Cambridge Hospital

The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother–father–child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10−8 per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research. This issue of Nature contains the first publication from The 1000 Genomes Project, an international collaboration that will produce an extensive public catalogue of human genetic variation. The plan, in fact, is to sequence about 2,000 unidentified individuals from 20 populations around the world. This first paper presents the results from the project's pilot phase, testing three different strategies for genome-wide sequencing with high-throughput platforms: low-coverage whole-genome sequencing of 179 individuals in three population groups, high-coverage sequencing of two mother–father–child trios, and exon-targeted sequencing of 697 individuals from seven populations. The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp(3) (Fsp(3)) where Fsp(3) = (number of sp(3) hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp(3)) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting.

The self-medication hypothesis of addictive disorders derives primarily from clinical observations of patients with substance use disorders. Individuals discover that the specific actions or effects of each class of drugs relieve or change a range of painful affect states. Self-medication factors occur in a context of self-regulation vulnerabilities--primarily difficulties in regulating affects, self-esteem, relationships, and self-care. Persons with substance use disorders suffer in the extreme with their feelings, either being overwhelmed with painful affects or seeming not to feel their emotions at all. Substances of abuse help such individuals to relieve painful affects or to experience or control emotions when they are absent or confusing. Diagnostic studies provide evidence that variously supports and fails to support a self-medication hypothesis of addictive disorders. The cause-consequence controversy involving psychopathology and substance use/abuse is reviewed and critiqued. In contrast, clinical observations and empirical studies that focus on painful affects and subjective states of distress more consistently suggest that such states of suffering are important psychological determinants in using, becoming dependent upon, and relapsing to addictive substances. Subjective states of distress and suffering involved in motives to self-medicate with substances of abuse are considered with respect to nicotine dependence and to schizophrenia and posttraumatic stress disorder comorbid with a substance use disorder.

CONTEXT: Studies of selected groups of persons with mental illness, such as those who are institutionalized or seen in mental health clinics, have reported rates of smoking to be higher than in persons without mental illness. However, recent population-based, nationally representative data are lacking. OBJECTIVE: To assess rates of smoking and tobacco cessation in adults, with and without mental illness. DESIGN, SETTING, AND PARTICIPANTS: Analysis of data on 4411 respondents aged 15 to 54 years from the National Comorbidity Survey, a nationally representative multistage probability survey conducted from 1991 to 1992. MAIN OUTCOME MEASURES: Rates of smoking and tobacco cessation according to the number and type of psychiatric diagnoses, assessed by a modified version of the Composite International Diagnostic Interview. RESULTS: Current smoking rates for respondents with no mental illness, lifetime mental illness, and past-month mental illness were 22.5%, 34.8%, and 41.0%, respectively. Lifetime smoking rates were 39.1%, 55.3%, and 59.0%, respectively (P<.001 for all comparisons). Smokers with any history of mental illness had a self-reported quit rate of 37.1% (P =.04), and smokers with past-month mental illness had a self-reported quit rate of 30. 5% (P<.001) compared with smokers without mental illness (42.5%). Odds ratios for current and lifetime smoking in respondents with mental illness in the past month vs respondents without mental illness, adjusted for age, sex, and region of the country, were 2.7 (95% confidence interval [CI], 2.3-3.1) and 2.7 (95% CI, 2.4-3.2), respectively. Persons with a mental disorder in the past month consumed approximately 44.3% of cigarettes smoked by this nationally representative sample. CONCLUSIONS: Persons with mental illness are about twice as likely to smoke as other persons but have substantial quit rates. JAMA. 2000;284:2606-2610.

Journal Article Protection and Real Wages Get access Wolfgang F. Stolper, Wolfgang F. Stolper Swarthmore, Penna. Search for other works by this author on: Oxford Academic Google Scholar Paul A. Samuelson Paul A. Samuelson Cambridge, Mass. Search for other works by this author on: Oxford Academic Google Scholar The Review of Economic Studies, Volume 9, Issue 1, November 1941, Pages 58–73, https://doi.org/10.2307/2967638 Published: 01 November 1941

Journal Article A Note on Measurement of Utility Get access Paul A. Samuelson Paul A. Samuelson Cambridge, Mass. Search for other works by this author on: Oxford Academic Google Scholar The Review of Economic Studies, Volume 4, Issue 2, February 1937, Pages 155–161, https://doi.org/10.2307/2967612 Published: 01 February 1937

The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies. Although recognized as reasonable, they have not been closely followed nor rigorously validated. Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation. The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate. The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and sample size calculations, and disclosing potential conflicts of interest. After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia. Another consideration is the use of clinically relevant biomarkers in animal studies. Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success.

Two chief problems of the theory of knowledge are the question of meaning and the question of verification. The first question asks under what conditions a sentence has meaning, in the sense of cognitive, factual meaning. The second one asks how we get to know something, how we can find out whether a given sentence is true or false. The second question presupposes the first one. Obviously we must understand a sentence, i.e. we must know its meaning, before we can try to find out whether it is true or not. But, from the point of view of empiricism, there is a still closer connection between the two problems. In a certain sense, there is only one answer to the two questions. If we knew what it would be for a given sentence to be found true then we would know what its meaning is. And if for two sentences the conditions under which we would have to take them as true are the same, then they have the same meaning. Thus the meaning of a sentence is in a certain sense identical with the way we determine its truth or falsehood; and a sentence has meaning only if such a determination is possible.

Subjects with borderline personality disorder (N = 21) or borderline traits (N = 11) and nonborderline subjects with closely related diagnoses (N = 23) were interviewed in depth regarding experiences of major childhood trauma. Significantly more borderline subjects (81%) gave histories of such trauma, including physical abuse (71%), sexual abuse (68%), and witnessing serious domestic violence (62%); abuse histories were less common in those with borderline traits and least common in the subjects with no borderline diagnosis. These results demonstrate a strong association between a diagnosis of borderline personality disorder and a history of abuse in childhood.

CONTEXT: Recently approved drugs may be more likely to have unrecognized adverse drug reactions (ADRs) than established drugs, but no recent studies have examined how frequently postmarketing surveillance identifies important ADRs. OBJECTIVE: To determine the frequency and timing of discovery of new ADRs described in black box warnings or necessitating withdrawal of the drug from the market. DESIGN AND SETTING: Examination of the Physicians' Desk Reference for all new chemical entities approved by the US Food and Drug Administration between 1975 and 1999, and all drugs withdrawn from the market between 1975 and 2000 (with or without a prior black box warning). MAIN OUTCOME MEASURES: Frequency of and time to a new black box warning or drug withdrawal. RESULTS: A total of 548 new chemical entities were approved in 1975-1999; 56 (10.2%) acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) acquired 1 or more black box warnings and 16 (2.9%) were withdrawn from the market. In Kaplan-Meier analyses, the estimated probability of acquiring a new black box warning or being withdrawn from the market over 25 years was 20%. Eighty-one major changes to drug labeling in the Physicians' Desk Reference occurred including the addition of 1 or more black box warnings per drug, or drug withdrawal. In Kaplan-Meier analyses, half of these changes occurred within 7 years of drug introduction; half of the withdrawals occurred within 2 years. CONCLUSIONS: Serious ADRs commonly emerge after Food and Drug Administration approval. The safety of new agents cannot be known with certainty until a drug has been on the market for many years.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

BACKGROUND: A decade ago, the administrative costs of health care in the United States greatly exceeded those in Canada. We investigated whether the ascendancy of computerization, managed care, and the adoption of more businesslike approaches to health care have decreased administrative costs. METHODS: For the United States and Canada, we calculated the administrative costs of health insurers, employers' health benefit programs, hospitals, practitioners' offices, nursing homes, and home care agencies in 1999. We analyzed published data, surveys of physicians, employment data, and detailed cost reports filed by hospitals, nursing homes, and home care agencies. In calculating the administrative share of health care spending, we excluded retail pharmacy sales and a few other categories for which data on administrative costs were unavailable. We used census surveys to explore trends over time in administrative employment in health care settings. Costs are reported in U.S. dollars. RESULTS: In 1999, health administration costs totaled at least 294.3 billion dollars in the United States, or 1,059 dollars per capita, as compared with 307 dollars per capita in Canada. After exclusions, administration accounted for 31.0 percent of health care expenditures in the United States and 16.7 percent of health care expenditures in Canada. Canada's national health insurance program had overhead of 1.3 percent; the overhead among Canada's private insurers was higher than that in the United States (13.2 percent vs. 11.7 percent). Providers' administrative costs were far lower in Canada. Between 1969 and 1999, the share of the U.S. health care labor force accounted for by administrative workers grew from 18.2 percent to 27.3 percent. In Canada, it grew from 16.0 percent in 1971 to 19.1 percent in 1996. (Both nations' figures exclude insurance-industry personnel.) CONCLUSIONS: The gap between U.S. and Canadian spending on health care administration has grown to 752 dollars per capita. A large sum might be saved in the United States if administrative costs could be trimmed by implementing a Canadian-style health care system.

Abstract. We consider the problem min {f(x)\\x 201, and propose algorithms of the form xk+, = [xt-akDkvf(xk)]+, where [.I+ denotes projection on the positive orthant, ak is a stepsize chosen by an Armijo-like rule and Dk is a positive definite symmetric matrix which is partly diagonal. We show that Dk can be calculated simply on the basis of second derivatives off so that the resulting Newton-like algorithm has a typically superlinear rate of convergence. With other choices of Dk convergence at a typically linear rate is obtained. The algorithms are almost as simple as their unconstrained counterparts. They are well suited for problems of large dimension such as those arising in optimal control while being competitive with existing methods for low-dimensional problems. The effectiveness of the Newton-like algorithm is demonstrated via computational examples involving as many as 10,000 variables. Extensions to general linearly constrained problems are also provided. These extensions utilize a notion of an active generalized rectangle patterned after the notion of an active manifold used in manifold suboptimization methods. By contrast with these methods, many constraints can be added or subtracted from the binding set at each iteration without the need to solve a quadratic programming problem. 1. Introduction. We

Journal Article Prices of Factors and Goods in General Equilibrium Get access Paul A. Samuelson Paul A. Samuelson Cambridge, Mass. Search for other works by this author on: Oxford Academic Google Scholar The Review of Economic Studies, Volume 21, Issue 1, 1953, Pages 1–20, https://doi.org/10.2307/2296256 Published: 01 January 1953

The longest fibers of the main optic tract reach the upper layers of the superior colliculus (SC) of the midbrain. Destruction of this terminal area in newborn hamsters caused striking anomalies in the distribution of the optic tract, studied after the animals were fully grown. Evidence of termination was found in areas normally devoid of such termination: in the remaining tissue of the colliculus and in the thalamic nucleus lateralis posterior (LP). An abnormally high density of termination was found in part of the ventral nucleus of the lateral geniculate body. These thalamic regions normally receive connections from SC. Retinofugal axons could also be induced to terminate in the medial geniculate body of the thalamus if the brachium of the inferior colliculus, which normally carries auditory information to this cell group, was ablated at birth together with the lesion of SC.If the superficial layers of SC were destroyed unilaterally at birth, axons from the eye contralateral to the lesion not only reached the area of early damage, but also formed an abnormal decussation, crossing the tectal midline to terminate in the medial zone of the undamaged colliculus. Axons from the two eyes competed for terminal space in this intact colliculus, for they terminated in a nonoverlapping manner, and if the axons from the eye contralateral to the remaining SC were eliminated at birth, the anomalously recrossing axons increased in quantity and spread across the entire SC on the 'wrong' side of the midbrain. Hamsters with such an anomaly showed wrong-direction turning in response to visual stimuli in a large part of the visual field.The less the amount of termination found in SC, the greater was the amount in LP. Thus, optic tract axons showed a 'pruning effect' which may be attributed to a tendency for axons to conserve the quantity of their terminal arborizations. The pruning effect alone may account for the hypertrophy we found, after early SC lesions, of the dorsal terminal nucleus of the accessory optic tract. The tendency to invade vacated terminal space may be sufficient to account for an effect of early unilateral eye removal, namely, a pronounced increase in an ipsilateral retinal projection to the medial terminal nucleus of the accessory optic tract.The greatest alterations in axonal projections were seen when the two effects, competition and pruning, seemed to act jointly. Additional factors may have to be considered in fully explaining such neuroplasticity; some of these have been suggested.

The traditional approach to clinical education has involved a series of rotations in various clinical settings. This article which concludes the medical education series, presents evidence and musters arguments for longitudinal integration of the medical curriculum.

Parable and Realism in Capital Theory: The Surrogate Production Function Get access Paul A. Samuelson Paul A. Samuelson Cambridge, Mass. Search for other works by this author on: Oxford Academic Google Scholar The Review of Economic Studies, Volume 29, Issue 3, June 1962, Pages 193–206, https://doi.org/10.2307/2295954 Published: 01 June 1962

OBJECTIVES: To determine if bipolar disorder is accurately diagnosed in clinical practice and to assess the effects of antidepressants on the course of bipolar illness. METHOD: Charts of outpatients with affective disorder diagnoses seen in an outpatient clinic during 1 year (N = 85 with bipolar or unipolar disorders) were reviewed. Past diagnostic and treatment information was obtained by patient report and systematic psychiatric history. Bipolar diagnosis was based on DSM-IV criteria using a SCID-based interview. RESULTS: Bipolar disorder was found to be misdiagnosed as unipolar depression in 37% of patients who first see a mental health professional after their first manic/hypomanic episode. Antidepressants were used earlier and more frequently than mood stabilizers, and 23% of this unselected sample experienced a new or worsening rapid-cycling course attributable to antidepressant use. CONCLUSION: These results suggest that bipolar disorder tends be misdiagnosed as unipolar major depressive disorder and that antidepressants seem to be associated with a worsened course of bipolar illness. However, this naturalistic trial was uncontrolled, and more controlled research is required to confirm or refute these findings.

This article reviews recent attachment-related studies of early aggression. That aggressive behavior toward peers is related to disorganized or controlling patterns of attachment behavior toward parents but not to avoidant or ambivalent patterns. Longitudinal attachment studies indicate that risk factors identified in cross-sectional studies of aggressive school-age children, such as family adversity, parental hostility, parental depression, and child cognitive deficits, are already evident in infancy and predictive of later aggression, before the onset of coercive child behavior. In infancy, these risk factors are associated with disorganized attachment behaviors toward the caregiver characterized by signs of fear or dysphoria, irresolvable conflict between opposing behavioral tendencies, and elevated cortisol levels after separation. Disorganized attachment behaviors, in turn, predict aggression in school-age children with other family factors controlled.

This study of 62 low-income families examined the relation between maternal and infant measures assessed at 18 months infant age and child behavior problems at age 5 as rated by preschool teachers. The infancy assessments included measures of mother-infant interaction, maternal psychosocial problems, infant cognitive development, and infant attachment security, including the disorganized/disoriented classification. The strongest single predictor of deviant levels of hostile behavior toward peers in the classroom was earlier disorganized/disoriented attachment status, with 71% of hostile preschoolers classified as disorganized in their attachment relationships in infancy. Maternal psychosocial problems independently predicted hostile aggression in preschool and combined additively with infant attachment security in prediction. Results are discussed in relation to the asymmetry of forward and backward prediction that characterized the findings and in relation to the potential significance of disorganized attachment behavior as a precursor to later maladaptation.