozen matched pairs of cadaveric shoulders were repaired by using dual-site fixation with both suture anchors and transosseous tunnels on one side (technique 1). Fixation was achieved by using suture anchors with horizontal mattress sutures and bone tunnels with modified Mason-Allen sutures. Half of the contralateral matched shoulders underwent fixation with suture anchors and simple sutures to simulate commonly used arthroscopic methods (technique 2) and, in the rest, fixation was achieved by using transosseous tunnels and modified Mason-Allen sutures (technique 3). Repaired specimens then underwent cyclic loading at physiologic rates and loads. The number of cycles to failure, which was defined as a 1-cm gap at the repair site, was then recorded. An arbitrary cut-off point of 5000 cycles was chosen. RESULTS: The mean number of cycles to failure with technique 1 (3694 +/- 1980 cycles) was significantly greater than that with either technique 2 (1414 +/- 1888 cycles) or technique 3 (528 +/- 683 cycles). Failure was predominantly through bone. CONCLUSIONS: The initial fixation strength of our double-layer repair exceeds that of isolated single-layer repairs with either suture anchors or transosseous tunnels.     

Tumour necrosis factor receptor type II 196M/R genotype correlates with circulating soluble receptor levels in normal subjects and with graft-versus-host disease after sibling allogeneic bone marrow transplantation

BACKGROUND: A single nucleotide polymorphism in the tumor necrosis factor type II receptor (TNFRII) gene, codon 196, results in the substitution of arginine (R allele) for methionine (M allele). The 196R allele is reportedly associated with an increased susceptibility to autoimmune disease, and donor 196R allele carriage correlates with increased severity of acute graft-versus-host disease (GVHD) after matched unrelated bone marrow transplantation (BMT). METHODS: We investigated the impact of donor and recipient TNFRII genotype on GVHD incidence and severity among 104 adult recipients of myeloablative sibling BMTs. RESULTS: 196R allele frequency was 0.28 among recipients, donors, and controls. There was an increased incidence of acute GVHD among 196R-positive recipients (odds ratio [OR] 3.6, P=0.05). This association was confirmed in multivariate analysis (relative risk 4, P=0.04), correcting for previously established clinical and genetic risk factors. Donor 196R homozygosity was associated with an increased incidence of extensive chronic GVHD (OR 18.5, P=0.02). This association was also confirmed in multivariate analysis (OR 11, P=0.02). To investigate the functional impact of the TNFRII 196 M/R polymorphism, 79 volunteer blood donors were genotyped at this locus, by polymerase chain reaction and single-strand conformational polymorphism analysis, and plasma soluble TNFRII (sTNFRII) levels were measured by ELISA. Mean plasma sTNFRII levels (pg/mL: +/-SEM) were 1224 (+/-26) and 1063 (+/-65) for 196M-postive (196 M homozygous or heterozygous) individuals and 196R homozygotes, respectively (P=0.02). CONCLUSIONS: Because sTNFRIIs can act as TNF antagonists, the association between recipient and donor TNFRII 196R allele status and acute or extensive chronic GVHD incidence, respectively, may reflect reduced circulating sTNFRII.     

Secular stability and reliability of measurements of the percentage of dense tissue on mammograms

Elevated mammographic density is associated with increased risk of breast cancer. We conducted a reliability study on mammographic density assessments to determine their potential usefulness for projecting individual breast cancer risk. We used baseline screening mammograms from 7251 women in the Breast Cancer Detection Demonstration Project (BCDDP). Repeated measurements from the same images were used to assess measurement variability by an experienced evaluator. Intraclass correlations of assessments over time usually exceeded 0.9, indicating usefulness for prospective applications. Data also indicated it may be reasonable to include cases identified in the first year of screening together with other cases in developing a risk model. Older ages and increased weight were associated with decreased mammographic density. The density of the right breast slightly exceeded that of the left. Among women who developed breast cancer, the baseline mammographic density of the ipsilateral (diseased) breast was 0.53 (95% confidence interval (CI) 0.20-0.86) percentage units higher than in the contralateral breast.     

Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells

Breast tumor kinase (BRK) is an intracellular tyrosine kinase expressed in differentiating epithelial cells of the gastrointestinal tract and skin, and in several epithelial cancers including carcinomas of the breast and colon. We examined expression of BRK and its mouse ortholog Src-related intestinal kinase (Sik) in prostate tissues and detected it in the nuclei of normal luminal prostate epithelial cells. BRK localization was then examined in 58 human prostate biopsy samples representing various grades of prostate cancer. While nuclear localization of BRK was present in well-differentiated tumors, it was absent in poorly differentiated tumors. However localization of Sam68, a nuclear substrate of BRK/Sik, was unaltered in all prostate tumors examined. Consistent with these results, nuclear BRK was detected in the more differentiated androgen-responsive LNCaP human prostate cancer cell line that is poorly tumorigenic in host animals, but it was primarily cytoplasmic in the undifferentiated androgen-unresponsive PC3 prostate cancer cell line that forms aggressive tumors. While PC3 cells expressed higher levels of endogenous BRK than LNCaP cells, BRK was less active in these cells. Our data suggest that BRK plays a role in differentiation of prostate epithelial cells. Altered BRK localization and/or activity may provide a prognostic indicator for prostate tumor progression and be a potential target for therapeutic intervention.