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Biomedical subjects

Donald K Milton

Publications and source records attributed to Donald K Milton.

At least 19 recordsLinked to original sources
PubMed2006

The validation of work-related self-reported asthma exacerbation.

OBJECTIVE: To determine the validity of work-related self-reported exacerbation of asthma using the findings from serial peak expiratory flow (PEF) measurements as the standard. METHODS: Adults with asthma treated in a health maintenance organisation were asked to conduct serial spirometry testing at home and at work for 3 weeks. Self-reported respiratory symptoms and medication use were recorded in two ways: a daily log completed concurrently with the serial PEF testing and a telephone questionnaire administered after the PEF testing. Three researchers evaluated the serial PEF records and judged whether a work relationship was evident. RESULTS: 95 of 382 (25%) working adults with asthma provided adequate serial PEF data, and 13 of 95 (14%) were judged to have workplace exacerbation of asthma (WEA) based on these data. Self-reported concurrent medication use was the most valid single operational definition, with a sensitivity of 62% and a specificity of 65%. CONCLUSIONS: A work-related pattern of self-reported asthma symptoms or medication use was usually not corroborated by serial PEF testing and failed to identify many people who had evidence of WEA based on the serial PEF measurements.

Asthma↗
PubMed2006

Partial questionnaire designs, questionnaire non-response, and attributable fraction: applications to adult onset asthma.

The attributable fraction (AF) is often used to explore the policy implications of an association between a disease and an exposure. To date, there have been no proposed estimators of AF in the context of partial questionnaire designs (PQD). The PQD, first proposed in a public health context by Wacholder is often used to enhance response rates in questionnaires. It involves eliciting responses from each subject on preassigned subsets of questions, thereby reducing the burden of response. We propose a computationally efficient method of estimating logistic (or more generally, binary) regression parameters from a PQD model where there is non-response to the questionnaire and the rates of non-response differ between sub-populations. Assuming a log-linear model for the distribution of missing covariates, we employ the methods of Wacholder to motivate consistent estimating equations, and weight each subject's contribution to the estimating function by the inverse probability of responding to the questionnaire. We also propose techniques for goodness-of-fit to assist in model selection. We then use the PQD regression estimates to derive an estimate of AF similar to that proposed by Bruzzi. Finally, we demonstrate our methods using data obtained from a study on adult occupational asthma, conducted within a Massachusetts HMO. Although we concentrate on a particular type of missing data mechanism, other missing data techniques can be incorporated into AF estimation in a similar manner.

Adolescent↗
PubMed2006

Suppression of ionization and optimization of assay for 3-hydroxy fatty acids in house dust using ion-trap mass spectrometry.

BACKGROUND: 3-Hydroxy fatty acids (3-OHFAs), components of lipid A of gram-negative bacteria are useful chemical markers of endotoxin. METHODS: We analyzed 3-OHFAs in house dust as trimethylsilyl (TMS) methyl ester derivatives in the electron impact ionization mode using gas chromatography ion-trap mass spectrometry. Linear calibrations with r > 0.995 were observed for all the 3-OHFA methyl ester external standards. RESULTS: Recovery efficiency experiments with house dust demonstrated that accurate quantification requires calibration curves to be subjected to phase separation and solid phase extraction (SPE) because of differing clean-up losses according to chain length of 3-OHFAs. Recovery experiments also demonstrated interference with detection of C16:0 by the ion trap, which may be due to suppression of ionization by a constituent in house dust. Interference was overcome by injecting 1:4 dilutions of derivatized samples. The range of recoveries was 89.3%-111.5% for 3-OHFAs added to house dust. The reproducibility of injections was high (CV for C14:0 = 2.36%). The limit of detection (LOD) was 0.15 ng/mg for each 3-OHFA. CONCLUSIONS: The modifications we made included: use of 3-hydroxy C11:0 and C13:0 methyl esters as internal standards, subjecting calibration standards to phase separation and SPE; addition of water to phase separation; addition of 1-pentadecanol as a carrier; injecting 1:4 diluted TMS derivatives of 3-OHFAs; and monitoring both m/z 131 and 133 ions to improve stability of area measurements for product ions. This method of optimization establishes an appropriate technique for quantification of 3-OHFAs in house dust.

Air Microbiology↗
PubMed2006

Recombinant factor C assay for measuring endotoxin in house dust: comparison with LAL, and (1 --> 3)-beta-D-glucans.

BACKGROUND: Measurement of exposure to environmental endotoxin is frequently performed using a Limulus amebocyte lysate (LAL) based assay. Recently, a new method has become available with similar sensitivity and potentially greater specificity using recombinant Factor C (rFC) from the horseshoe crab Carcinoscorpius rotundicauda. A preliminary study was carried out to determine the comparability of LAL and rFC in measuring endotoxins in house dust for large scale epidemiologic studies. METHODS: House dust samples were collected from family rooms by vacuuming 1 m2 of the center of the room. Sixty sieved house dust samples were assayed for endotoxin by LAL (Cambrex, KQCL lysate) and rFC (Pyrogene, Cambrex) and for (1 --> 3)-beta-D-glucans by ELISA. The resistant parallel line estimation was used for data analysis of LAL and rFC. A four-parameter logistic fit with inverse prediction was used to calculate (1 --> 3)-beta-D-glucan levels of the samples. RESULTS: The spike recovery was 113.63% (95% CI = 101.69, 125.57%) for LAL and 99.69% (95% CI = 90.14, 109.24%) for rFC assays. The LAL assay gave higher endotoxin estimates compared with rFC. The LAL and rFC estimates were highly correlated (r = 0.86, P < 0.0001). The difference between LAL and rFC endotoxin estimates correlated with the LAL estimates (r = 0.51, P < 0.0001). However, the difference was not correlated with (1 --> 3)-beta-D-glucans. CONCLUSION: LAL and rFC gave comparable results, hence either assay can be used for studies of endotoxin exposure. The current study shows that (1 --> 3)-beta-D-glucan is not a major factor interfering with endotoxin measurements in house dust using a Cambrex KQCL LAL preparation.

Air Microbiology↗
PubMed2006

History and results of the two inter-laboratory round robin endotoxin assay studies on cotton dust.

BACKGROUND: In the US cotton industry, airborne cotton dust levels are regulated, and other countries are moving to specify safety limits for airborne endotoxins. There is concern about potential respiratory health hazards associated with agricultural and other organic dusts. In laboratories, ranking which samples have high and low levels of endotoxin is usually in good agreement between laboratories. When different laboratories assay identical samples, the levels differ. The objective of this research was to evaluate the intra- and inter-laboratory variability for 13 laboratories measuring endotoxin in cotton dust. METHOD: Two inter-laboratory round robin endotoxin assay studies were conducted using cotton dust. In the first round robin, each laboratory used their normal in-house assay method and then used a common extraction protocol. In the second round robin, a common extraction protocol and endotoxin assay kit was used. RESULTS: The intra-laboratory results had small variations but inter-laboratory results had very high variations. The inter-laboratory results using a common extraction protocol showed reduced differences. Using the same extraction protocol and endotoxin assay kit, the intra-laboratory variation was small and inter-laboratory variation was reduced but not enough for inter-laboratory agreement. Most of the laboratories were able to discern between the high and low endotoxin concentration dusts. CONCLUSIONS: Standardization has reduced the differences in results between laboratories and possibly further standardization may bring closer inter-laboratory agreement.

Air Microbiology↗
PubMed2006

Case-by-case assessment of adult-onset asthma attributable to occupational exposures among members of a health maintenance organization.

OBJECTIVE: In a general population of employed persons with health insurance, what proportion of adult-onset asthma is caused by occupational exposures? METHOD: We conducted a 2-year prospective study to identify adult-onset asthma among health maintenance organization (HMO) members. Telephone interviews regarding occupational exposures, symptoms, medication use, and triggers were used to assess likelihood of work-related asthma for each case. Weighted estimating equations were used to adjust the proportion of asthma attributable to workplace exposures for factors associated with interview participation. RESULTS: Overall, 29% (95% confidence interval, 25-34%) of adult-onset asthma was attributable to workplace exposures; 26% (21-30%) and 22% (18-27%) of cases had asthma attributable to occupational irritant and sensitizer exposures, respectively. CONCLUSIONS: Occupational exposures, including irritants, are important causes of adult-onset asthma.

Adolescent↗
PubMed2006

Home endotoxin exposure and wheeze in infants: correction for bias due to exposure measurement error.

Exposure to elevated levels of endotoxin in family-room dust was previously observed to be significantly associated with increased wheeze in the first year of life among a cohort of 404 children in the Boston, Massachusetts, metropolitan area. However, it is likely that family-room dust endotoxin was a surrogate for airborne endotoxin exposure. Therefore, a related substudy characterized the relationship between levels of airborne household endotoxin and the level of endotoxin present in house dust, in addition to identifying other significant predictors of airborne endotoxin in the home. We now reexamine the relationship between endotoxin exposure and wheeze under the assumption that the level of airborne endotoxin in the home is the exposure of interest and that the amount of endotoxin in household dust is a surrogate for this exposure. We applied a measurement error correction technique, using all available data to estimate the effect of endotoxin exposure in terms of airborne concentration and accounting for the measurement error induced by using house-dust endotoxin as a surrogate measure in the portion of the data in which airborne endotoxin could not be directly measured. After adjusting for confounding by lower respiratory infection status and race/ethnicity, endotoxin exposure was found to be significantly associated with a nearly 6-fold increase in prevalence of wheeze for a one interquartile range increase in airborne endotoxin (95% confidence interval, 1.2-26) among the 360 children in households with dust endotoxin levels between the 5th and 95th percentiles.

Air Pollution, Indoor↗
PubMed2005

Interlaboratory evaluation of endotoxin analyses in agricultural dusts--comparison of LAL assay and mass spectrometry.

Endotoxin exposure is associated with wheeze and asthma morbidity, while early life exposure may reduce risk of allergy and asthma. Unfortunately, it is difficult to compare endotoxin results from different laboratories and environments. We undertook this study to determine if lipopolysaccharide (LPS) extraction efficiency could account for differences among laboratories. We generated and collected aerosols from chicken and swine barns, and corn processing. We randomly allocated side-by-side filter samples to five laboratories for Limulus assay of endotoxin. Lyophilized aliquots of filter extracts were analyzed for 3-hydroxy fatty acids (3-OHFAs) as a marker of LPS using gas chromatography-mass spectrometry. There were significant differences in endotoxin assay and GC-MS (LPS) results between laboratories for all dust types (p < 0.01). Patterns of differences between labs varied by dust type. Relationships between assay and GC/MS results also depended on dust type. The percentages of individual 3-OHFA chain lengths varied across labs (p < 0.0001) suggesting that each lab recovered a different fraction of the LPS available. The presence of large amounts of particle associated LPS and absence of a freezing thawing cycle were associated with lower correlations between LPS and bioactivity, consistent with an absence of Limulus response to cell-bound endotoxin. These data suggest that extraction methods affect endotoxin measurements. The LAL methods may be most suitable when comparing exposures within similar environments; GC-MS offers additional information helpful in optimizing sample treatment and extraction. GC-MS may be of use when comparing across heterogeneous environments and should be considered for inclusion in future studies of human health outcomes.

Aerosols↗
PubMed2005

Polymorphisms in the 5' region of the CD14 gene are associated with eczema in young children.

BACKGROUND: Variants in the CD14 gene (CD14) are hypothesized to be associated with atopic disorders. However, most studies have only investigated one polymorphism in this gene. OBJECTIVE: We sought to study the association of 5 single nucleotide polymorphisms (SNPs) in the 5' flanking region of CD14 with eczema and serum IgE levels in young children. METHODS: We genotyped 5 SNPs in an approximately 6.5-kb region in the 5' region of CD14 in 344 2-year-old white children from 2 birth cohorts in the northeastern United States. We examined the relation of both single SNPs and haplotypes in CD14 with the atopic outcomes. RESULTS: Two SNPs were significantly associated with eczema. In dominant models adjusted for potential confounders, SNP rs2569193 was associated with significantly decreased risk for eczema (odds ratio [OR] for CT/TT vs CC, 0.5; 95% CI, 0.3-0.8), whereas SNP rs2569190 (also reported as the C-159T) was associated with significantly increased risk for eczema (OR for CT/TT vs CC, 2.3; 95% CI, 1.4-3.8). The CT/TT genotypes of SNP rs2569190 also had higher geometric means of serum IgE than the CC genotype (24.6 vs 15 IU/mL, P = .025). Haplotype analyses provided results similar to those of the single SNP analyses. CONCLUSIONS: Our results contradict previous reports that have found a protective effect of the T allele of SNP rs2569190 (C-159T) against atopic disorders. Nevertheless, these results confirm the importance of polymorphisms in CD14 in the development of atopy, and future studies of this gene region will need to account for linkage disequilibrium and environmental exposures unique to the study population.

5' Flanking Region↗
PubMed2005

Infant home endotoxin is associated with reduced allergen-stimulated lymphocyte proliferation and IL-13 production in childhood.

BACKGROUND: Infant endotoxin exposure has been proposed as a factor that might protect against allergy and the early childhood immune responses that increase the risk of IgE production to allergens. OBJECTIVE: Using a prospective study design, we tested the hypothesis that early-life endotoxin exposure is associated with allergen- and mitogen-induced cytokine production and proliferative responses of PBMCs isolated from infants with a parental history of physician-diagnosed asthma or allergy. METHODS: We assessed household dust endotoxin at age 2 to 3 months and PBMC proliferative and cytokine responses to cockroach allergen (Bla g 2), dust mite allergen (Der f 1), cat allergen (Fel d 1), and the nonspecific mitogen PHA at age 2 to 3 years. RESULTS: We found that increased endotoxin levels were associated with decreased IL-13 levels in response to cockroach, dust mite, and cat allergens, but not mitogen stimulation. Endotoxin levels were not correlated with allergen- or mitogen-induced IFN-gamma, TNF-alpha, or IL-10. Increased endotoxin levels were associated with decreased lymphocyte proliferation after cockroach allergen stimulation. An inverse, although nonsignificant, association was also found between endotoxin and proliferation to the other tested stimuli. CONCLUSION: Increased early-life exposure to household endotoxin was associated with reduced allergen-induced production of the TH2 cytokine IL-13 and reduced lymphoproliferative responses at age 2 to 3 years in children at risk for allergy and asthma. Early-life endotoxin-related reduction of IL-13 production might represent one pathway through which increased endotoxin decreases the risk of allergic disease and allergy in later childhood.

Allergens↗
PubMed2005

Within-home versus between-home variability of house dust endotoxin in a birth cohort.

Endotoxin exposure has been proposed as an environmental determinant of allergen responses in children. To better understand the implications of using a single measurement of house dust endotoxin to characterize exposure in the first year of life, we evaluated room-specific within-home and between-home variability in dust endotoxin obtained from 470 households in Boston, Massachusetts. Homes were sampled up to two times over 5-11 months. We analyzed 1,287 dust samples from the kitchen, family room, and baby's bedroom for endotoxin. We fit a mixed-effects model to estimate mean levels and the variation of endotoxin between homes, between rooms, and between sampling times. Endotoxin ranged from 2 to 1,945 units per milligram of dust. Levels were highest during summer and lowest in the winter. Mean endotoxin levels varied significantly from room to room. Cross-sectionally, endotoxin was moderately correlated between family room and bedroom floor (r = 0.30), between family room and kitchen (r = 0.32), and between kitchen and bedroom (r = 0.42). Adjusting for season, the correlation of endotoxin levels within homes over time was 0.65 for both the bedroom and kitchen and 0.54 for the family room. The temporal within-home variance of endotoxin was lowest for bedroom floor samples and highest for kitchen samples. Between-home variance was lowest in the family room and highest for kitchen samples. Adjusting for season, within-home variation was less than between-home variation for all three rooms. These results suggest that room-to-room and home-to-home differences in endotoxin influence the total variability more than factors affecting endotoxin levels within a room over time.

Air Pollutants↗
PubMed2004

Detection of airborne rhinovirus and its relation to outdoor air supply in office environments.

Rhinoviruses are major causes of morbidity in patients with respiratory diseases; however, their modes of transmission are controversial. We investigated detection of airborne rhinovirus in office environments by polymerase chain reaction technology and related detection to outdoor air supply rates. We sampled air from 9 A.M. to 5 P.M. each workday, with each sample run for 1 work week. We directly extracted RNA from the filters for nested reverse transcriptase-polymerase chain reaction analysis of rhinovirus. Nasal lavage samples from building occupants with upper respiratory infections were also collected. Indoor carbon dioxide (CO2 concentrations were recorded every 10 minutes as a surrogate for outdoor air supply. To increase the range of CO2 concentrations, we adjusted the outdoor air supply rates every 3 months. Generalized additive models demonstrated an association between the probability of detecting airborne rhinovirus and a weekly average CO2 concentration greater than approximately 100 ppm, after controlling for covariates. In addition, one rhinovirus from a nasal lavage contained an identical nucleic acid sequence similar to that in the building air collected during the same week. These results suggest that occupants in buildings with low outdoor air supply may have an increased risk of exposure to infectious droplet nuclei emanating from a fellow building occupant.

Air Microbiology↗
PubMed2004

Characterization of lipopolysaccharides present in settled house dust.

The 3-hydroxy fatty acids (3-OHFAs) in lipopolysaccharides (LPS) play an important role in determining endotoxin activity, and childhood exposure to endotoxin has recently been associated with reduced risk of atopic diseases. To characterize the 3-OHFAs in house dust (HD), we used gas chromatography-mass spectrometry to assay 190 HD samples. Dust from beds, bedroom floors, family rooms, and kitchen floors was collected as part of a birth cohort study of childhood asthma (study 1) and a longitudinal study of home allergen and endotoxin (study 2). We also measured endotoxin activity with a Limulus assay and computed specific activity (endotoxin activity per nanomole of LPS). Longer-chain (C(16:0) and C(18:0)) 3-OHFAs were predominant in HD compared with short-chain (C(10:0), C(12:0), and C(14:0)) acids. Endotoxin activity was positively correlated with short-chain 3-OHFAs in both studies. In study 2, 3-OH C(16:0) was negatively correlated and 3-OH C(18:0) was not correlated with endotoxin activity, consistent with previous findings that the Limulus assay responds preferentially to LPS containing short-chain 3-OHFAs. Kitchen dust contained the highest concentrations of 3-OH C(10:0), the highest endotoxin activities, and the highest specific activities (P < 0.03). Bed dust contained the largest amounts of long-chain 3-OHFAs, the highest concentrations of LPS, and the lowest specific activities. Apartments had significantly different types of LPS (P = 0.03) compared with single-family homes in study 2. These data suggest that the Limulus assay may underestimate exposure to certain types of LPS. Because nontoxic LPS may have immune modulating effects, analysis of 3-OHFAs may be useful in epidemiologic studies.

Animals↗
PubMed2004

Endotoxin exposure and eczema in the first year of life.

OBJECTIVE: Exposure to endotoxin in early life has been proposed as a factor that may protect against the development of allergic diseases such as eczema. The objective of this study was to examine the relation between endotoxin exposure in early life and eczema in the first year of life in children with parental history of asthma or allergies. METHODS: This study used a prospective birth cohort study of 498 children who had a history of allergy or asthma in at least 1 parent and lived in metropolitan Boston. A subset of 401 living rooms had house dust samples adequate for analysis of endotoxin. RESULTS: In multivariate analyses adjusting for gender, income, and season of birth, endotoxin levels in the living room at 2 to 3 months of age was inversely associated with physician- or nurse-diagnosed eczema in the first year of life (odds ratio [OR] for each quartile increment: 0.76; 95% confidence interval [CI]: 0.61-0.96). Exposure to a dog in the home at age 2 to 3 months was also inversely associated with eczema in the first year of life, but the CI widened when endotoxin was included in the multivariate model (OR: 0.54; 95% CI: 0.27-1.09). Other variables associated with eczema in the first year of life included paternal history of eczema (OR: 1.91; 95% CI: 1.03-3.55) and maternal specific immunoglobulin E positivity to > or =1 allergen (OR: 1.61; 95% CI: 1.01-2.56). CONCLUSIONS: Among children with parental history of asthma or allergies, exposure to high levels of endotoxin in early life may be protective against eczema in the first year of life. In these children, paternal history of eczema and maternal sensitization to at least 1 allergen are associated with an increased risk of eczema in the first year of life.

Analysis of Variance↗
PubMed2003

Effect of ultraviolet germicidal lights installed in office ventilation systems on workers' health and wellbeing: double-blind multiple crossover trial.

BACKGROUND: Workers in modern office buildings frequently have unexplained work-related symptoms or combinations of symptoms. We assessed whether ultraviolet germicidal irradiation (UVGI) of drip pans and cooling coils within ventilation systems of office buildings would reduce microbial contamination, and thus occupants' work-related symptoms. METHODS: We undertook a double blind, multiple crossover trial of 771 participants. In office buildings in Montreal, Canada, UVGI was alternately off for 12 weeks, then turned on for 4 weeks. We did this three times with UVGI on and three times with it off, for 48 consecutive weeks. Primary outcomes of self-reported work-related symptoms, and secondary outcomes of endotoxin and viable microbial concentrations in air and on surfaces, and other environmental covariates were measured six times. FINDINGS: Operation of UVGI resulted in 99% (95% CI 67-100) reduction of microbial and endotoxin concentrations on irradiated surfaces within the ventilation systems. 771 participants appeared to remain masked, and reported no adverse effects. On the basis of within-person estimates, use of UVGI was associated with significantly fewer work-related symptoms overall (adjusted odds ratio 0.8 [95% CI 0.7-0.99]), as well as respiratory (0.6 [0.4-0.9]) and mucosal (0.7 [0.6-0.9]) symptoms than was non-use. Reduction of work-related mucosal symptoms was greatest among atopic workers (0.6 [0.5-0.8]), and never-smokers (0.7 [0.5-0.9]). With UVGI on, never-smokers also had large reduction of work-related respiratory (0.4 [0.2-0.9]), and musculoskeletal symptoms (0.5 [0.3-0.9]). INTERPRETATION: Installation of UGVI in most North American offices could resolve work-related symptoms in about 4 million employees, caused by microbial contamination of heating, ventilation, and air-conditioning systems. The cost of UVGI installation could in the long run prove cost-effective compared with the yearly losses from absence because of building-related illness.

Adult↗
PubMed2003

A longitudinal study of adult-onset asthma incidence among HMO members.

BACKGROUND: HMO databases offer an opportunity for community based epidemiologic studies of asthma incidence, etiology and treatment. The incidence of asthma in HMO populations and the utility of HMO data, including use of computerized algorithms and manual review of medical charts for determining etiologic factors has not been fully explored. METHODS: We identified adult-onset asthma, using computerized record searches in a New England HMO. Monthly, our software applied exclusion and inclusion criteria to identify an "at-risk" population and "potential cases". Electronic and paper medical records from the past year were then reviewed for each potential case. Persons with other respiratory diseases or insignificant treatment for asthma were excluded. Confirmed adult-onset asthma (AOA) cases were defined as those potential cases with either new-onset asthma or reactivated mild intermittent asthma that had been quiescent for at least one year. We validated the methods by reviewing charts of selected subjects rejected by the algorithm. RESULTS: The algorithm was 93 to 99.3% sensitive and 99.6% specific. Sixty-three percent (n = 469) of potential cases were confirmed as AOA. Two thirds of confirmed cases were women with an average age of 34.8 (SD 11.8), and 45% had no evidence of previous asthma diagnosis. The annualized monthly rate of AOA ranged from 4.1 to 11.4 per 1000 at-risk members. Physicians most commonly attribute asthma to infection (59%) and allergy (14%). New-onset cases were more likely attributed to infection, while reactivated cases were more associated with allergies. Medical charts included a discussion of work exposures in relation to asthma in only 32 (7%) cases. Twenty-three of these (72%) indicated there was an association between asthma and workplace exposures for an overall rate of work-related asthma of 4.9%. CONCLUSION: Computerized HMO records can be successfully used to identify AOA. Manual review of these records is important to confirm case status and is useful in evaluation of provider consideration of etiologies. We demonstrated that clinicians attribute most AOA to infection and tend to ignore the contribution of environmental and occupational exposures.

Adult↗