Accelerating diagnosis of Parkinson's disease through risk prediction.

BACKGROUND: Characterization of prediagnostic Parkinson's Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. METHODS: We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. RESULTS: We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. CONCLUSIONS: Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.

Adjuvant endocrine therapy uptake, toxicity, quality of life, and prediction of early discontinuation.

BACKGROUND: Many patients receiving adjuvant endocrine therapy (ET) for breast cancer experience side effects and reduced quality of life (QoL) and discontinue ET. We sought to describe these issues and develop a prediction model of early discontinuation of ET. METHODS: Among patients with hormone receptor-positive and HER2-negative stage I-III breast cancer of the Cancer Toxicities cohort (NCT01993498) who were prescribed adjuvant ET between 2012 and 2017, upon stratification by menopausal status, we evaluated adjuvant ET patterns including treatment change and patient-reported discontinuation and ET-associated toxicities and impact on QoL. Independent variables included clinical and demographic features, toxicities, and patient-reported outcomes. A machine-learning model to predict time to early discontinuation was trained and evaluated on a held-out validation set. RESULTS: Patient-reported discontinuation rate of the first prescribed ET at 4 years was 30% and 35% in 4122 postmenopausal and 2087 premenopausal patients, respectively. Switching to a new ET was associated with higher symptom burden, poorer QoL, and higher discontinuation rate. Early discontinuation rate of adjuvant ET before treatment completion was 13% in postmenopausal and 15% in premenopausal patients. The early discontinuation model obtained a C index of 0.62 in the held-out validation set. Many aspects of QoL, most importantly fatigue and insomnia (European Organization for Research and Treatment of Cancer QoL questionnaire 30), were associated with early discontinuation. CONCLUSION: Tolerability and adherence to ET remains a challenge for patients who switch to a second ET. An early discontinuation model using patient-reported outcomes identifies patients likely to discontinue their adjuvant ET. Improved management of toxicities and novel more tolerable adjuvant ETs are needed for maintaining patients on treatment.

Reliability and validity of the brief insomnia questionnaire in the America insomnia survey.

STUDY OBJECTIVES: to evaluate the reliability and validity of the Brief Insomnia Questionnaire (BIQ), a fully structured questionnaire developed to diagnose insomnia according to hierarchy-free Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR), International Classification of Diseases-10 (ICD-10), and research diagnostic criteria/International Classification of Sleep Disorders-2 (RDC/ICSD-2) general criteria without organic exclusions in the America Insomnia Survey (AIS). DESIGN: probability subsamples of AIS respondents, oversampling BIQ positives, completed short-term test-retest interviews (n = 59) or clinical reappraisal interviews (n = 203) to assess BIQ reliability and validity. SETTING: the AIS is a large (n = 10,094) epidemiologic survey of the prevalence and correlates of insomnia. PARTICIPANTS: adult subscribers to a national managed healthcare plan. INTERVENTION: None MEASUREMENTS AND RESULTS: BIQ test-retest correlations were 0.47-0.94 for nature of the sleep problems (initiation, maintenance, nonrestorative sleep [NRS]), 0.72-0.95 for problem frequency, 0.66-0.88 for daytime impairment/distress, and 0.62 for duration of sleep. Good individual-level concordance was found between BIQ diagnoses and diagnoses based on expert interviews for meeting hierarchy-free inclusion criteria for diagnoses in any of the diagnostic systems, with area under the receiver operating characteristic curve (AUC, a measure of classification accuracy insensitive to disorder prevalence) of 0.86 for dichotomous classifications. The AUC increased to 0.94 when symptom-level data were added to generate continuous predicted-probability of diagnosis measures. The AUC was lower for dichotomous classifications based on RDC/ICSD-2 (0.68) and ICD-10 (0.70) than for DSM-IV-TR (0.83) criteria but increased consistently when symptom-level data were added to generate continuous predicted-probability measures of RDC/ICSD-2, ICD-10, and DSM-IV-TR diagnoses (0.92-0.95). CONCLUSIONS: these results show that the BIQ generates accurate estimates of the prevalence and correlates of hierarchy-free insomnia in the America Insomnia Survey.

The associations of insomnia with costly workplace accidents and errors: results from the America Insomnia Survey.

CONTEXT: Insomnia is a common and seriously impairing condition that often goes unrecognized. OBJECTIVES: To examine associations of broadly defined insomnia (ie, meeting inclusion criteria for a diagnosis from International Statistical Classification of Diseases, 10th Revision, DSM-IV, or Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition) with costly workplace accidents and errors after excluding other chronic conditions among workers in the America Insomnia Survey (AIS). DESIGN/SETTING: A national cross-sectional telephone survey (65.0% cooperation rate) of commercially insured health plan members selected from the more than 34 million in the HealthCore Integrated Research Database. PARTICIPANTS: Four thousand nine hundred ninety-one employed AIS respondents. MAIN OUTCOME MEASURES: Costly workplace accidents or errors in the 12 months before the AIS interview were assessed with one question about workplace accidents "that either caused damage or work disruption with a value of $500 or more" and another about other mistakes "that cost your company $500 or more." RESULTS: Current insomnia with duration of at least 12 months was assessed with the Brief Insomnia Questionnaire, a validated (area under the receiver operating characteristic curve, 0.86 compared with diagnoses based on blinded clinical reappraisal interviews), fully structured diagnostic interview. Eighteen other chronic conditions were assessed with medical/pharmacy claims records and validated self-report scales. Insomnia had a significant odds ratio with workplace accidents and/or errors controlled for other chronic conditions (1.4). The odds ratio did not vary significantly with respondent age, sex, educational level, or comorbidity. The average costs of insomnia-related accidents and errors ($32 062) were significantly higher than those of other accidents and errors ($21 914). Simulations estimated that insomnia was associated with 7.2% of all costly workplace accidents and errors and 23.7% of all the costs of these incidents. These proportions are higher than for any other chronic condition, with annualized US population projections of 274 000 costly insomnia-related workplace accidents and errors having a combined value of US $31.1 billion. CONCLUSION: Effectiveness trials are needed to determine whether expanded screening, outreach, and treatment of workers with insomnia would yield a positive return on investment for employers.

Insomnia, comorbidity, and risk of injury among insured Americans: results from the America Insomnia Survey.

STUDY OBJECTIVES: To estimate associations of broadly defined insomnia (i.e., meeting inclusion criteria for International Classification of Diseases, Tenth Revision (ICD-10), Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition (RDC/ICSD-2) diagnosis) with workplace/nonworkplace injuries controlling for comorbid conditions among workers in the America Insomnia Survey (AIS). DESIGN/SETTING: Cross-sectional telephone survey. PARTICIPANTS: National sample of 4,991 employed health plan subscribers (age 18 yr and older). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Broadly defined insomnia with duration of at least 12 mo was assessed with the Brief Insomnia Questionnaire (BIQ). Injuries in the 12 mo before interview were assessed with a standard self-report measure of injuries causing role impairment or requiring medical attention. Eighteen comorbid condition clusters were assessed with medical/pharmacy claims records and self-reports. Insomnia had significant gross associations (odds ratios, ORs) with both workplace and nonworkplace injuries (OR 2.0 and 1.5, respectively) in logistic regression analyses before controlling for comorbid conditions. The significant population attributable risk proportions (PARPs) of total injuries with insomnia was 4.6% after controlling for comorbid conditions. Only 2 other conditions had PARPs exceeding those of insomnia. The associations of insomnia with injuries did not vary significantly with worker age, sex, or education, but did vary significantly with comorbid conditions. Specifically, insomnia was significantly associated with workplace and nonworkplace injuries (OR 1.8 and 1.5, respectively) among workers having no comorbid conditions, with workplace but not nonworkplace injuries (OR 1.8 and 1.2, respectively) among workers having 1 comorbid condition, and with neither workplace nor nonworkplace injuries (OR 0.9 and 1.0, respectively) among workers having 2 or more comorbid conditions. CONCLUSIONS: The associations of insomnia with injuries vary with comorbid conditions in ways that could have important implications for targeting workplace interventions.

Insomnia and the performance of US workers: results from the America insomnia survey.

STUDY OBJECTIVES: To estimate the prevalence and associations of broadly defined (i.e., meeting full ICD-10, DSM-IV, or RDC/ICSD-2 inclusion criteria) insomnia with work performance net of comorbid conditions in the America Insomnia Survey (AIS). DESIGN/SETTING: Cross-sectional telephone survey. PARTICIPANTS: National sample of 7,428 employed health plan subscribers (ages 18+). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Broadly defined insomnia was assessed with the Brief Insomnia Questionnaire (BIQ). Work absenteeism and presenteeism (low on-the-job work performance defined in the metric of lost workday equivalents) were assessed with the WHO Health and Work Performance Questionnaire (HPQ). Regression analysis examined associations between insomnia and HPQ scores controlling 26 comorbid conditions based on self-report and medical/pharmacy claims records. The estimated prevalence of insomnia was 23.2%. Insomnia was significantly associated with lost work performance due to presenteeism (χ² (1) = 39.5, P < 0.001) but not absenteeism (χ² (1) = 3.2, P = 0.07), with an annualized individual-level association of insomnia with presenteeism equivalent to 11.3 days of lost work performance. This estimate decreased to 7.8 days when controls were introduced for comorbid conditions. The individual-level human capital value of this net estimate was $2,280. If we provisionally assume these estimates generalize to the total US workforce, they are equivalent to annualized population-level estimates of 252.7 days and $63.2 billion. CONCLUSIONS: Insomnia is associated with substantial workplace costs. Although experimental studies suggest some of these costs could be recovered with insomnia disease management programs, effectiveness trials are needed to obtain precise estimates of return-on-investment of such interventions from the employer perspective.

Nighttime insomnia symptoms and perceived health in the America Insomnia Survey (AIS).

STUDY OBJECTIVES: To explore the distribution of the 4 cardinal nighttime symptoms of insomnia-difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), and nonrestorative sleep (NRS)-in a national sample of health plan members and the associations of these nighttime symptoms with sociodemographics, comorbidity, and perceived health. DESIGN/SETTING/PARTICIPANTS: Cross-sectional telephone survey of 6,791 adult respondents. INTERVENTION: None. MEASUREMENTS/RESULTS: Current insomnia was assessed using the Brief Insomnia Questionnaire (BIQ)-a fully structured validated scale generating diagnoses of insomnia using DSM-IV-TR, ICD-10, and RDC/ICSD-2 inclusion criteria. DMS (61.0%) and EMA (52.2%) were more prevalent than DIS (37.7%) and NRS (25.2%) among respondents with insomnia. Sociodemographic correlates varied significantly across the 4 symptoms. All 4 nighttime symptoms were significantly related to a wide range of comorbid physical and mental conditions. All 4 also significantly predicted decrements in perceived health both in the total sample and among respondents with insomnia after adjusting for comorbid physical and mental conditions. Joint associations of the 4 symptoms predicting perceived health were additive and related to daytime distress/impairment. Individual-level associations were strongest for NRS. At the societal level, though, where both prevalence and strength of individual-level associations were taken into consideration, DMS had the strongest associations. CONCLUSIONS: The extent to which nighttime insomnia symptoms are stable over time requires future long-term longitudinal study. Within the context of this limitation, the results suggest that core nighttime symptoms are associated with different patterns of risk and perceived health and that symptom-based subtyping might have value.

Prevalence and perceived health associated with insomnia based on DSM-IV-TR; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; and Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition criteria: results from the America Insomnia Survey.

BACKGROUND: Although several diagnostic systems define insomnia, little is known about the implications of using one versus another of them. METHODS: The America Insomnia Survey, an epidemiological survey of managed health care plan subscribers (n = 10,094), assessed insomnia with the Brief Insomnia Questionnaire, a clinically validated scale generating diagnoses according to DSM-IV-TR; International Statistical Classification of Diseases, Tenth Revision (ICD-10); and Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition (RDC/ICSD-2) criteria. Regression analysis examines associations of insomnia according to the different systems with summary 12-item Short-Form Health Survey scales of perceived health and health utility. RESULTS: Insomnia prevalence estimates varied widely, from 22.1% for DSM-IV-TR to 3.9% for ICD-10 criteria. Although ICD insomnia was associated with significantly worse perceived health than DSM or RDC/ICSD insomnia, DSM-only cases also had significant decrements in perceived health. Because of its low prevalence, 66% of the population-level health disutility associated with overall insomnia and 84% of clinically relevant cases of overall insomnia were missed by ICD criteria. CONCLUSIONS: Insomnia is highly prevalent and associated with substantial decrements in perceived health. Although ICD criteria define a narrower and more severe subset of cases than DSM criteria, the fact that most health disutility associated with insomnia is missed by ICD criteria, while RDC/ICSD-only cases do not have significant decrements in perceived health, supports use of the broader DSM criteria.

Days-out-of-role associated with insomnia and comorbid conditions in the America Insomnia Survey.

BACKGROUND: Insomnia is highly prevalent and impairing but also highly comorbid with other chronic physical/mental disorders. Population-based research has yet to differentiate the role impairments uniquely associated with insomnia per se from those due to comorbidity. METHODS: A representative sample of 6791 adult subscribers to a large national US commercial health plan was surveyed by telephone about sleep and health. Twenty-one conditions previously found to be comorbid with insomnia were assessed with medical/pharmacy claims data and validated self-report scales. The Brief Insomnia Questionnaire, a fully structured, clinically validated scale, generated insomnia diagnoses according to inclusion criteria of DSM-IV-TR, ICD-10, and Research Diagnostic Criteria/International Classification of Sleep Disorders: Diagnostic and Coding Manual, Second Edition. The World Health Organization Disability Assessment Schedule-II assessed number of days in the past 30 when health problems prevented respondents from conducting their usual daily activities. Regression analyses estimated associations of insomnia with days-out-of-role controlling comorbidity. RESULTS: Insomnia was significantly associated with days-out-of-role (.90 days/month) in a gross model. The association was reduced when controls were introduced for comorbidity (.42 days/month). This net association did not vary with number or type of comorbid conditions but was confined to respondents 35+ years of age. Insomnia was one of the most important conditions studied not only at the individual level, where it was associated with among the largest mean days-out-of-role, but also at the aggregate level, where it was associated with 13.6% of all days-out-of-role. CONCLUSIONS: Insomnia has a strong net association with days-out-of-role that does not vary as a function of comorbidity.

Lack of effect of amisulpride on the pharmacokinetics and safety of lithium.

Lithium may be used as adjuvant therapy in schizophrenic patients and antipsychotics can be employed during the early phases of lithium therapy in patients with bipolar disorder. The issue of interactions between lithium and antipsychotics is therefore important. This study investigates the potential influence of repeated administration of amisulpride, an atypical antipsychotic, on the pharmacokinetics of lithium at steady state. Twenty-four healthy male volunteers (aged 1833 yr) received lithium carbonate (500 mg b.i.d.) for 14 d. All subjects were shown to have stable lithium serum concentrations after 57 d and were then randomized to receive double-blind administration of amisulpride (100 mg b.i.d.) or placebo bid from day 8 of lithium administration. Complete pharmacokinetic profiles were obtained on days 7 and 14 for lithium and trough plasma concentrations on days 10, 12 and 14 for amisulpride. Co-administration of amisulpride appeared to exert no effect on the pharmacokinetics of lithium. All treatments were well tolerated and safety assessment revealed no differences between the lithium+placebo and lithium+amisulpride groups. This finding permits the flexible use of amisulpride in patients already receiving lithium therapy.