Respiratory Disorders

Ross Lazarus, M.D., Ph.D.
Visiting Associate Professor of Medicine, Harvard Medical School
Visiting Associate Professor of Medicine, Brigham and Women's Hospital
ross.lazarus@channing.harvard.edu

I am currently on Leave from my tenured position at the University of Sydney, holding a position as Visiting Associate Professor of Medicine at Harvard Medical School and Brigham and Women’s Hospital, where I am the primary Faculty member responsible for bioinformatics developments and infrastructure in the Innate Immunity Program for Genomic Applications and other related projects.

Sydney

I am an Associate Investigator on an NHMRC funded research project on viral transmission associated with endoscopic procedures. I am involved in ongoing collaboration on a major population study of childhood obesity based at the Royal Childrens’ Hospital in Melbourne and in the nutritional research associated with the NHMRC funded Blue Mountains Health Studies. I have a number of smaller informal ongoing collaborations with clinical services at Westmead Hospital including the Neurosciences, Allergy and Dental groups where I provide epidemiological and statistical advice.

I worked as a Family Physician for 4 years after graduation, then as an Occupational Physician for 5 years in the Electricity industry before my current career in Information Sciences, Epidemiology and Public Health.

I chaired one full semester Unit in the Master of Public Health entitled “Introduction to Informatics in Public Health” which I introduced in 1999. This was the first flexibly (internet) delivered unit available in the MPH degree and proved very popular with students. I chaired another unit in the Master of Medicine (Clinical Epidemiology) program entitled “Clinical Epidemiological Applications”. I served as a Problem Based Learning Tutor on the University of Sydney Medical Program. I taught Biostatistics in the Physician Training Program of the Postgraduate Committee in Medicine, Literature searching in the MMed and MPH programs and I served as a tutor in the Evidence Based Medicine course in the first two years of the University of Sydney Medical Program.

As Sub-Dean for Information Technology, my responsibilities in the University of Sydney Medical Program included strategic planning for the use of IT in all aspects of the Faculty and supervising staff responsible for maintaining the IT infrastructure of the largely web-supported University of Sydney Medical Program. In particular, I was responsible for the design, implementation and management of the document management application used to deliver the first two years of the course. I was also heavily involved in the planning, management and administration of our current Medical Program through membership of a number of the principle committees.

Publications

1. Silverman, E. K., D. J. Kwiatkowski, et al. (2003). "Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program." J Allergy Clin Immunol 112(5): 870-6.
   
2. BACKGROUND: beta(2)-Adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies. OBJECTIVE: We sought to apply family-based association methods to individual single nucleotide polymorphisms (SNPs) and haplotypes of SNPs in B2AR to define the relationship of these genetic variants to asthma-related phenotypes. METHODS: DNA samples were obtained from 707 Childhood Asthma Management Program participants, representing 650 sibships, as well as their parents. Genotyping was performed at 8 B2AR SNPs. Qualitative asthma-related phenotypes were analyzed with single SNPs and haplotypes by using TRANSMIT; quantitative asthma-related phenotypes were analyzed with the Family-Based Association Test. RESULTS: Several SNPs, including SNP -654 and SNP +46, demonstrated significant associations (P <.05) to postbronchodilator FEV(1) as both a qualitative (<80% of predicted value) and quantitative phenotype. Quantitative phenotypic association analysis demonstrated significant evidence for association of SNP +523 with bronchodilator responsiveness expressed as a percentage of baseline FEV(1) (P =.012) or a percentage of predicted FEV(1) (P =.008). Similar evidence for association between the +523 SNP and qualitative bronchodilator responsiveness phenotypes was also found. Analysis of haplotypes supported an association of B2AR variants with spirometric values and bronchodilator responsiveness. CONCLUSION: B2AR variants are associated with spirometric values and bronchodilator responsiveness, but different regions of the gene provide evidence for association with these phenotypes.
   
   
3. Sebastiani, P., R. Lazarus, et al. (2003). "Minimal haplotype tagging." Proc Natl Acad Sci U S A 100(17): 9900-5.
   
4. The high frequency of single-nucleotide polymorphisms (SNPs) in the human genome presents an unparalleled opportunity to track down the genetic basis of common diseases. At the same time, the sheer number of SNPs also makes unfeasible genome-wide disease association studies. The haplotypic nature of the human genome, however, lends itself to the selection of a parsimonious set of SNPs, called haplotype tagging SNPs (htSNPs), able to distinguish the haplotypic variations in a population. Current approaches rely on statistical analysis of transmission rates to identify htSNPs. In contrast to these approximate methods, this contribution describes an exact, analytical, and lossless method, called BEST (Best Enumeration of SNP Tags), able to identify the minimum set of SNPs tagging an arbitrary set of haplotypes from either pedigree or independent samples. Our results confirm that a small proportion of SNPs is sufficient to capture the haplotypic variations in a population and that this proportion decreases exponentially as the haplotype length increases. We used BEST to tag the haplotypes of 105 genes in an African-American and a European-American sample. An interesting finding of this analysis is that the vast majority (95%) of the htSNPs in the European-American sample is a subset of the htSNPs of the African-American sample. This result seems to provide further evidence that a severe bottleneck occurred during the founding of Europe and the conjectured "Out of Africa" event.
   
   
5. Raby, B. A., E. K. Silverman, et al. (2003). "Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes." Hum Mol Genet 12(16): 1973-9.
   
6. Chromosome 12q13-24 is among the regions most frequently identified in genome-wide surveys for asthma susceptibility loci, with reports of two distinct clusters of positive linkage signals: one near the interferon gamma locus, the other near the nitric oxide synthase 1 locus. These results suggest that 12q harbors several asthma susceptibility loci. We evaluated this possibility in a subset of families ascertained through the Childhood Asthma Management Program (CAMP) Genetics Ancillary Study. Fifty-five nuclear families with at least two asthmatic siblings (212 individuals) were genotyped using 32 microsatellite markers. Non-parametric linkage analysis was performed for the asthma phenotype (qualitative). Multipoint variance component-based linkage analysis was performed for five quantitative asthma-related traits: (i) percent predicted forced expiratory volume in one second (FEV(1)); (ii) dose of methacholine resulting in 20% fall in FEV(1) from baseline (PC(20)); (iii) post-bronchodilator percent change in FEV(1) (BDPR); (iv) serum eosinophil levels (EOS); and (v) total serum IgE levels (IgE). Three separate and distinct loci demonstrated evidence suggestive of linkage: asthma at 68 cM (exact P-value=0.05), airways responsiveness (PC(20)) at 147 cM (P=0.01), and indices of pulmonary function (FEV1, BDPR) at 134 cM (P=0.05 and P<0.01, respectively). No linkage was observed for the atopy-related phenotypes. We provide further evidence supporting the presence of an asthma susceptibility locus at the proximal end of chromosome 12q, as well as new evidence for additional loci more distally that account for unique features of the asthma phenotype. Fine mapping efforts for these loci are warranted.
   
   
7. Lazarus, R., W. T. Klimecki, et al. (2003). "Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies." Genomics 81(1): 85-91.
   
8. TLR9 is a mammalian Toll-like receptor homologue that appears to function as an innate immune pattern recognition protein for motifs that are far more common in bacterial than in mammalian DNA. The gene was sequenced in 71 subjects from three self-identified U.S. ethnic groups to identify single-nucleotide polymorphisms (SNPs). A total of 20 SNPs were found of which only 20% were in the public dbSNP database. Four SNPs were relatively common in all three ethnic samples. Using these four SNPs, seven distinct haplotypes were statistically inferred, of which four accounted for 75% or more chromosomes. These four haplotypes could be distinguished from each other by the alleles of two SNPs (-1237 and 2848). Five exploratory nested case-control disease-association studies (asthma, DVT, MI, and COPD in European Americans and asthma in African Americans) were performed by genotyping DNA collected from four ongoing cohort studies. There was evidence suggesting increased risk for asthma with a C allele at -1237 (odds ratio 1.85, 95%CI 1.05 to 3.25) among European Americans (genotypes available from 67 cases and 152 controls). No other significant disease associations were detected. Replication of this finding in other, larger samples is needed. This study suggests that there is substantial diversity in human TLR9, possibly associated with asthma in Europeans but not African Americans. No association was detected with three other diseases potentially related to innate immunity.
   
   
9. Barlow-Stewart, K., L. Burnett, et al. (2003). "A genetic screening programme for Tay-Sachs disease and cystic fibrosis for Australian Jewish high school students." J Med Genet 40(4): e45.
   
   
10. Abraham, N., W. Selby, et al. (2003). "Is smoking an indirect risk factor for the development of ulcerative colitis? An age- and sex-matched case-control study." J Gastroenterol Hepatol 18(2): 139-46.
    
11. BACKGROUND: It has been suggested that smoking protects against the development of ulcerative colitis (UC). Evidence is mainly driven from the way data from a multitude of case-control studies have been interpreted. METHODS: An age- and sex-matched case-control study was conducted to further assess the association between history of smoking, past surgery, childhood, and other potential causative factors with the development of UC using the answers to a detailed questionnaire. The data were analyzed using univariate analysis and logistic regression. The results are presented as odds ratios (OR) and 95% confidence intervals. RESULTS: One hundred and two cases and an equal number of matched controls were included in the study. Using a three-level comparison, at the age of diagnosis, the risks of developing UC were 0.41 (0.19-0.87), 3.45 (1.62-7.35) and 0.78 (0.44-1.37) for smokers, ex-smokers and non-smokers, respectively. When compared to individuals who have never smoked, ex-smokers were at a higher risk of developing the disease (OR = 3.00 (1.38-6.51)). The specific history of quitting smoking prior to the age of onset of symptoms was associated with an increased risk for developing the disease (OR = 3.45 (1.62-7.35)). CONCLUSIONS: Active smoking was associated with a low risk for the development of UC, but the lack of history of smoking was not associated with an increase in the risk. History of quitting smoking prior to the onset of symptoms, in contrast, was associated with a significant increase in the risk of developing the disease. These findings make the theory of a simple protective effect of smoking on the development of UC difficult to justify. It may be plausible to suggest that the withdrawal of the immunosuppressive effect of smoking triggers the disease onset in a genetically susceptible individual or simply unmasks its symptoms.
    
    
12. Raby, B. A., W. T. Klimecki, et al. (2002). "Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes." Am J Respir Crit Care Med 166(11): 1449-56.
    
13. Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin recognition, and functional variants in the gene confer endotoxin-hyporesponsiveness in humans. Furthermore, there is evidence that endotoxin exposure during early life is protective against the development of atopy and asthma, although this relationship remains poorly understood. It is therefore possible that genetic variation in the TLR4 locus contributes to asthma susceptibility. In this study we characterize the genetic diversity in the TLR4 locus and test for association between the common genetic variants and asthma-related phenotypes. In a cohort of 90 ethnically diverse subjects, we resequenced the TLR4 locus and identified a total of 29 single nucleotide polymorphisms. We assessed five common polymorphisms for evidence of association with asthma in two large family-based cohorts: a heterogeneous North American cohort (589 families), and a more homogenous population from northeastern Quebec, Canada (167 families). Using the transmission-disequilibrium test, we found no evidence of association for any of the polymorphisms tested, including two functional variants. Furthermore, we found no evidence for association between the TLR4 variants and four quantitative intermediate asthma- and atopy-related phenotypes. Based on these results, we found no evidence that genetic variation in TLR4 contributes to asthma susceptibility.
    
    
14. Lazarus, R., K. Kleinman, et al. (2002). "Use of automated ambulatory-care encounter records for detection of acute illness clusters, including potential bioterrorism events." Emerg Infect Dis 8(8): 753-60.
    
15. The advent of domestic bioterrorism has emphasized the need for enhanced detection of clusters of acute illness. We describe a monitoring system operational in eastern Massachusetts, based on diagnoses obtained from electronic records of ambulatory-care encounters. Within 24 hours, ambulatory and telephone encounters recording patients with diagnoses of interest are identified and merged into major syndrome groups. Counts of new episodes of illness, rates calculated from health insurance records, and estimates of the probability of observing at least this number of new episodes are reported for syndrome surveillance. Census tracts with unusually large counts are identified by comparing observed with expected syndrome frequencies. During 1996-1999, weekly counts of new cases of lower respiratory syndrome were highly correlated with weekly hospital admissions. This system complements emergency room- and hospital-based surveillance by adding the capacity to rapidly identify clusters of illness, including potential bioterrorism events.
    
    
16. Lazarus, R., W. T. Klimecki, et al. (2002). "Single-nucleotide polymorphisms in the interleukin-10 gene: differences in frequencies, linkage disequilibrium patterns, and haplotypes in three United States ethnic groups." Genomics 80(2): 223-8.
    
17. Interleukin-10 (IL-10) is a cytokine that seems to function as a downregulator of the innate (nonadaptive) immune system. Approximately three-quarters of interindividual variability in human IL-10 levels has been attributed to genetic variation, and there is evidence suggesting a potential role for IL-10 in a range of human diseases. To provide a basis for haplotype analysis and future disease association studies, we characterized genetic variation in IL10 by sequencing all exons, and 2.5 kb of the 5'- and the 3'-flanking region in a panel of DNA samples from 24 African Americans, 23 European Americans, and 24 Hispanic Americans. The region sequenced was found to contain 28 single-nucleotide polymorphisms (SNPs), 16 with frequency >2% and 14 with frequency >5%. All SNPs with frequency >5% were present in subjects from all three populations. No SNP caused amino acid changes. Differences in pairwise linkage-disequilibrium (LD) patterns and in SNP and haplotype frequency distributions among the three populations may be of potential importance for disease association studies.
    
    
18. Lazarus, R., D. Vercelli, et al. (2002). "Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease." Immunol Rev 190: 9-25.
    
19. Under selective pressure from infectious microorganisms, multicellular organisms have evolved immunological defense mechanisms, broadly categorized as innate or adaptive. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may play a role in the development of asthma and related diseases. As part of a systematic assessment of genetic variability in innate immunity genes, we have thus far have examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples (European American, African American and Hispanic American) and a sample of European American asthmatics. Approaches to discovering and understanding variation and the subsequent implementation of disease association studies are described and illustrated. Although highly conserved across a wide range of species, the innate immune genes we have sequenced demonstrate substantial interindividual variability predominantly in the form of single nucleotide polymorphisms (SNPs). Genetic variation in these genes may play a role in determining susceptibility to a range of common, chronic human diseases which have an inflammatory component. Differences in population history have produced distinctive patterns of SNP allele frequencies, linkage disequilibrium and haplotypes when ethnic groups are compared. These and other factors must be taken into account in the design and analysis of disease association studies.
    
    
20. Arora, S. C., Y. M. Mudaliar, et al. (2002). "Non-bronchoscopic bronchoalveolar lavage in the microbiological diagnosis of pneumonia in mechanically ventilated patients." Anaesth Intensive Care 30(1): 11-20.
    
21. A prospective study comparing standardized non-bronchoscopic bronchoalveolar lavage (sNB-BAL) and non-specific endotracheal aspirate (NsETA) in the microbiological diagnosis of pneumonia in mechanically ventilated patients is described. One hundred episodes in 82 mechanically ventilated patients with or without radiological and clinical diagnostic criteria of pneumonia were studied. NsETA and sNB-BAL was performed on the day of study. Fifty-one patients had pneumonia (21 ventilator-associated, 12 hospital-acquired, 18 community-acquired) and 49 had no pneumonia as defined by widely accepted clinico-radiological criteria. The sNB-BAL was found to be significantly more specific (0. 73) compared to NsETA (0.35) for the microbiological diagnosis of pneumonia. Colonization rates with NsETA were significantly higher compared to sNB-BAL (P value <0.0001). No patient had complications attributable to the sNB-BAL procedure. We conlude that sNB-BAL is a safe, effective, sensitive, specific and inexpensive procedure for the serial evaluation of pneumonia in mechanically ventilated patients.
    
    
22. Lazarus, R., K. P. Kleinman, et al. (2001). "Using automated medical records for rapid identification of illness syndromes (syndromic surveillance): the example of lower respiratory infection." BMC Public Health 1(1): 9.
    
23. BACKGROUND: Gaps in disease surveillance capacity, particularly for emerging infections and bioterrorist attack, highlight a need for efficient, real time identification of diseases. METHODS: We studied automated records from 1996 through 1999 of approximately 250,000 health plan members in greater Boston. RESULTS: We identified 152,435 lower respiratory infection illness visits, comprising 106,670 episodes during 1,143,208 person-years. Three diagnoses, cough (ICD9CM 786.2), pneumonia not otherwise specified (ICD9CM 486) and acute bronchitis (ICD9CM 466.0) accounted for 91% of these visits, with expected age and sex distributions. Variation of weekly occurrences corresponded closely to national pneumonia and influenza mortality data. There was substantial variation in geographic location of the cases. CONCLUSION: This information complements existing surveillance programs by assessing the large majority of episodes of illness for which no etiologic agents are identified. Additional advantages include: a) sensitivity, uniformity and efficiency, since detection of events does not depend on clinicians' to actively report diagnoses, b) timeliness, the data are available within a day of the clinical event; and c) ease of integration into automated surveillance systems.These features facilitate early detection of conditions of public health importance, including regularly occurring events like seasonal respiratory illness, as well as unusual occurrences, such as a bioterrorist attack that first manifests as respiratory symptoms. These methods should also be applicable to other infectious and non-infectious conditions. Knowledge of disease patterns in real time may also help clinicians to manage patients, and assist health plan administrators in allocating resources efficiently.
    
    
24. Lazarus, R., D. Sparrow, et al. (1998). "Temporal relations between obesity and insulin: longitudinal data from the Normative Aging Study." Am J Epidemiol 147(2): 173-9.
    
25. Although obesity and insulin levels are generally associated in cross-sectional data, the temporal and causal nature of their association is not yet clear. Increased obesity may have preceded increased insulin levels or vice versa. The authors examined the temporal relations between fasting insulin blood levels and weight in longitudinal data from the ongoing Normative Aging Study. Two insulin measurements from which a rate of change (delta Insulin) could be calculated were available from 376 non-diabetic male subjects (mean age = 62.1 years). Rate of change in weight could be calculated for the previous inter-examination period (delta Weight1), the contemporaneous period (delta Weight2), and the inter-examination period following the second insulin measurement (delta Weight3). delta Weight2 was a significant predictor (p = 0.0005) of delta insulin in multiple linear regression models that included control for potential confounders (body mass index, waist-to-hip ratio, antihypertensive and diuretic medication use, and age) and for correlation between the initial level and change in insulin (mean fasting insulin). delta Weight1 was added to the model and was found not to be statistically significant (p = 0.15). When the model was stratified by age tertile, the regression coefficient on delta Weight1 was -0.44 (p = 0.018) for the youngest stratum, -0.06 (p = 0.72) for the middle stratum, and 0.21 (p = 0.19) for the oldest men. Similarly, delta Insulin was a significant predictor of delta Weight3 (p = 0.026) in a separate regression model. These findings are consistent with both possible temporal sequences of association between changes in insulin and obesity. The intricate homeostatic mechanisms that regulate changes in insulin and obesity may not be readily amenable to description in terms of cause and effect.
    
    
26. Lazarus, R., D. Sparrow, et al. (1998). "Impaired ventilatory function and elevated insulin levels in nondiabetic males: the Normative Aging Study." Eur Respir J 12(3): 635-40.
    
27. Lower levels of baseline ventilatory function have consistently been associated with increased risk of cardiovascular mortality in prospective studies, but the underlying mechanisms are not known. Increased risk of coronary heart disease is associated with higher serum insulin levels. This report examines the relationship between ventilatory function and indirect measures of insulin resistance. Cross-sectional data from 922 nondiabetic participants in the Normative Aging Study were analysed using multiple linear regression models with adjustment for potential confounders. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were examined in relation to indicators of insulin resistance, i.e. fasting insulin and the fasting insulin resistance index (FIRI). Diabetics were excluded because impaired insulin secretion interferes with the validity of these as measures of insulin resistance. Fasting insulin and FIRI were negatively correlated with FVC and FEV1 (all p< 0.001). These associations persisted after adjusting for potential confounders including age, height, body mass index, waist to hip circumference ratio, physical activity, alcohol intake and smoking in separate multiple linear regression models, for both insulin (all p< or =0.0008) and FIRI (all p< or =0.0001). Negative cross-sectional associations between ventilatory function and indirect measures of insulin resistance were found in nondiabetic males. Insulin resistance may contribute to the previously unexplained association between ventilatory function impairment and cardiovascular mortality. Mechanisms underlying the relationship between insulin resistance and decreased ventilatory function remain to be elucidated.
    
    
28. Lazarus, R., D. Sparrow, et al. (1998). "Baseline ventilatory function predicts the development of higher levels of fasting insulin and fasting insulin resistance index: the Normative Aging Study." Eur Respir J 12(3): 641-5.
    
29. A consistent but as yet unexplained association between baseline ventilatory function and risk of coronary heart disease (CHD) has been reported from many prospective studies. Insulin-resistant states are associated with increased risk of CHD. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow rate (MMEF) at study entry were examined as predictors for indirect measures of insulin resistance after a mean follow-up interval of 20.9 yrs in 1050 nondiabetic male subjects in the Normative Aging Study. Males in the top quintile of insulin or fasting insulin resistance index (FIRI) levels at follow-up were defined as being relatively insulin resistant. FVC was negatively associated with risk of being relatively insulin resistant using the insulin (p=0.002) or FIRI (p=0.0001) criteria at follow-up in logistic regression models adjusting for baseline age, body mass index, fat distribution pattern and cigarette smoking. Similar associations were found for FEV1 and MMEF. Additional adjustment for baseline postcarbohydrate challenge glucose levels made little difference to the results, suggesting that baseline glucose intolerance was not a significant source of bias. These findings are consistent with the possibility that insulin resistance may be one of the factors mediating the previously unexplained prospective association between impairment of ventilatory function and risk of mortality from coronary heart disease.
    
    
30. Lazarus, R., G. Colditz, et al. (1997). "Effects of body fat on ventilatory function in children and adolescents: cross-sectional findings from a random population sample of school children." Pediatr Pulmonol 24(3): 187-94.
    
31. Childhood obesity is associated with a range of adverse consequences, and the prevalence is increasing in developed nations. Most of the literature on obesity and ventilatory function in children concerns samples selected for gross obesity with relatively little detail available from random population samples. This report examines the effect of total body fat as a percentage of weight (TBF%) on ventilatory function in a nationally representative sample of 2,464 Australian school children aged 9, 12, and 15 years. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were used as measures of ventilatory function. TBF% was estimated from skinfold thickness measurements. Ventilatory function was adjusted (for height and then for both height and weight) using linear regression on a logarithmic scale. Adjustment was performed within separate strata of age and gender. Analysis of covariance was used for hypothesis testing. Height-adjusted FVC and FEV1 values increased significantly with increasing weight within each age and gender group and for all subjects combined (P < 0.0001). The effect of TBF% independent of lean tissue was examined using FVC and FEV1 values adjusted for both height and weight, because body weight measures both lean and fat mass. Adjusted FVC and FEV1 values decreased significantly with increasing TBF% within each age and gender group and for all subjects combined (P < 0.0001). Ventilatory function decreased with increasing proportions of body fat. This is consistent with previous findings on lean tissue mass and ventilatory function. Although the magnitude of the effect was relatively small in clinical terms, from a public health perspective our findings indicate yet another adverse consequence of childhood obesity.
    
    
32. Lazarus, R., D. Sparrow, et al. (1997). "Effects of obesity and fat distribution on ventilatory function: the normative aging study." Chest 111(4): 891-8.
    
33. OBJECTIVE: Although the influence of obesity on ventilatory function has long been recognized, the nature of the relationship and the mechanisms are not yet clear. The purpose of this report was to examine the effects of overall obesity and fat distribution on ventilatory function. METHODS: Multiple measurements over > 30 years from 507 subjects with lifelong tobacco consumption of < or = 1 pack-year were analyzed separately in five age decades from 30 to 79 years. FVC, FEV1, ratio of FEV1 to FVC, and maximal midexpiratory flow rate (MMEF) were each adjusted for age and stature. Relative adiposity (or obesity) was assessed using the body mass index (BMI). Subscapular skinfold thickness, abdominal girth, and the ratio of abdominal girth to hip breadth (AG/HB) were used as measures of body fat distribution. Multiple linear regression was used to explore the effects of overall adiposity and body fat distribution on ventilatory function. RESULTS: BMI was positively associated with the ratio of FEV1 to FVC at all ages (p < 0.01), and negatively with FVC and MMEF between 40 and 69 years (p < 0.01). After adjustment for BMI, subscapular skinfold thickness was negatively associated with both FVC and FEV1 (p < or = 0.02) among men aged 30 to 59 years, whereas AG/HB was negatively associated with FVC and FEV1 in men aged 50 to 59 years only (p < or = 0.0004). CONCLUSIONS: Body fat distribution has independent effects on ventilatory function after adjustment for overall obesity in men. The finding that age modifies this association has implications for future research.
    
    
34. Lazarus, R., D. Sparrow, et al. (1997). "Alcohol intake and insulin levels. The Normative Aging Study." Am J Epidemiol 145(10): 909-16.
    
35. Much remains to be clarified in the apparently protective effect of moderate alcohol use against coronary heart disease risk. Insulin levels are positively associated with coronary heart disease risk, so recent reports of decreased insulin sensitivity among nondrinkers and lower fasting insulin levels with increasing alcohol intake suggest the possibility that insulin may play a role. Between 1987 and 1991, the authors examined fasting insulin concentrations and the empiric fasting insulin resistance index in relation to reported alcohol intake (mean, 15.3 g/day; standard deviation, 19.6; range, 0-120.6) and potential confounders. The latter included age, obesity, fat distribution, smoking, energy, saturated fat intake, antihypertensive medication, and physical activity. Participants in this cross-sectional analysis were 938 nondiabetic men from the Boston, Massachusetts, area who were part of the Normative Aging Study. Unadjusted fasting insulin levels were significantly different (p = 0.008) between categories of alcohol intake, as were fasting insulin resistance index values (p = 0.01). After adjustment for potential confounders, analysis revealed that subjects consuming moderate amounts of alcohol had the lowest fasting insulin and fasting insulin resistance index values. Compared with values from moderate drinkers, fasting insulin resistance index values were higher in those subjects reporting no alcohol intake (p = 0.011), low intake (p = 0.004), and high intake (p = 0.04). A similar pattern was observed for fasting insulin values. Among this sample of nondiabetic men, moderate drinkers had the lowest levels of fasting insulin resistance index and fasting insulin, consistent with lower levels of insulin resistance and thus lower risk for coronary heart disease. These findings suggest the possibility that the coronary heart disease-protective effects of moderate alcohol use are at least partially mediated by insulin.
    
    
36. Lazarus, R., D. Sparrow, et al. (1997). "Handgrip strength and insulin levels: cross-sectional and prospective associations in the Normative Aging Study." Metabolism 46(11): 1266-9.
    
37. Hyperinsulinemia is associated with insulin resistance and with the development of diabetes, hypertension, and coronary heart disease. Physical activity appears to be negatively associated with insulin resistance, although the mechanism is unclear. The relationship between physical activity and insulin resistance could be mediated, in part, by direct effects on skeletal muscle, a significant site for insulin-mediated glucose disposal. This report examines the relationship between skeletal muscle strength (as measured by handgrip dynamometry) and fasting insulin levels in a cohort of men in the ongoing Normative Aging Study (NAS). Handgrip strength was negatively associated (P = .013) with logarithmic (log) fasting insulin in cross-sectional data from 655 subjects after adjustment for potential confounders including age, body mass index (BMI), ratio of abdominal girth to hip breadth (AG/HB), usual physical activity level, and alcohol intake in a multiple regression model. In data collected prospectively among 1,195 subjects, handgrip strength measured at study entry was negatively predictive of log fasting insulin (P = .017) measured 22.9 +/- 2.6 years later, after adjustment for age, BMI, and AG/HB at study entry in a multiple linear regression model. A cross-sectional association was confirmed in an analysis of prospective data on the relationship between handgrip strength and fasting insulin levels. The findings suggest that skeletal muscle weakness may precede and predict the development of insulin resistance, and raise the intriguing possibility of some common cause in skeletal muscle pathophysiology.
    
    
38. Gliksman, M. D., R. Lazarus, et al. (1995). "Social support, marital status and living arrangement correlates of cardiovascular disease risk factors in the elderly." Soc Sci Med 40(6): 811-4.
    
39. Marital status and indices of social support are associated with mortality due to coronary heart disease and stroke. This association seems not entirely due to differences in recognised cardiovascular disease risk factors. The Western Sydney Stroke risk in the Elderly Study examined the relationship between marital status, living arrangements, widowhood and extent of social support, and risk factors for cardiovascular disease in men and women aged over 65 years. Unmarried men had the lowest mean HDL-C levels. Men living alone had the highest mean systolic blood pressures. The lower mean HDL-C levels and higher DBP levels seen among widows were not statistically significant after adjustment for differences in past medical history and education levels. The extent of social support was not associated with any significant differences in cardiovascular risk factor levels among men or women. We conclude that some of the increased risk of cardiovascular disease associated with socio-demographic factors among men in this age-group may be due to differences in primary cardiovascular disease risk factors. However, some of the mechanisms underlying risk of cardiovascular disease in this age-group remains obscure.
    
    
40. Gliksman, M. D., R. Lazarus, et al. (1994). "The Western Sydney Stroke Risk in the Elderly Study. A 5-year prospective study." Ann Epidemiol 4(1): 59-66.
    
    Aging of the Australian population, as in other developed nations, will ensure that stroke remains one of the most important causes of death and disability. The Stroke Risk in the Elderly (SITE) study aims to measure prospectively the independent contribution of dietary, sociodemographic, blood lipid, blood pressure, and hemostatic factors to risk of stroke and other cardiovascular outcomes. The target population included all independently living men and women aged 65 years and over, residents in several retirement villages in western metropolitan Sydney, New South Wales, Australia. The study cohort consists of 225 men and 787 women, selected as a convenience sample from all eligible residents in the local government areas (LGAs) adjacent to Westmead Hospital. Participants attended a baseline session to complete dietary, life-style, medical, and sociodemographic questionnaires. Anthropomorphic variables and blood pressure were measured. Blood was taken for measurement of serum lipid, glucose, and hemostatic factors. Questionnaire results were compared with an age/sex-stratified, randomly selected sample drawn from the community (in the same LGAs), in order to quantify potential sampling and selection biases. The study cohort will be followed for a minimum of 5 years. The attendance rate of eligible residents for a baseline medical, dietary, life-style, and sociodemographic assessment was 72% for males and 69% for females. The study cohort was older, better educated, less ethnically diverse, and among women, less likely to have ever been married compared to people aged over 65 years in the comparison group. The baseline results suggest that hemostatic factors may be of importance in assessing risk of cardiovascular disease, (CVD), particularly in older men.(ABSTRACT TRUNCATED AT 250 WORDS)