The Sociology of the Deceased Harvard Medical Unit at Boston City Hospital.

Many graduates of the Harvard Medical Unit (HMU) at Boston City Hospital, in either the clinical training/residency program or the research program at the Thorndike Memorial Laboratory, contributed in major ways to the HMU and constantly relived their HMU experiences. The HMU staff physicians, descending from founder and mentor physicians Francis W. Peabody, Soma Weiss, and George R. Minot, were dedicated to the teaching, development, and leadership of its clinical and research trainees, whose confidence and dedication to patient care as a result of their mentorship led many to lifelong achievements as clinicians, teachers, and mentors. Their experience also led to a lifelong love of the HMU (despite its loss), camaraderie, happiness, and intense friendships with their associates.

The rise of pathophysiologic research in the United States: the role of two Harvard hospitals.

Pathophysiologic research, the major approach to understanding and treating disease, was created in the 20th century, and two Harvard-affiliated hospitals, the Peter Bent Brigham Hospital and Boston City Hospital, played a key role in its development. After the Flexner Report of 1910, medical students were assigned clinical clerkships in teaching hospitals. Rockefeller-trained Francis Weld Peabody, who was committed to investigative, pathophysiologic research, was a critical leader in these efforts. At the Brigham, Harvard medical students observed patients closely and asked provocative questions about their diseases. Additionally, physicians returned from World War I with questions concerning the pathophysiology of wartime injuries. At the Boston City Hospital's new Thorndike Memorial Laboratory, Peabody fostered investigative question-based research by physicians. These physicians expanded pathophysiologic investigation from the 1920s. Post-war, Watson and Crick's formulation of the structure of DNA led shortly to modern molecular biology and new research approaches that are being furthered at the Boston Hospitals.

Soma Weiss, Alfred S. Reinhart, and the care of the patient.

Soma Weiss, a brilliant clinician, researcher, and teacher at Harvard Medical School, cared for Alfred S. Reinhart, who succumbed to subacute bacterial endocarditis in his final year at Harvard Medical School. Reinhart recorded his observations and experiences while a patient in the Thorndike Memorial Laboratory at the Boston City Hospital, and Weiss incorporated these in a paper some 10 years after Reinhart's death. In the tradition of Francis Weld Peabody, Weiss used Reinhart's memoir to emphasize the importance of listening to patients, of projecting sympathy, and of understanding and responding to their psychological needs.

Can comparison of MZ- and DZ-twin concordance rates be used invariably to estimate heritability?

Proponents of the validity of the classical MZ-DZ twin comparison model for calculating heritability claim that the environments influencing MZ and DZ twin individuals are essentially identical. This 'equal environments assumption' may or may not be universally true when applied to the analysis of subjective traits. We examined the validity of this assumption as applied to the propensity for smoking cigarettes, reasoning that equality of environments should lead to equal smoking prevalences in MZ and DZ twin individuals. We identified 8 twin populations with data on smoking. We compiled odds ratios (ORs) for ever smoking in MZ and DZ twin individuals in these 8 studies and overall, using a fixed-effects meta-analytic method based on the Mantel-Haenszel procedure. The prevalence of smoking was less in MZ twin individuals than in DZ twin individuals in 7 of 8 studies. The overall OR was 0.86 (95% confidence interval 0.84, 0.89). ORs were virtually unchanged when the analyses were stratified for gender and age, and no differences were found in relation to the location of the study, the date of the study or the birth years of the cohorts. For cigarette smoking, the environments of MZ and DZ twins may not be co-equal. For subjective traits, heritability estimates may be influenced by these unequal environmental factors that differentially affect their development and characteristics in MZ and DZ twins.

Whole genome scan for obstructive sleep apnea and obesity in African-American families.

Obstructive sleep apnea (OSA) is a common, chronic disease associated with obesity. OSA and obesity are both prevalent in African Americans, who are also at increased risk for secondary complications. To identify susceptibility loci for OSA, we undertook a 9-centimorgans genome scan in 59 African-American pedigrees ascertained on the basis of either an affected individual with laboratory-confirmed disease or a proband who was a neighborhood control subject. Variance component linkage analysis was performed for the quantitative phenotypes apnea-hypopnea index (AHI) and body mass index. A candidate region on chromosome 8q (logarithm of odds [LOD] = 1.29, p = 0.006) gave the only evidence for linkage to the AHI. Body mass index was linked to multiple regions, most significantly to markers on chromosome 4q (LOD = 2.63, p = 0.0006) and 8q (LOD = 2.56, p = 0.0007). Evidence of linkage to the AHI was only slightly reduced after adjustment for body mass index. After adjustment for the AHI, some of the primary linkages to body mass index were greatly reduced whereas others remained suggestive. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity, and that the genetic determinants of obesity in this population may be modulated by apnea severity.

Predictors of longitudinal change in sleep-disordered breathing in a nonclinic population.

STUDY OBJECTIVES: To quantify and identify the determinants of the 5-year change in the respiratory disturbance index (RDI). DESIGN: Longitudinal cohort study (Cleveland Family Study). Multivariate analyses were used to quantify baseline RDI and RDI change. SETTING: Community-based study. PARTICIPANTS: 486 cohort members (62% from families of probands with sleep-disordered breathing [SDB])--mean age 31.6 +/- 17.9 (SD) years, 60% female, 21% Black ethnicity--who underwent 2 assessments over 5.3 +/- 0.9 (SD) years. INTERVENTIONS: NA. MEASUREMENTS: The RDI was measured twice over approximately 5 years with in-home monitoring. Symptoms and medical histories were obtained from standardized questionnaires, and weight, height, and blood pressure were measured. RESULTS: The prevalence of SDB (defined by a RDI > or = 15), increased from 13.7% to 23.4% (P < 0.01) in men and from 8.3% to 11.4% (P = 0.13) in females. Baseline and follow-up mean RDIs were 6.0 +/- 10.0 and 8.6 +/- 14.3; both were higher in older individuals, in men, and in those with a higher body mass index. Median 5-year change in RDI varied nonlinearly with age (-0.1, 1.1, 2.3, and 0.9, for those < 18, 19-40, 41-54, and > or = 55 years, respectively) and obesity (2.8 vs -0.1, for the top versus lowest body mass index quartile). The effects of changing weight and aging varied in population subgroups. At any given age and weight, the RDI increased less in women. CONCLUSIONS: Longitudinal change in the RDI varies nonuniformly with age, sex, and weight. Older heavier men may experience the highest rate of increase in RDI over time and, thus, may benefit most from prospective monitoring.

Incidence of sleep-disordered breathing in an urban adult population: the relative importance of risk factors in the development of sleep-disordered breathing.

CONTEXT: Sleep-disordered breathing (SDB) is both prevalent and associated with serious chronic illness. The incidence of SDB and the effect of risk factors on this incidence are unknown. OBJECTIVE: To determine the 5-year incidence of SDB overall and as influenced by risk factors. DESIGN, SETTING, AND PARTICIPANTS: Of the 1149 participants in the Cleveland Family Study, those aged 18 years or older, from either case or control families, who had 2 in-home sleep studies 5 years apart. The first had to have been performed before June 30, 1997, and had to have normal results (apnea hypopnea index [AHI] <5). Data included questionnaire information on medical and family history, SDB symptoms; measurement of height, weight, blood pressure, waist and hip circumference, and serum cholesterol concentration; and overnight sleep monitoring. MAIN OUTCOME MEASURE: Apnea hypopnea index, defined as number of apneas and hypopneas per hour of sleep. Sleep-disordered breathing was defined by an AHI of at least 10 (mild to moderate) or of at least 15 (moderate). RESULTS: Forty-seven (16%) of 286 eligible participants, (95% confidence interval [CI], 13%-21%) had a second-study AHI of at least 10 and 29 (10%) participants (95% CI, 7%-14%) had a second-study AHI result of at least 15. For the AHI results of at least 15, we estimate that about 2.5% may represent test variability. By ordinal logistic regression analysis, AHI was significantly associated with age (odds ratio [OR] per 10-year increase, 1.79; 95% CI, 1.41-2.27), body mass index (BMI; OR per 1-unit increase, 1.14; 95% CI, 1.10-1.19), sex (OR for men vs women, 4.12; 95% CI, 2.29-7.43), waist-hip ratio (OR per 0.1 unit increase, 1.61; 95% CI, 1.04-2.28), and serum cholesterol concentration (OR per 10-mg/dL [0.25-mmol/L] increase, 1.11; 95% CI, 1.03-1.19). Interactions were noted between age and both sex (P =.003) and BMI (P =.05). The OR for increased AHI per 10-year age increase was 2.41 in women (95% CI, 1.78-3.26) and 1.15 in men (95% CI, 0.78-1.68), with the male vs female OR decreasing from 5.04 (95% CI, 2.19-11.6) at age 30 years to 0.54 (95% CI, 0.15-1.99) at age 60 years. The OR for increased AHI per 1-unit increase in BMI decreased from 1.21 (95% CI, 1.11-1.31) at age 20 years to 1.05 (95% CI, 0.96-1.15) at age 60 years. CONCLUSIONS: The 5-year incidence is about 7.5% for moderately severe SDB and 16% (or less) for mild to moderately severe SDB. Incidence of SDB is influenced independently by age, sex, BMI, waist-hip ratio, and serum cholesterol concentration. Predominance in men diminishes with increasing age, and by age 50 years, incidence rates among men and women are similar. The effect of BMI also decreases with age and may be negligible at age 60 years.

A whole-genome scan for obstructive sleep apnea and obesity.

Obstructive sleep apnea (OSA) is a common, chronic, complex disease associated with serious cardiovascular and neuropsychological sequelae and with substantial social and economic costs. Along with male gender, obesity is the most characteristic feature of OSA in adults. To identify susceptibility loci for OSA, we undertook a 9-cM genome scan in 66 white pedigrees (n=349 subjects) ascertained on the basis of either an affected individual with laboratory-confirmed OSA or a proband who was a neighborhood control individual. Multipoint variance-component linkage analysis was performed for the OSA-associated quantitative phenotypes apnea-hypopnea index (AHI) and body mass index (BMI). Candidate regions on chromosomes 1p (LOD score 1.39), 2p (LOD score 1.64), 12p (LOD score 1.43), and 19p (LOD score 1.40) gave the most evidence for linkage to AHI. BMI was also linked to multiple regions, most significantly to markers on chromosomes 2p (LOD score 3.08), 7p (LOD score 2.53), and 12p (LOD score 3.41). Extended modeling indicated that the evidence for linkage to AHI was effectively removed after adjustment for BMI, with the exception of the candidate regions on chromosomes 2p (adjusted LOD score 1.33) and 19p (adjusted LOD score 1.45). After adjustment for AHI, the primary linkages to BMI remained suggestive but were roughly halved. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity and that the interrelationship of OSA and obesity in white individuals may be partially explained by a common causal pathway involving one or more genes regulating both AHI and BMI levels.

Genetics of the apnea hypopnea index in Caucasians and African Americans: I. Segregation analysis.

Differences in age of presentation and anatomic risk factors for obstructive sleep apnea (OSA) in Caucasians and African Americans suggest possible racial differences in the genetic underpinnings of the disorder. In this study, we assess transmission patterns in a Caucasian sample consisting of 177 families (N = 1,195) and in an African American sample consisting of 125 families (N = 720) for two variables: 1) apnea hypopnea index (AHI) log transformed and adjusted for age, and 2) AHI log transformed and adjusted for age and body mass index (BMI). We allowed for residual familial correlations and sex-specific means in all models. Analysis of the Caucasian sample showed transmission patterns consistent with that of a major gene that were stronger in the age-adjusted variable than in the age- and BMI-adjusted variable. However, in the African American families, adjusting for BMI in addition to age gave stronger evidence for segregation of a codominant gene with an allele frequency of 0.14, accounting for 35% of the total variance. These results provide support for an underlying genetic basis for OSA that in African Americans is independent of the contribution of BMI.

The role of genotype in determining the effects of cigarette smoking on pulmonary function.

The effect of cigarette smoking on pulmonary function is highly variable. Some heavy smokers retain normal pulmonary function and others experience profound pulmonary function loss. The role of genotype in this process is unknown. We tested for gene by environment interaction (GxE) in smoking-associated loss of forced expiratory volume in one second (FEV1) using repeated pulmonary function and smoke-exposure measures from 352 twin pairs enrolled in the NHLBI Male Veteran Twin Study. Inferences using global [Jinks and Fulker, 1970] and dichotomous [Ramakrishnan et al., 1992] procedures were supplemented with a new model for repeatedly observed twinships. The model facilitates testing of standard heritability hypotheses and families of hypotheses regarding the dependence of quantitative twin-twin phenotypic similarity on continuously varying twin-twin exposure concordance. The global and dichotomous procedures were suggestive of GxE in smoke-associated loss of FEV1 (p < 0.01, p = 0.08, respectively). With the new model, overall twin-twin correlation of FEV1 for concordant-smoking MZ and DZ twin pairs was estimated at 0.71 and 0.34, respectively. For twins with little or no difference in cigarette use, the intra-pair correlations of FEV(1) did not differ according to cigarette exposure over a wide range of exposures (0 - > or = 200 pack years). Even great twin-twin discordance in cigarette smoking (> or =10 pack years) had little effect of correlations. We conclude that a constant factor, such as genotype, appears to be interposed between the environmental toxin (cigarette smoke) and phenotype (FEV1).

The genetics of sleep apnea.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a complex chronic condition that is undoubtedly influenced by multiple factors. Accumulating data suggest that there are strong genetic underpinnings for this condition. It has been estimated that approximately 40% of the variance in the apnea hypopnea index (AHI) may be explained by familial factors. It is likely that genetic factors associated with craniofacial structure, body fat distribution and neural control of the upper airway muscles interact to produce the OSAHS phenotype. Although the role of specific genes that influence the development of OSAHS have not yet been identified, current research in rodents suggests that several genetic systems may be important. In this chapter, we shall first define the OSAHS phenotype, and then review the evidence that suggests an underlying genetic basis of OSAHS, the risk factors for OSAHS that may be inherited, and potential candidate genes.