Systematic review and meta-analysis of epidemiologic data on vaccine response in relation to exposure to five principal perfluoroalkyl substances.

BACKGROUND: Epidemiologic studies of serum per- and polyfluoroalkyl substances (PFAS) and antibody response to vaccines have suggested an adverse association, but the consistency and magnitude of this association remain unclear. OBJECTIVE: The goal of this systematic review was to determine the size of the association between a doubling in perfluoroalkyl substances (PFAS) serum concentration and difference in loge antibody concentration following a vaccine, with a focus on five PFAS: perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA). DATA SOURCE: We conducted online searches of PubMed and Web of Science through May 17, 2022 and identified 14 eligible reports published from 2012 to 2022. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We included studies conducted in humans, including mother-child pairs, which examined serum PFAS concentration in relation to serum concentration of antibody to a specific antigen following a vaccine. STUDY APPRAISAL AND SYNTHESIS METHODS: We used the risk of bias assessment for non-randomized studies of exposure and certainty assessment method proposed by Morgan et al. (2019). Using a multilevel meta-regression model, we quantitatively synthesized the data. RESULTS: The 14 reports represented 13 unique groups of subjects; the frequency of studies of a given antibody was Tetanus (n = 7); followed by Diphtheria (6); Measles (4); Rubella (3); Haemophilus influenzae type b and Influenza A H1N1 (2 each); and Hepatitis A, Hepatitis B, Influenza A H2N3, Influenza B, and Mumps (1 each). There were approximately 4,830 unique participants included in the analyses across the 14 reports. The models of coefficients between antibody concentration and the five principal PFAS showed homogeneity of associations across antibody types for each principal PFAS. In the models with all antibodies treated as one type, evidence of effect modification by life stage was present for PFOA and PFOS, and for consistency, all associations were evaluated for all ages and for children. The summary associations (coefficients for difference in loge[antibody concentration] per doubling of serum PFAS) with 95% confidence intervals that excluded zero ("statistical support"), and certainty of evidence ratings were as follows: for PFOA and all antibodies treated as one type in all ages, -0.06 (-0.10, -0.01; moderate) and in children, -0.10 (-0.16, -0.03; moderate); for Diphtheria in children, -0.12 (-0.23, -0.00; high); for Rubella in all ages, -0.09 (-0.17, -0.01; moderate), and for Tetanus in children, -0.12 (-0.24, -0.00; moderate). For PFOS the summary associations were, for all antibodies treated as one type in all ages, -0.06 (-0.11, -0.01; moderate) and in children, -0.10 (-0.18, -0.03; moderate); for Rubella in all ages, -0.09 (-0.15, -0.03; high) and in children, -0.12 (-0.20, -0.04; high). For PFHxS the summary associations were, for all antibodies treated as one type in all ages, -0.03 (-0.06, -0.00; moderate) and in children, -0.05 (-0.09, -0.00; low); and for Rubella in children, -0.07 (-0.11, -0.02; high). Summary associations for PFNA and PFDA did not have statistical support, but all PFAS studied tended to have an inverse association with antibody concentrations. LIMITATIONS AND CONCLUSIONS: Epidemiologic data on immunosuppression and five principal PFAS suggest an association, with support across antibodies against multiple types of antigens. Data on Diphtheria, Rubella, and Tetanus were more supportive of an association than for other antibodies, and support was greater for associations with PFOA, PFOS, and PFHxS, than for PFNA or PFDA. The data on any specific antibody were scarce. Confounding factors that might account for the relation were not identified. Nearly all studies evaluated were judged to have a low or moderate risk of bias.

Underground salt and potash workers exposed to nitrogen oxides and diesel exhaust: assessment of specific effect biomarkers.

PURPOSE: Occupational exposure limits (OEL) for nitrogen oxides (NO, NO2) and diesel exhaust (EC-DPM) were reassessed by the German authorities in 2016/2017. We performed a clinical cross-sectional study among salt and potash underground workers exposed to these substances at relatively high levels to examine possible indicators of acute effects on workers' health. METHODS: We measured post- versus pre-shift differences in cardiovascular, inflammatory, immune, and respiratory effect biomarkers and assessed their associations with personal exposures measured during the same shift. We also compared post- versus pre-shift differences in biomarker levels between exposure groups defined based on work site and job type. RESULTS: None of the above-ground workers exceeded the OEL for NO2 and only 5% exceeded the OEL for EC-DPM exposure. Among underground workers, 33% of miners and 7% underground maintenance workers exceeded the OEL for NO2; the OEL for EC-DPM was exceeded by 56% of miners and 17% of maintenance workers. Some effect biomarkers (thrombocytes, neutrophils, MPO, TNF-α, IgE, FeNO) showed statistically significant differences between pre- versus post-shift measurements; however, there were no consistent associations between pre- and post-shift differences and exposure group or personal exposure measurements during the shift. CONCLUSIONS: We did not find evidence of associations between workplace exposure to NO, NO2 or EC-DPM and clinically relevant indicators of acute cardiovascular, inflammatory and immune, or respiratory effects among salt and potash underground workers in Germany.

Birth weight and perfluorooctane sulfonic acid: a random-effects meta-regression analysis.

Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental contaminant. Most people in developed countries have detectable serum concentrations. Lower birth weight has been associated with serum PFOS in studies world-wide, many of which have been published only recently. METHODS: To facilitate a causal assessment of the birth weight and PFOS association, we updated previous meta-analyses of the association and employed a method that facilitated inclusion of all available data in one analysis. Our analysis was based on observations from 29 studies. RESULTS: The random effects summary was -3.22 g/ng/ml (95% confidence interval [CI] = -5.11, -1.33). In a subgroup analysis stratified by when in pregnancy the PFOS concentration was measured, the summary for the early group was -1.35 (95% CI = -2.33, -0.37) and for the later group was -7.17 (95% CI = -10.93, -3.41). In a meta-regression model including a term for timing of blood draw, the intercept was slightly positive but essentially zero (0.59 g/ng/ml, 95% CI = -1.94, 3.11). In other words, the model indicated that when blood was drawn at the very beginning of pregnancy, there was essentially no relation of birth weight to PFOS. The results from the subgroup analyses differed from those from the model because the average gestational age at blood draw in the early group was 14 weeks, when bias would still be expected. A stronger inverse association in Asian studies was not completely explained by their blood draws being from later in pregnancy. CONCLUSIONS: The evidence was weakly or not supportive of a causal association.

Cancer Risk Associated With Exposure to Bitumen and Bitumen Fumes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate whether cancer risks are increased among bitumen (asphalt) workers. METHODS: Systematic review and meta-analysis of cancer risks (lung, upper aerodigestive tract (UADT), esophagus, bladder, kidney, stomach, and skin) and bitumen exposure. Certainty in the epidemiological evidence that bitumen-exposed workers experience increased cancer risks was rated using Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS: After excluding lower-quality studies, lung cancer risks were not increased among bitumen-exposed workers (meta-relative risk [RR] 0.94, 95% CI 0.74 to 1.20, eight studies). Increased risks of UADT and stomach cancers were observed (meta-RR 1.31, 95% CI 1.03 to 1.67, 10 studies and meta-RR 1.29, 95% CI 1.03 to 1.62, seven studies, respectively). CONCLUSIONS: Except for lung cancer, evidence for increased cancer risks among bitumen-exposed workers was judged to be of low certainty, due to inadequate exposure characterization and unmeasured confounders (coal tar exposure, smoking, and alcohol consumption).

Quantitative estimated exposure to vinyl chloride and risk of angiosarcoma of the liver and hepatocellular cancer in the US industry-wide vinyl chloride cohort: mortality update through 2013.

OBJECTIVE: To evaluate mortality risks of angiosarcoma of the liver (ASL), primary hepatocellular carcinoma (HCC) and other cancers among 9951 men employed between 1942 and 1972 at 35 US vinyl chloride (VC) or polyvinyl chloride plants followed for mortality through 31 December 2013. METHODS: SMR and time-dependent Cox proportional hazards analyses were used to evaluate mortality risks by cumulative VC exposure. RESULTS: Liver cancer mortality was elevated (SMR=2.87, 95% CI 2.40 to 3.40), and ASL and HCC were strongly associated with cumulative VC exposure ≥865 parts per million-years (ppm-years) (ASL: HR=36.3, 95% CI 13.1 to 100.5; and HCC: HR=5.3, 95% CI 1.6 to 17.7 for ≥2271 ppm-years). Excess deaths due to connective and soft tissue cancers (SMR=2.43, 95% CI 1.48 to 3.75), mesothelioma (SMR=2.29, 95% CI 1.18 to 4.00) and explosions (SMR=3.43, 95% CI 1.25 to 7.47) were seen. Mortalities due to melanoma, brain cancer, lung cancer and non-Hodgkin's lymphoma were not increased or associated with VC exposure. CONCLUSION: The association between VC and ASL first reported in this cohort 44 years ago persisted and was strongest among workers most highly exposed. VC exposure also was associated with HCC mortality, although it remains possible that misdiagnosis of early ASLs influenced findings.

Cohort Study of Carbon Black Exposure and Risk of Malignant and Nonmalignant Respiratory Disease Mortality in the US Carbon Black Industry.

OBJECTIVE: To evaluate lung cancer and respiratory disease mortality associations with cumulative inhalable carbon black exposure among 6634 US carbon black workers. METHODS: This analysis was performed using standardized mortality ratio (SMRs) and Cox regression analyses. RESULTS: Lung cancer mortality was decreased overall (SMR = 0.77; 95% confidence interval [CI], 0.67 to 0.89) but less so among hourly male workers (SMR = 0.87; 95% CI, 0.71 to 1.05). No exposure-response association was observed with time-dependent cumulative inhalable carbon black: hazard ratio [HR] = 1.0 (95% CI, 0.6 to 1.6) for 20 to less than 50 mg/m·yr); HR = 1.3 (95% CI, 0.8 to 2.1) for 50 to less than 100 mg/m·yr; and HR = 1.4 (95% CI, 0.9 to 2.1) for 100 mg/m·yr or more compared with referent (<20 mg/m·yr). No consistent associations were observed between cumulative inhalable carbon black exposure and respiratory disease mortality. CONCLUSION: Quantitative carbon black exposure estimates were not related to lung cancer or nonmalignant respiratory disease mortality.

Formaldehyde Exposure and Mortality Risks From Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute Cohort Study of Workers in Formaldehyde Industries.

OBJECTIVES: To evaluate associations between cumulative and peak formaldehyde exposure and mortality from acute myeloid leukemia (AML) and other lymphohematopoietic malignancies. METHODS: Cox proportional hazards analyses. RESULTS: Acute myeloid leukemia was unrelated to cumulative exposure. Hodgkin lymphoma relative risk estimates in the highest exposure categories of cumulative and peak exposures were, respectively, 3.76 (Ptrend = 0.05) and 5.13 (Ptrend = 0.003). There were suggestive associations with peak exposure observed for chronic myeloid leukemia, albeit based on very small numbers. No other lymphohematopoietic malignancy was associated with either chronic or peak exposure. CONCLUSIONS: Insofar as there is no prior epidemiologic evidence supporting associations between formaldehyde and either Hodgkin leukemia or chronic myeloid leukemia, any causal interpretations of the observed risk patterns are at most tentative. Findings from this re-analysis do not support the hypothesis that formaldehyde is a cause of AML.

Prescribing Patterns of Metformin in High-risk Patients with Prediabetes.

AIMS: The primary objective of this study is to examine the rates of metformin prescribing in patients with prediabetes who are either less than 60 years of age, have a BMI greater than 35 kg/m2, or women with a history of gestational diabetes mellitus (GDM). Secondary objectives include: 1) examination of the time from diagnosis of prediabetes to the initiation of metformin and 2) if metformin initiation status and length of time correlates to the patient having any other additional diabetes mellitus (DM) risk factors. METHODS: This was a single center, retrospective cohort study. This study included all patients with prediabetes, defined as having hemoglobin A1c (HbA1c) of 39 through 46 mmol/mol (5.7-6.4 percent), who were patients at the Interim LSU Hospital and Clinics from January 2012-September 2013. RESULTS: There were a total of 13 patients out of 160 patients in the study population who were prescribed metformin for an overall metformin initiation rate of 8.1 percent. The metformin initiation rate for the three individual groups; history of GDM, aged less than 60 years, and BMI greater than 35 kg/m2 were 0 percent, 9.0 percent, and 17.5 percent respectively. CONCLUSION: Metformin initiation rates in patients with prediabetes are not in accordance with current recommendations, and provider education is necessary to increase rates to delay or prevent the progression of prediabetes to type 2 Diabetes Mellitus.

Perineal powder use and risk of ovarian cancer.

BACKGROUND: Case-control studies have reported an increased risk of ovarian cancer among talc users; however, the only cohort study to date found no association except for an increase in serous invasive ovarian cancers. The purpose of this analysis was to assess perineal powder use and risk of ovarian cancer prospectively in the Women's Health Initiative Observational Study cohort. METHODS: Perineal powder use was assessed at baseline by self-report regarding application to genitals, sanitary napkins, or diaphragms and duration of use. The primary outcome was self-reported ovarian cancer centrally adjudicated by physicians. Cox proportional hazard regression was used to estimate risk, adjusting for covariates, including person-time until diagnosis of ovarian cancer (n = 429), death, loss to follow-up, or September 17, 2012. All statistical tests were two-sided. RESULTS: Among 61576 postmenopausal women, followed for a mean of 12.4 years without a history of cancer or bilateral oophorectomy, 52.6% reported ever using perineal powder. Ever use of perineal powder (hazard ratio [HR]adj = 1.06, 95% confidence interval [CI] = 0.87 to 1.28) was not associated with risk of ovarian cancer compared with never use. Individually, ever use of powder on the genitals (HRadj = 1.12, 95% CI = 0.92 to 1.36), sanitary napkins (HRadj = 0.95, 95% CI = 0.76 to 1.20), or diaphragms (HRadj = 0.92, 95% CI = 0.68 to 1.23) was not associated with risk of ovarian cancer compared with never use, nor were there associations with increasing durations of use. Estimates did not differ when stratified by age or tubal ligation status. CONCLUSION: Based on our results, perineal powder use does not appear to influence ovarian cancer risk.

Perineal powder use and risk of endometrial cancer in postmenopausal women.

BACKGROUND: Most known endometrial cancer risk factors involve genetics or exposure to unopposed estrogens; less is known about risk due to environmental exposures. While several studies have found an increased risk of ovarian cancer associated with perineal powder use, only two studies have addressed perineal powder use and endometrial cancer risk. METHODS: We used Cox proportional hazards regression to examine the association between perineal powder use and endometrial cancer risk using the Women's Health Initiative Observational Study Research Materials obtained from the National Heart, Lung, and Blood Institute Biological Specimen and Data Repository Coordinating Center. RESULTS: Of the 48,526 women in our primary analysis, 25,181 (52 %) reported ever use of perineal powder. During 364,134 person-years of follow-up, 447 participants were diagnosed with endometrial cancer. Ever use of perineal powder was not associated with increased risk of endometrial cancer (multivariable-adjusted hazard ratio, 1.06; 95 % confidence interval, 0.87-1.28). External use of powder on the genitals and/or on sanitary napkins was also not significantly associated with risk of endometrial cancer. However, use of powder on a diaphragm for twenty or more years was associated with a threefold increase in risk of endometrial cancer compared to women who never used perineal powder (multivariable-adjusted hazard ratio, 3.06; 95 % CI, 2.00-4.70). CONCLUSIONS: Any duration of external use of perineal powder was not associated with increased risk of endometrial cancer; however, long-term use of powder on a diaphragm may increase the risk of endometrial cancer.

Effect of occupational exposures on decline of lung function in early chronic obstructive pulmonary disease.

RATIONALE: Several occupational exposures adversely affect lung function. OBJECTIVES: This study reports the influence of continued occupational dust and fume exposures on the rate of decline of lung function in participants with early chronic obstructive pulmonary disease (COPD) studied in a population-based study. METHODS: Subjects consisted of 5,724 participants in the Lung Health Study, a multicenter study of smoking cessation and anticholinergic bronchodilator administration in smokers with early COPD (3,592 men; 2,132 women). Average post-bronchodilator FEV1 at entry was 78.4% predicted for men and 78.2% predicted for women; all participants had an FEV1/FVC ratio less than 0.70. MEASUREMENTS AND MAIN RESULTS: Participants underwent a baseline evaluation and five annual follow-up assessments, including questionnaires and spirometry. The effect of ongoing dust or fume exposure on FEV1 in each follow-up year was statistically evaluated with a mixed-effects regression model, which was adjusted for FEV1 at entry, age, airway responsiveness to methacholine, baseline smoking intensity, and time-varying (yearly) smoking status during each follow-up year. In men with early COPD, each year of continued fume exposure was associated with a 0.25% predicted reduction in post-bronchodilator FEV1% predicted. Continued smoking and airway hyperresponsiveness were also associated with reduction in FEV1 during each year of follow-up in both men and women. Statistically significant effects of dust exposure on the rate of decline were not found, nor were effects of fume exposure noted in women. CONCLUSIONS: These results suggest a need for secondary prevention by controlling occupational fume exposures.

Computer algorithm for automated work group classification from free text: the DREAM technique.

OBJECTIVE: This study developed and tested a computer method to automatically assign subjects to aggregate work groups based on their free text work descriptions. METHODS: The Double Root Extended Automated Matcher (DREAM) algorithm classifies individuals based on pairs of subjects' free text word roots in common with those of standard classification systems and several explicitly defined linkages between term roots and aggregates. RESULTS: DREAM effectively analyzed free text from 5887 participants in a multisite chronic obstructive pulmonary disease prevention study (Lung Health Study). For a test set of 533 cases, DREAMs classifications compared favorably with those of a four-human panel. The humans rated the accuracy of DREAM as good or better in 80% of the test cases. CONCLUSIONS: Automated text interpretation is a promising tool for analyzing large data sets for applications in data mining, research, and surveillance. Work descriptive information is most useful when it can link an individual to aggregate entities that have occupational health relevance. Determining the appropriate group requires considerable expertise. This article describes a new method for making such assignments using a computer algorithm to reduce dependence on the limited number of occupational health experts. In addition, computer algorithms foster consistency of assignments.

Mesothelioma in patients with nonoccupational asbestos exposure. An evidence-based approach to causation assessment.

The specific parameters of nonoccupational asbestos exposures (NOAE) that can distinguish an idiopathic from an asbestos-caused malignant mesothelioma (MM) are controversial. A systematic literature review yielded 1028 cases with this putative association. Only 287 of those reports had a defined single exposure to a household, building occupant, or neighborhood/community asbestos source. The available "evidence" was used to develop semiarbitrary evidence-based causation guideline rules for the assessment of putative associations between MM and NOAE. The rules are classified into class A (tissue burden analysis shows asbestos body counts or fiber counts in lung tissues comparable to MM caused by occupational exposure to asbestos) and classes B to D based on whether certain combinations of NOAE features and MM (evidence) have been described in over 15% (class B), 5% to 15% (class C), and less than 5% (class D) of the patients reviewed. The proposed 4 classes of evidence-based causation guidelines provide a semiarbitrary framework to evaluate the causation of individual MM patients by NOAE based on decreasing levels of currently available evidence. The neoplasms in classes A to C patients are probably caused by NOAE, with decreasing weight of evidence in the 3 groups. There is minimal evidence to support the causation of MM by NOAE in class D patients. There is no evidence or only anecdotal evidence to support a causal association between MM and NOAE in individuals who cannot be classified into any of the 4 classes. Future studies are needed to provide more comprehensive data regarding the association between MM and NOAE.

Working words: real-life lexicon of North American workers.

OBJECTIVE: This study describes a new computer methodology for analyzing workers' free text work descriptions. METHODS: Computerized lexical analysis was applied to work descriptions of participants in the Lung Health Study, a smoking-cessation study in persons with early chronic obstructive pulmonary disease. Text was parsed and analyzed as single term roots and pairs of roots commonly occurring together. RESULTS: The frequencies of terms reflect the work of a population; our subjects' most frequently used terms included "sale, office, service, business, engine[er], secretary, construct, driv[e], comput[e], teach, truck." Standard classification schemes (NAICS and SOC) and textbooks use terms inconsistent with those of actual workers. Many common empirical terms imply both industry and job information content, although traditional coding schemes separate industry and job title. CONCLUSIONS: Formal analyses of language may facilitate communication, identify translation priorities, and allow automated work coding.

Work environment and occupational health of dental hygienists: a qualitative assessment.

OBJECTIVE: We sought to characterize the work environment and identify factors that influence the occupational health of dental hygienists. METHODS: We conducted a qualitative analysis of dental hygiene work based on five national focus groups. RESULTS: We found that musculoskeletal symptoms are common, particularly after 10 years; common ergonomic problems included instruments and chairs. Important non-physical workplace problems include role ambiguity (eg, employee vs. independent practitioner), inadequate recognition, role identity (eg, distinction from dental assistants), role conflict (eg, with dentists and spousal office managers), and social isolation. CONCLUSIONS: Work organizational factors (eg, frequent part-time work, inadequate breaks, perception as a "second team" distinct from the dentist and dental-assistant team) impede the remediation of ergonomics and other problems. Job flexibility encourages hygienists to change work hours or location rather than deal with work conditions. Occupational health interventions should address social environment and work organization.

Work environment of dental hygienists.

OBJECTIVE: We sought to evaluate how musculoskeletal disorders and workplace psychosocial factors affect dental hygienists' work hours and productivity. METHODS: We mailed a survey to dental hygienists in Los Angeles and Orange Counties, California. RESULTS: Musculoskeletal pain caused 27% of hygienists to decrease work hours and 8.7% to change office locations. Hand/wrist pain caused the most missed workdays. Conversely, conflicts with the dentist caused 28.2% of dental hygienists to change jobs and 12.7% to decrease work hours. Conflicts with staff caused 17.1% to change office locations but only 7.0% to decrease work hours. This pattern was confirmed with multiple logistic regression analyses. CONCLUSIONS: Musculoskeletal and psychosocial factors affect dental hygienists differently: musculoskeletal discomfort is more likely to cause dental hygienists to decrease their working hours, whereas professional and social conflicts are more likely to lead to change in work location.

Influence of residency training on occupational medicine practice patterns.

OBJECTIVES: A relatively high proportion of occupational medicine (OM) specialists have not had formal residency training in OM. Members of the Western Occupational and Environmental Medicine Association, a professional organization of OM specialists, completed a postal questionnaire (160 of 561 members). METHODS: Educational background, practice setting, practice activities, and skills considered relevant were compared between those with and without formal training. RESULTS: Both groups had considerable focus in clinical care, musculoskeletal medicine, and workers' compensation. However, those with formal training practice in a broader variety of settings were less likely to have practiced another specialty, and used additional skills (toxicology, industrial hygiene, and epidemiology) in their practices. Formal education appears to create a greater diversity of skills and opportunities, but it does not appear to create a group of physicians disinterested in "front-line" occupational medicine practice. CONCLUSIONS: The data support the need for formal residency programs but also highlight the importance of access to formal training for midcareer physicians.

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.

A genomewide scan for loci involved in attention-deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs.