Cancer vaccines: Building a bridge over troubled waters.

Cancer vaccines aim to direct the immune system to eradicate cancer cells. Here we review the essential immunologic concepts underpinning natural immunity and highlight the multiple unique challenges faced by vaccines targeting cancer. Recent technological advances in mass spectrometry, neoantigen prediction, genetically and pharmacologically engineered mouse models, and single-cell omics have revealed new biology, which can help to bridge this divide. We particularly focus on translationally relevant aspects, such as antigen selection and delivery and the monitoring of human post-vaccination responses, and encourage more aggressive exploration of novel approaches.

Impact of electronic reminder systems on hepatitis C screening in primary care.

Screening for hepatitis C virus (HCV) was recommended in 2012 by the Centers for Disease Control (CDC) for the population born between 1946 and 1965. Reminder systems are effective at promoting HCV screening, but the yield of positive tests among various population subgroups and the linkage to specialty HCV treatment is not well understood. We sought to determine: (i) the effect of the CDC recommendation alone, and the effect of an electronic medical record (EMR) reminder on the proportion of the population screened; (ii) the yield of positive HCV tests as screening strategies have evolved, and according to a patient's history of serum aminotransferase testing; (iii) the proportion of positive cases followed up for HCV treatment. This retrospective cohort study included 60 000 primary care patients at a northeast US academic medical centre serving an urban and rural population in which an EMR reminder was instituted in 2014. Results demonstrated an increase in proportion tested for HCV from 12% prior to the CDC recommendation to 37% after the reminder system. The yield of positive HCV antibody (HCV Ab) tests decreased from 7% in the "case-finding" era to 1.6% after the EMR reminder prompted screening of a lower risk population (P < .001). Patients with a history of abnormal aminotransferase tests had a fivefold higher rate of positive HCV Ab testing (6.7% vs 1.5%, P < .001). Ninety per cent of patients with confirmed HCV infection were seen in specialty care.

Kinetic risk factors of running-related injuries in female recreational runners.

Our objective was to prospectively investigate the association of kinetic variables with running-related injury (RRI) risk. Seventy-four healthy female recreational runners ran on an instrumented treadmill while 3D kinetic and kinematic data were collected. Kinetic outcomes were vertical impact transient, average vertical loading rate, instantaneous vertical loading rate, active peak, vertical impulse, and peak braking force (PBF). Participants followed a 15-week half-marathon training program. Exposure time (hours of running) was calculated from start of program until onset of injury, loss to follow-up, or end of program. After converting kinetic variables from continuous to ordinal variables based on tertiles, Cox proportional hazard models with competing risks were fit for each variable independently, before analysis in a forward stepwise multivariable model. Sixty-five participants were included in the final analysis, with a 33.8% injury rate. PBF was the only kinetic variable that was a significant predictor of RRI. Runners in the highest tertile (PBF < -0.27 BW) were injured at 5.08 times the rate of those in the middle tertile and 7.98 times the rate of those in the lowest tertile. When analyzed in the multivariable model, no kinetic variables made a significant contribution to predicting injury beyond what had already been accounted for by PBF alone. Findings from this study suggest PBF is associated with a significantly higher injury hazard ratio in female recreational runners and should be considered as a target for gait retraining interventions.

Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.

BACKGROUND: Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS: We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS: Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS: Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).

Intellectual abilities in tuberous sclerosis complex: risk factors and correlates from the Tuberous Sclerosis 2000 Study.

BACKGROUND: Tuberous sclerosis complex (TSC) is associated with intellectual disability, but the risk pathways are poorly understood. METHOD: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of the natural history of TSC. One hundred and twenty-five UK children age 0-16 years with TSC and born between January 2001 and December 2006 were studied. Intelligence was assessed using standardized measures at ≥2 years of age. The age of onset of epilepsy, the type of seizure disorder, the frequency and duration of seizures, as well as the response to treatment was assessed at interview and by review of medical records. The severity of epilepsy in the early years was estimated using the E-Chess score. Genetic studies identified the mutations and the number of cortical tubers was determined from brain scans. RESULTS: TSC2 mutations were associated with significantly higher cortical tuber count than TSC1 mutations. The extent of brain involvement, as indexed by cortical tuber count, was associated with an earlier age of onset and severity of epilepsy. In turn, the severity of epilepsy was strongly associated with the degree of intellectual impairment. Structural equation modelling supported a causal pathway from genetic abnormality to cortical tuber count to epilepsy severity to intellectual outcome. Infantile spasms and status epilepticus were important contributors to seizure severity. CONCLUSIONS: The findings support the proposition that severe, early onset epilepsy may impair intellectual development in TSC and highlight the potential importance of early, prompt and effective treatment or prevention of epilepsy in tuberous sclerosis.

A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity.

In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24-22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non-parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.

Patient ratings in exercise therapy for the management of tendinopathy: a systematic review with meta-analysis.

OBJECTIVE: To synthesise exercise therapy intervention data investigating patient rating outcomes for the management of tendinopathy. DESIGN: A systematic review and meta-analysis of randomized controlled trials investigating exercise therapy interventions and reporting patient rating outcomes. SETTING: Any setting in any country listed as very high on the human development index. PARTICIPANTS: People with a diagnosis of any tendinopathy of any severity or duration. INTERVENTIONS: Exercise therapy for the management of tendinopathy comprising five different therapy classes: 1) resistance; 2) plyometric; 3) vibration; 4) flexibility, and 5) movement pattern retraining modalities, were considered for inclusion. MAIN OUTCOME MEASURES: Outcomes measuring patient rating of condition, including patient satisfaction and Global Rating of Change (GROC). RESULTS: From a total of 124 exercise therapy studies, 34 (Achilles: 41%, rotator cuff: 32%, patellar: 15%, elbow: 9% and gluteal: 3%) provided sufficient information to be meta-analysed. The data were obtained across 48 treatment arms and 1246 participants. The pooled estimate for proportion of satisfaction was 0.63 [95%CrI: 0.53-0.73], and the pooled estimate for percentage of maximum GROC was 53 [95%CrI: 38-69%]. The proportion of patients reporting positive satisfaction and perception of change increased with longer follow-up periods from treatment onset. CONCLUSION: Patient satisfaction and GROC appear similar and are ranked moderately high demonstrating that patients generally perceive exercise therapies positively. Further research including greater consistency in measurement tools is required to explore and where possible, identify patient- and exercise-related moderating factors that can be used to improve person-centred care. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO ID=CRD42020168187 CONTRIBUTION OF PAPER.

A Perfect Storm Averted: Flawed Systems, a Dropped Ball, and Cognitive Biases Delay a Critical Diagnosis.

This is the first case of Cancer Morbidity, Mortality, and Improvement Rounds, a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. This case highlights how multiple overlapping factors contributed to a delay in diagnosing disseminated tuberculosis in a patient with lung cancer. The discussion focuses on the ways that cognitive biases contributed to the delayed diagnosis in a patient who, with the benefit of hindsight, exhibited several signs and symptoms suggesting tuberculosis.Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.1.

Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease.

PURPOSE: The risk of immune checkpoint inhibitor therapy-related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors. PATIENTS AND METHODS: We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events. RESULTS: Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn's disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event-related deaths were recorded. Anti-cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively). CONCLUSION: Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.

Mentalising skills in generic mental healthcare settings: can we make our day-to-day interactions more therapeutic?

Aims and methodCaring for patients with personality disorder is one of the biggest challenges in psychiatric work. We investigated whether mentalisation-based treatment skills (MBT-S) teaching improves clinicians' understanding of mentalising and attitudes towards personality disorder. Self-report questionnaires (Knowledge and Application of MBT (KAMQ) and Attitudes to Personality Disorder (APDQ)) were completed at baseline and after a 2-day MBT-S workshop. RESULTS: Ninety-two healthcare professionals completed questionnaires before and after training. The mean within-participant increase in scores from baseline to end-of-programme was 11.6 points (95% CI 10.0-13.3) for the KAMQ and 4.0 points (1.8-6.2) for the APDQ.Clinical implicationsMBT-S is a short intervention that is effective in improving clinicians' knowledge of personality disorder and mentalisation. That attitudes to personality disorder improved overall is encouraging in relation to the possibility of deeper learning in staff and, ultimately, improved care for patients with personality disorder.Declaration of interestNone.

Methods to develop arthritis and osteoporosis measures: a view from the National Committee for Quality Assurance (NCQA).

OBJECTIVE: Performance measurement at various levels of the health care system promotes improved processes that can result in the provision of more consistent and effective care. This chapter articulates the methodology and criteria utilized in measures development to ensure accountability and serve the information needs of physicians, health care systems, health plans and consumers, using arthritis and osteoporosis as example conditions. METHODS: Observational studies conducted to assess the validity and feasibility of performance measures focused on arthritis and osteoporosis. Clinical expert panels were convened to develop measure specifications based on guidelines and evidence supporting critical aspects of care. The aspects of care that were assessed included: DMARD utilization for patients with rheumatoid arthritis; appropriate gastrointestinal prophylaxis for patients utilizing NSAIDS; comprehensive osteoarthritis care; comprehensive symptom assessment and medical management of woman over 65 years who experienced a bone fracture. RESULTS: The implementation of performance measures for key aspects of arthritis and osteoporosis care is challenged by the availability of administrative data. However, potential for improvement is evident in each of the areas studied. CONCLUSION: The key challenge to the feasibility of arthritis performance measures is the lack of administrative data to identify the eligible population. Administrative data capture suffers as a result of under-coding and under-recognition of arthritis. Consensus around a single set of measures creates a powerful tool for focusing on key components of care as a basis for quality improvement and allows for a valid comparison of care within and across health care settings.

Exclusion of linkage between schizophrenia and the D2 dopamine receptor gene region of chromosome 11q in 112 Irish multiplex families.

A leading theory hypothesizes that schizophrenia arises from dysregulation of the dopamine system in certain brain regions. As this dysregulation could arise from abnormal expression of D2 dopamine receptors, the D2 receptor gene (DRD2) on chromosome 11q is a candidate locus for schizophrenia. We tested whether allelic variation at DRD2 and five surrounding loci cosegregated with schizophrenia in 112 small- to moderate-size Irish families containing two or more members affected with schizophrenia or schizoaffective disorder, defined by DSM-III-R. Evidence of linkage was assessed using varying definitions of illness and modes of transmission. Assuming genetic homogeneity, linkage between schizophrenia and large regions of 11q around DRD2 could be strongly excluded. Assuming genetic heterogeneity, variation at the DRD2 locus could be rejected as a major risk factor for schizophrenia in more than 50% of these families for all models tested and in as few as 25% of the families for certain models. The DRD2 linkage in fewer than 25% of these families could not be excluded under any of the models tested. Our results suggest that the major component of genetic susceptibility to schizophrenia is not due to allelic variation at the DRD2 locus or other genes in the surrounding chromosomal region.

Smoking and major depression. A causal analysis.

Among 1566 personally evaluated female twins from a population-based register, average lifetime daily cigarette consumption was strongly related to lifetime prevalence and to prospectively assessed 1-year prevalence of major depression (MD). Using the cotwin control method, we evaluated whether the association between smoking and lifetime MD was causal or noncausal. While the relative risk (95% confidence interval) for ever smoking given a lifetime history of MD was 1.48 (1.30 to 1.65) in the entire sample, it was 1.18 (0.88 to 1.47) and 0.98 (0.71 to 1.26), respectively, in dizygotic and monozygotic twin pairs discordant for a history of MD. The relative risk for a history of MD given ever smoking was 1.60 (1.39 to 1.83) in the entire sample, while in dizygotic and monozygotic twins discordant for smoking, it was 1.29 (0.87 to 1.74) and 0.96 (0.59 to 1.42), respectively. Controlling for personal smoking history, family history of smoking predicted risk for MD; controlling for the personal history of MD, family history of MD predicted smoking. The best-fitting bivariate twin model suggested that the relationship between lifetime smoking and lifetime MD resulted solely from genes that predispose to both conditions. These results suggest that the association between smoking and MD in women is not a causal one but arises largely from familial factors, which are probably genetic, that predispose to both smoking and MD.

The incidence and prognosis of unrecognized myocardial infarction in the Honolulu, Hawaii, Heart Program.

The incidence of clinically unrecognized myocardial infarctions among 7331 Japanese-American men in Hawaii, aged 45 to 68 years and free of coronary heart disease at entry, was studied on the basis of electrocardiographic changes between successive examinations during 6 years of follow-up. The proportion of asymptomatic myocardial infarction accounted for 33% of transmural (Q-wave) myocardial infarctions identified by temporal changes on electrocardiogram and 22% of all nonfatal infarctions ascertained by either repeated examinations or hospital surveillance. The 10-year prognosis of unrecognized infarction, in terms of mortality from all causes, cardiovascular disease, and coronary heart disease, was worse (with risk ratios of 1.5 to 1.7) than that of recognized infarction, even after adjusting for age and other possible determinants, although the differences were not statistically significant. These findings suggest that regular health check-ups with an electrocardiogram would be important to detect asymptomatic myocardial infarction and to increase the opportunity of taking secondary preventive measures. However, the conclusion should await further studies based on intervention trials to determine the comparative effects of the secondary prevention on the prognosis of clinically recognized vs unrecognized infarction.

Comparison of cross-sectional and longitudinal measurements of age-related changes in bone mineral content.

Age-related, postmenopausal bone loss was examined among a cohort of Japanese-American women living in Hawaii. None of the women were using estrogens or thiazides. Cross-sectional and longitudinal measurements of bone mineral content were compared at the calcaneus, the proximal radius, and the distal radius. Cross-sectional measurements were also available for the lumbar spine. The longitudinal data showed a slowing rate of bone loss with increasing age at the radius sites. By contrast, the cross-sectional data suggested constant rates of bone loss for all ages at both radius sites and the spine. The calcaneus demonstrated a complex pattern of bone loss in both cross-sectional and longitudinal analyses. The loss rates among women in their fifties were greater than for those in their sixties. From the middle sixties onward calcaneal bone loss remained essentially constant. Because of the sustained bone loss, however, women in their seventies were actually losing greater percentages of their calcaneal bone mineral than they had in their sixties.

The genetic epidemiology of bulimia nervosa.

OBJECTIVE: The authors seek to clarify, from both an epidemiologic and genetic perspective, the major risk factors for bulimia nervosa and to understand the relationship between narrowly defined bulimia and bulimia-like syndromes. METHOD: Personal structured psychiatric interviews were conducted with 2,163 female twins from a population-based register. Psychiatric disorders were assessed using DSM-III-R criteria. RESULTS: Lifetime prevalence and risk for narrowly defined bulimia were 2.8% and 4.2%, respectively. Including bulimia-like syndromes increased these estimates to 5.7% and 8.0%, respectively. Risk factors for bulimia included 1) birth after 1960, 2) low paternal care, 3) a history of wide weight fluctuation, dieting, or frequent exercise, 4) a slim ideal body image, 5) low self-esteem, 6) an external locus of control, and 7) high levels of neuroticism. Significant comorbidity was found between bulimia and anorexia nervosa, alcoholism, panic disorder, generalized anxiety disorder, phobia, and major depression. Proband-wise concordance for narrowly defined bulimia was 22.9% in monozygotic and 8.7% in dizygotic twins. The best-fitting model indicated that familial aggregation was due solely to genetic factors with a heritability of liability of 55%. A multiple threshold model indicated that narrowly defined bulimia nervosa and bulimia-like syndromes represented different levels of severity on the same continuum of liability. CONCLUSIONS: The liability to fully syndromal bulimia nervosa, which affects around one in 25 women at some point in their lives, is substantially influenced by both epidemiologic and genetic risk factors. The same factors that influence the risk for narrowly defined bulimia also influence the risk for less severe bulimia-like syndromes.

Stressful life events, genetic liability, and onset of an episode of major depression in women.

OBJECTIVE: This study was undertaken to clarify how genetic liability and stressful life events interact in the etiology of major depression. METHOD: Information about stressful life events and onset of major depressive episodes in the past year was collected in a population-based sample of female-female twin pairs including 2,164 individuals, 53,215 person-months of observation, and 492 onsets of depression. RESULTS: Nine "personal" and three aggregate "network" stressful events significantly predicted onset of major depression in the month of occurrence, four of which predicted onset with an odds ratio of > 10 and were termed "severe": death of a close relative, assault, serious marital problems, and divorce/breakup. Genetic liability also had a significant impact on risk of onset of depression. For severe stressful events, as well as for 10 of the 12 individual stressful events, the best-fitting model for the joint effect of stressful events and genetic liability on onset of major depression suggested genetic control of sensitivity to the depression-inducing effects of stressful life events. In individuals at lowest genetic risk (monozygotic twin, co-twin unaffected), the probability of onset of major depression per month was predicted to be 0.5% and 6.2%, respectively, for those unexposed and exposed to a severe event. In those at highest genetic risk (monozygotic twin, co-twin affected), these probabilities were 1.1% and 14.6%, respectively. Linear regression analysis indicated significant Genotype by Environment interaction in the prediction of onset of major depression. CONCLUSIONS: Genetic factors influence the risk of onset of major depression in part by altering the sensitivity of individuals to the depression-inducing effect of stressful life events.

Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families: evidence for possible etiologic heterogeneity.

OBJECTIVE: The authors sought to determine whether the clinical manifestations of schizophrenia and other psychotic disorders are correlated in affected sibling pairs. METHOD: They examined, in 256 sibling pairs concordant for DSM-III-R schizophrenia and 457 sibling pairs concordant for all nonaffective psychoses ascertained in the Irish Study of High-Density Schizophrenia Families, similarity for 1) symptoms, course, and outcome; 2) symptom factors; and 3) syndromes, defined by latent class analysis. RESULTS: Global course and outcome, as well as all major symptoms except hallucinations, were modestly but significantly correlated in sibling pairs concordant for schizophrenia. Three symptom factors-negative symptoms, positive symptoms, and affective symptoms-were all significantly correlated in concordant sib pairs. Latent class analysis suggested five schizophrenic syndromes. Class membership was significantly correlated in concordant sibling pairs. Similar results were found for sibling pairs concordant for nonaffective psychoses. CONCLUSIONS: The clinical manifestations of the schizophrenic syndrome (both narrowly and broadly defined) are moderately influenced by familial factors. From a familial/genetic perspective, schizophrenia as currently defined may be etiologically heterogeneous.

Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of High-Density Schizophrenia Families.

OBJECTIVE: Schizophrenia is clinically heterogeneous. Recent linkage studies suggest that multiple genes are important in the etiology of schizophrenia. The authors examined the hypothesis of whether the clinical variability in schizophrenia is due to genetic heterogeneity. METHOD: Using data from the Irish Study of High-Density Schizophrenia Families (N=265 pedigrees; N=1,408 individuals), the authors attempted to predict, from major symptoms and signs of psychosis, evidence for linkage within families for schizophrenia-related disorders to chromosomal regions 5q21-5q31, 6p24-6p22, 8p22-8p21, and 10p15-10p11. RESULTS: No substantial evidence was found for associations between clinical features of schizophrenia and linkage to chromosomes 5q, 6p, or 10p. However, affected individuals from families with evidence for linkage to 8p had significantly more affective deterioration, poorer outcome, more thought disorder, and fewer depressive symptoms than affected individuals from the other families in the study. CONCLUSIONS: These results raise the possibility that the putative susceptibility gene for schizophrenia localized in the 8p22-8p21 region may predispose individuals to the core dementia-praecox syndrome described by Kraepelin more than 100 years ago.

Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families.

OBJECTIVE: This study was an attempt to replicate evidence for a vulnerability locus for schizophrenia and associated disorders in the 8p22-21 region reported by Pulver and colleagues. METHOD: The linkage sample of the Irish Study of High-Density Schizophrenia Families consists of 265 multiplex families containing 1,408 individuals. Fifteen markers covering 30 centimorgans on chromosome 8p were tested. Three statistical methods were used: two-point and multipoint heterogeneity lod scores and a multipoint nonparametric test. RESULTS: According to two-point heterogeneity lod scores, the strongest evidence for linkage was found for markers D8S1731 (maximum lod score = 2.00), D8S1715 (maximum lod score = 2.52), and D8S133 (maximum lod score = 2.08) by assuming a phenotypic definition of all psychiatric illness and a range of genetic models. According to multipoint heterogeneity lod scores, the strongest evidence for linkage (maximum lod score = 2.34), found by using a dominant genetic model and a broad definition of the schizophrenia spectrum, extended over a 10-cM region between markers D8S1715 and D8S1739. Multipoint nonparametric linkage found the strongest evidence (maximum z = 2.51) over a broader region when either a diagnosis of core schizophrenia or a narrow definition of the schizophrenia spectrum was used. This putative vulnerability locus was segregating in 10%-25% of the families studied. CONCLUSIONS: This study supports the existence of a vulnerability locus for schizophrenia on chromosome 8p. In this sample, this locus appears to influence the risk of illness in only a modest proportion of families and predisposes to a range of schizophrenia spectrum and possibly nonspectrum disorders.