Analysis of the physiological stress profile: The interrupted time-series design

Most research employing physiological stress profiling procedures has relied upon statistical analyses that are flawed in two ways: (a) These analyses typically average the physiological levels observed across a series of observations during any one phase of the profile, thereby ignoring rate of change as a relevant parameter, and (b) the problem of autocorrelation, or the natural correlation of time-series observations of the same physiologic activity, is unaddressed. We hope to introduce the biofeedback field to the technique of interrupted time-series analysis, which effectively deals with these two flaws. Interrupted time-series analysis additionally permits statistical conclusions based upon the stress profile of a single individual, thereby providing an objective basis for decisions concerning the effectiveness of training or the timing of changes in training for a single client. We describe the application of the technique to the analysis of a stress profile of a subject diagnosed as hypertensive.The authors gratefully acknowledge the assistance provided by Judith Green, Mark Lewis, Robert Shellenberger, and John Turner of the Aims Biofeedback Institute, Greeley, Colorado, in conducting this research.     

Policy changes and physicians opting out from Medicare in Quebec: an interrupted time-series analysis

BACKGROUND:In all Canadian provinces, physicians can decide to either bill the provincial public system (opt in) or work privately and bill patients directly (opt out). We hypothesized that 2 policy events were associated with an increase in physicians opting out in Quebec.METHODS:The 2 policy events of interest were the 2005 Supreme Court of Canada ruling on Chaoulli v. Quebec and a regulatory clampdown forbidding double billing that was implemented by Quebec’s government in 2017. We used interrupted time-series analyses of the Quebec government’s yearly list of physicians who chose to opt out from 1994 to 2019 to analyze the relation between these events and physician billing status.RESULTS:The number of family physicians who opted out increased from 9 in 1994 to 347 in 2019. Opting out increased after the Chaoulli ruling, and our analysis suggested that between 2005 and 2019, 284 more family physicians opted out than if pre-Chaoulli trends had continued. The number of specialist physicians who opted out rose from 23 in 1994 to 150 in 2019. Our analysis suggested that an additional 69 specialist physicians opted out after the 2017 clampdown on double billing than previous trends would have predicted.INTERPRETATION:We found that the number of physicians who opted out increased in Quebec, and increases after 2 policy actions suggest an association with these policy interventions. Opting out decisions are likely important inputs into decision-making by physicians, which, in turn may influence the provision of publicly funded health care.

In all Canadian provinces, most physicians work as part of a private business. Whether they are solo practitioners or part of larger group practices, physicians can bill the provincial public Medicare system, or work privately and bill patients directly. Engaging in both is referred to as “dual practice,” and evidence exists to suggest that it can negatively affect the accessibility of care in the public system where it is permitted.¹ As a result, most provinces have enacted legal barriers designed to prohibit or discourage dual practice.² In Quebec, British Columbia, Alberta, Saskatchewan and New Brunswick, physicians have to opt out formally from the public system to be able to bill patients for publicly covered services. In Ontario, Manitoba and Nova Scotia, physicians who decide to rely on private billing are not permitted to bill their patients more than the public fee schedule. Given these regulations, it is widely thought that only a small proportion of Canadian physicians choose to work outside of the public funding scheme for medical care. Nevertheless, private out-of-pocket payment to physicians still accounts for hundreds of millions of dollars per year in Canada³ and, in Quebec, the number of physicians who opt out has been steadily growing for the past decade. However, our understanding of how policies and legal events have affected these rates in Quebec or other Canadian provinces is limited. Over the past 20 years, 2 important policy events directly related to dual practice have occurred in Quebec.First, in 2005, in its ruling for Chaoulli v. Quebec, the Supreme Court of Canada concluded that Quebec’s prohibition of private insurance for publicly insured medical services violated Section 1 of the Quebec Charter of Human Rights and Freedoms.^4–6 Quebec’s government was granted 1 year to adjust its laws to the ruling, during which time there were intense policy debates about the private system.^7–9 Many argued that there was a demand for out-of-pocket privately financed medical services, pushing many private investors, physicians and patients to debate the role of private delivery of health services.^7,10–12 Second, in the years following this ruling, Quebec witnessed substantial interest and investments in private facilities for elective medical interventions. In many specialties with a high volume of outpatient elective interventions (e.g., ophthalmology, dermatology and orthopedic surgery), a certain level of double billing became the norm. Patients were routinely asked to pay out-of-pocket to cover things like eye drops, anesthetics, use of the intervention room and record management — so-called “frais accessoires” [“incidental expenses”]. Faced with increased public and media scrutiny of the legality of those fees and strong pressures from Ottawa, Quebec started, in January 2017, to enforce a new regulation that clearly outlawed double billing for publicly funded medical services.¹³ Because many clinics had come to rely on these added fees, this clampdown threatened their business model, which may have pushed some physicians to opt out of the public system altogether.As physicians who have opted out are not available to deliver services for publicly insured patients, any trend toward more privately delivered care will have obvious implications for delivery of publicly funded health care in Canada. Furthermore, international evidence suggests that dual practice is associated with challenges to equity and efficiency.^14–16 Therefore, we analyzed the association of these 2 policy events with physicians’ decisions to opt out in Quebec.     

Analysis of the physiological stress profile: the interrupted time-series design

Most research employing physiological stress profiling procedures has relied upon statistical analyses that are flawed in two ways: These analyses typically average the physiological levels observed across a series of observations during any one phase of the profile, thereby ignoring rate of change as a relevant parameter, and the problem of autocorrelation, or the natural correlation of time-series observations of the same physiologic activity, is unaddressed. We hope to introduce the biofeedback field to the technique of interrupted time-series analysis, which effectively deals with these two flaws. Interrupted time-series analysis additionally permits statistical conclusions based upon the stress profile of a single individual, thereby providing an objective basis for decisions concerning the effectiveness of training or the timing of changes in training for a single client. We describe the application of the technique to the analysis of a stress profile of a subject diagnosed as hypertensive.     

The effects of pay for performance on disparities in stroke, hypertension, and coronary heart disease management: interrupted time series study

Background

The Quality and Outcomes Framework (QOF), a major pay-for-performance programme, was introduced into United Kingdom primary care in April 2004. The impact of this programme on disparities in health care remains unclear. This study examines the following questions: has this pay for performance programme improved the quality of care for coronary heart disease, stroke and hypertension in white, black and south Asian patients? Has this programme reduced disparities in the quality of care between these ethnic groups? Did general practices with different baseline performance respond differently to this programme?

Methodology/Principal Findings

Retrospective cohort study of patients registered with family practices in Wandsworth, London during 2007. Segmented regression analysis of interrupted time series was used to take into account the previous time trend. Primary outcome measures were mean systolic and diastolic blood pressure, and cholesterol levels. Our findings suggest that the implementation of QOF resulted in significant short term improvements in blood pressure control. The magnitude of benefit varied between ethnic groups with a statistically significant short term reduction in systolic BP in white and black but not in south Asian patients with hypertension. Disparities in risk factor control were attenuated only on few measures and largely remained intact at the end of the study period.

Conclusions/Significance

Pay for performance programmes such as the QOF in the UK should set challenging but achievable targets. Specific targets aimed at reducing ethnic disparities in health care may also be needed.     

Cellular proliferation in complicated versus uncomplicated atherosclerotic lesions: Total cell population, foam cells and newly formed microvessels

Although cellular proliferation is a key component in the progression of atherosclerosis, research so far has been focused primarily on VSMCs. In this study we attempted to evaluate overall proliferation rates in general, as well as foam cells and the endothelial cells lining newly formed plaque microvessels in particular. For this purpose, cellular proliferation was assessed through immunohistochemical staining for PCNA in 10 fresh human carotid artery samples received from patients undergoing carotid endarterectomy. Overall proliferative activity was found significantly higher (P ≤ 0.01) among complicated type VI lesions compared to uncomplicated type V lesions. A similar assessment focused on foam cells alone also revealed a significantly higher (P ≤ 0.05) proliferative index among complicated lesions. On the other hand, the proliferation rate for the endothelial cells lining the interior walls of newly formed microvessels was harder to properly assess, since only two of the uncomplicated lesions bore signs of neovascularization. Still, both of these samples displayed proliferation rates similar to those of the complicated type VI lesions. Thus, it seems that, although total cell population and foam cells are probably affected by the stimulating factors that are expressed during acute events, the same does not apply to the endothelial cells lining plaque vessels.     

Detection of chaos: New approach to atmospheric pollen time-series analysis

Pollen and spores are biological particles that are ubiquitous to the atmosphere and are pathologically significant, causing plant diseases and inhalant allergies. One of the main objectives of aerobiological surveys is forecasting. Prediction models are required in order to apply aerobiological knowledge to medical or agricultural practice; a necessary condition of these models is not to be chaotic. The existence of chaos is detected through the analysis of a time series. The time series comprises hourly counts of atmospheric pollen grains obtained using a Burkard spore trap from 1987 to 1989 at Mar del Plata. Abraham's method to obtain the correlation dimension was applied. A low and fractal dimension shows chaotic dynamics. The predictability of models for atomspheric pollen forecasting is discussed.     

High-resolution analysis of tomato leaf elongation: the application of novel time-series analysis techniques

This paper demonstrates the use of a novel suite of data-based, recursive modelling techniques for the investigation of biological and other time-series data, including high resolution leaf elongation. The Data-Based Mechanistic (DBM) modelling methodology rejects the common practice of empirical curve fitting for a more objective approach where the model structure is not assumed a priori, but instead is identified directly from the data series in a stochastic form. Further, this novel approach takes advantage of the latest techniques in optimal recursive estimation of non-stationary and non-linear time-series. Here, the utility and ease of use of these techniques is demonstrated in the examination of two time-series of leaf elongation in an expanding leaf of tomato (Lycopersicon esculentum L. cv. Ailsa Craig) growing in a root pressure vessel (RPV). Using this analysis, the component signals of the elongation series are extracted and considered in relation to physiological processes. It is hoped that this paper will encourage the wider use of these new techniques, as well as the associated Data-Based Mechanistic (DBM) modelling strategy, in analytical plant physiology.     

Healthcare utilization and maternal and child mortality during the COVID-19 pandemic in 18 low- and middle-income countries: An interrupted time-series analysis with mathematical modeling of administrative data

BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic has had wide-reaching direct and indirect impacts on population health. In low- and middle-income countries, these impacts can halt progress toward reducing maternal and child mortality. This study estimates changes in health services utilization during the pandemic and the associated consequences for maternal, neonatal, and child mortality.Methods and findingsData on service utilization from January 2018 to June 2021 were extracted from health management information systems of 18 low- and lower-middle-income countries (Afghanistan, Bangladesh, Cameroon, Democratic Republic of the Congo (DRC), Ethiopia, Ghana, Guinea, Haiti, Kenya, Liberia, Madagascar, Malawi, Mali, Nigeria, Senegal, Sierra Leone, Somalia, and Uganda). An interrupted time-series design was used to estimate the percent change in the volumes of outpatient consultations and maternal and child health services delivered during the pandemic compared to projected volumes based on prepandemic trends. The Lives Saved Tool mathematical model was used to project the impact of the service utilization disruptions on child and maternal mortality. In addition, the estimated monthly disruptions were also correlated to the monthly number of COVID-19 deaths officially reported, time since the start of the pandemic, and relative severity of mobility restrictions. Across the 18 countries, we estimate an average decline in OPD volume of 13.1% and average declines of 2.6% to 4.6% for maternal and child services. We projected that decreases in essential health service utilization between March 2020 and June 2021 were associated with 113,962 excess deaths (110,686 children under 5, and 3,276 mothers), representing 3.6% and 1.5% increases in child and maternal mortality, respectively. This excess mortality is associated with the decline in utilization of the essential health services included in the analysis, but the utilization shortfalls vary substantially between countries, health services, and over time. The largest disruptions, associated with 27.5% of the excess deaths, occurred during the second quarter of 2020, regardless of whether countries reported the highest rate of COVID-19-related mortality during the same months. There is a significant relationship between the magnitude of service disruptions and the stringency of mobility restrictions. The study is limited by the extent to which administrative data, which varies in quality across countries, can accurately capture the changes in service coverage in the population.ConclusionsDeclines in healthcare utilization during the COVID-19 pandemic amplified the pandemic’s harmful impacts on health outcomes and threaten to reverse gains in reducing maternal and child mortality. As efforts and resource allocation toward prevention and treatment of COVID-19 continue, essential health services must be maintained, particularly in low- and middle-income countries.

Tashrik Ahmed and co-workers study health-care use and maternal and child health outcomes across low- and lower-middle-income countries during the COVID-19 pandemic.     

Towards the elimination of leprosy in Yunnan,China: A time-series analysis of surveillance data

BackgroundThis study reviews the progress of leprosy elimination in Yunnan, China, over the past 30 years and identifies the challenges for the next stage of the program.Methodology/Principal findingsData were collected from the Leprosy Management Information System in China (LEPMIS). The progress made in the elimination of leprosy between 1990 and 2019 was measured. We defined two time periods, time period 1 (1990–2003) and time period 2 (2004–2019), because multidrug therapy (MDT) was launched for the treatment of leprosy in 1990 and a special fund from the central government was established for leprosy in 2004. During the past 30 years, the number of newly detected leprosy patients in Yunnan has steadily declined. In total, 703 newly detected leprosy patients were reported in 1990, and 353 and 136 cases were reported at the end of 2003 and 2019, respectively. At the end of 1990, 90.7% (117/129) of counties in Yunnan Province were identified as leprosy-endemic counties (>1 case per 100,000 population). By the end of 2003 and 2019, 39.3% (46/117) and 85.5% (100/117) of the leprosy-endemic counties, respectively, had dropped below the elimination threshold. The main challenges are the remaining leprosy-endemic counties, the high rate of cases with a contact history, insufficient early detection, and leprosy cases resulting in physical disability.Conclusions/SignificanceA multifaceted strategy for leprosy elimination in Yunnan Province has been successfully implemented, and remarkable progress has been made in the elimination of leprosy in this area. The priorities for leprosy elimination in the next stage are securing sustainable support and investment from the government, establishing an effective surveillance system, ensuring prompt early detection, providing treatment with MDT, preventing transmission of M. leprae, preventing disability, providing health education, and preventing recurrence of the epidemic situation of leprosy.     

The effect of weather and climate on dengue outbreak risk in Peru, 2000-2018: A time-series analysis

BackgroundDengue fever is the most common arboviral disease in humans, with an estimated 50-100 million annual infections worldwide. Dengue fever cases have increased substantially in the past four decades, driven largely by anthropogenic factors including climate change. More than half the population of Peru is at risk of dengue infection and due to its geography, Peru is also particularly sensitive to the effects of El Niño Southern Oscillation (ENSO). Determining the effect of ENSO on the risk for dengue outbreaks is of particular public health relevance and may also be applicable to other Aedes-vectored viruses.MethodsWe conducted a time-series analysis at the level of the district-month, using surveillance data collected from January 2000 to September 2018 from all districts with a mean elevation suitable to survival of the mosquito vector (<2,500m), and ENSO and weather data from publicly-available datasets maintained by national and international agencies. We took a Bayesian hierarchical modeling approach to address correlation in space, and B-splines with four knots per year to address correlation in time. We furthermore conducted subgroup analyses by season and natural region.ResultsWe detected a positive and significant effect of temperature (°C, RR 1.14, 95% CI 1.13, 1.15, adjusted for precipitation) and ENSO (ICEN index: RR 1.17, 95% CI 1.15, 1.20; ONI index: RR 1.04, 95% CI 1.02, 1.07) on outbreak risk, but no evidence of a strong effect for precipitation after adjustment for temperature. Both natural region and season were found to be significant effect modifiers of the ENSO-dengue effect, with the effect of ENSO being stronger in the summer and the Selva Alta and Costa regions, compared with winter and Selva Baja and Sierra regions.ConclusionsOur results provide strong evidence that temperature and ENSO have significant effects on dengue outbreaks in Peru, however these results interact with region and season, and are stronger for local ENSO impacts than remote ENSO impacts. These findings support optimization of a dengue early warning system based on local weather and climate monitoring, including where and when to deploy such a system and parameterization of ENSO events, and provide high-precision effect estimates for future climate and dengue modeling efforts.     

Ecological time-series analysis through structural modelling with latent constructs: concepts, methods and applications

Time-series analyses in ecology usually involve the use of autoregressive modelling through direct and/or delayed difference equations, which severely restricts the ability of the modeler to structure complex causal relationships within a multivariate frame. This is especially problematic in the field of population regulation, where the proximate and ultimate causes of fluctuations in population size have been hotly debated for decades. Here it is shown that this debate can benefit from the implementation of structural modelling with latent constructs (SEM) to time-series analysis in ecology. A nonparametric bootstrap scheme illustrates how this modelling approach can circumvent some problems posed by the climate-ecology interface. Stochastic Monte Carlo simulation is further used to assess the effects of increasing time-series length and different parameter estimation methods on the performance of several model fit indexes. Throughout, the advantages and limitations of the SEM method are highlighted.     

Monoclonal antibodies: Longitudinal prescribing information analysis of hypersensitivity reactions

Monoclonal antibodies (mAbs) are known to cause hypersensitivity reactions (HSRs). The reactions pose a significant challenge to investigators, regulators, and health providers. Because HSRs cannot be predicted through the pharmacological basis of a therapy, clinical data are often relied upon to detect the reactions. Unfortunately, clinical studies are often unable to adequately characterize HSRs especially in therapies for orphan diseases. HSRs can go undetected until post-marketing safety surveillance when a large number of patients have been exposed to the therapy. The presented data demonstrates how hypersensitivity reaction warnings have changed over time in the prescribing information (PI), i.e., the drug package insert, through August 1, 2011 for 28 US-marketed mAbs. Tracking all PI revisions for each mAb over time revealed that hypersensitivity warning statements were expanded to include more severe manifestations. Over the course of a mAb therapy’s life cycle, the hypersensitivity warning is twice more likely to be upgraded than downgraded in priority. Approximately 85% of hypersensitivity-associated fatality warnings were added in PI revisions as a result of post-marketing experience. Over 60% (20/33) of revisions to hypersensitivity warnings occurred within 3–4 y of product approval. While HSRs are generally recognized and described in the initial PI of mAbs, fatal HSRs are most commonly observed in post-marketing surveillance. Results of this study suggest that initial product labeling information may not describe rare but clinically significant occurrences of severe or fatal HSRs, but subsequent label revisions include rare events observed during post-marketed product use.