Cost-effectiveness of the McGill interactive pediatric oncogenetic guidelines in identifying Li-Fraumeni syndrome in female patients with osteosarcoma.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a penetrant cancer predisposition syndrome (CPS) associated with the development of many tumor types in young people including osteosarcoma and breast cancer (BC). The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) decision-support tool provides a standardized approach to identify patients at risk of CPSs. METHODS: We conducted a cost-utility analysis, from the healthcare payer perspective, to compare MIPOGG-guided, physician-guided, and universal genetic testing strategies to detect LFS in female patients diagnosed at an age of less than 18 years with osteosarcoma. We developed a decision tree and discrete-event simulation model to simulate the clinical and cost outcomes of the three genetic referral strategies on a cohort of female children diagnosed with osteosarcoma, especially focused on BC as subsequent cancer. Outcomes included BC incidence, quality-adjusted life-years (QALYs), healthcare costs, and incremental cost-utility ratios (ICURs). We conducted probabilistic and scenario analyses to assess the uncertainty surrounding model parameters. RESULTS: Compared to the physician-guided testing, the MIPOGG-guided strategy was marginally more expensive by $105 (-$516; $743), but slightly more effective by 0.003 (-0.04; 0.045) QALYs. Compared to MIPOGG, the universal testing strategy was $1333 ($732; $1953) more costly and associated with 0.011 (-0.043; 0.064) additional QALYs. The ICUR for the MIPOGG strategy was $33,947/QALY when compared to the physician strategy; the ICUR for universal testing strategy was $118,631/QALY when compared to the MIPOGG strategy. DISCUSSION: This study provides evidence for clinical and policy decision-making on the cost-effectiveness of genetic referral strategies to identify LFS in the setting of osteosarcoma. MIPOGG-guided strategy was most likely to be cost-effective at a willingness-to-pay threshold value of $50,000/QALY.

Performance of the eHealth decision support tool, MIPOGG, for recognising children with Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin syndromes.

BACKGROUND: Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation. METHODS: This study assessed MIPOGG's performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period. RESULTS: MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG's ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS. CONCLUSION: This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG's strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS.

Pilot study of positive airway pressure usage, patient journey and program engagement for users of a digital obstructive sleep apnea program.

Purpose: This single-arm, decentralized pilot study assessed patient journey, positive airway pressure (PAP) usage and program satisfaction for users of an entirely virtual telemedicine program for obstructive sleep apnea (OSA) diagnosis and management. This analysis focuses specifically on the subset of participants in the program who were diagnosed with OSA and prescribed PAP therapy. Methods: The Verily Clinical Studies Platform was used for virtual screening, consent, and enrolling eligible patients from North Carolina and Texas. After completing the virtual OSA diagnosis process, participants diagnosed with OSA and prescribed PAP therapy downloaded the program's mobile app. The app featured tools such as educational content, live coaching support, and motivational enhancement. Results: Of the patients included in this analysis (N = 105), the majority were female (58%), and white (90%). The mean time from first televisit to PAP initiation was 29.2 (SD 12.8) days and f 68 out of the 105 patients (65%) reached 90-day adherence. On average, patients used their PAP device for 4.4 h per day, and 5.4 h on days used. Engagement with the app was associated with higher rates of PAP adherence. Adherent individuals used the mobile app 52 out of the 90 days on average, compared to non-adherent individuals who used the app on 35 out of the 90 days on average (p = 0.0003). Conclusions: All of the 105 patients in this program diagnosed with OSA and prescribed PAP therapy were able to efficiently complete the entire OSA diagnostic pathway. The majority of these individuals also were able to adhere to their prescribed PAP therapy and had clinically meaningful PAP usage rates over the 90 days of therapy. Future studies might further evaluate the impact of this type of end-to-end virtual program on longer-term adherence and clinical outcomes over time. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04599803?term=NCT04599803&draw=2&rank=1, identifier NCT04599803.

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes.

IMPORTANCE: Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. OBJECTIVE: To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. DESIGN, SETTING, AND PARTICIPANTS: In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. EXPOSURES: Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. MAIN OUTCOMES AND MEASURES: The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. RESULTS: In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. CONCLUSIONS AND RELEVANCE: In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

Utility of a Cancer Predisposition Screening Tool for Predicting Subsequent Malignant Neoplasms in Childhood Cancer Survivors.

PURPOSE: Childhood cancer survivors (CCS) are at risk of developing subsequent malignant neoplasms (SMNs) resulting from exposure to prior therapies. CCS with underlying cancer predisposition syndromes are at additional genetic risk of SMN development. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer at increased likelihood of having a cancer predisposition syndrome, guiding clinicians through a series of Yes or No questions that generate a recommendation for or against genetic evaluation. We evaluated MIPOGG's ability to predict SMN development in CCS. METHODS: Using the provincial cancer registry (Ontario, Canada), and adopting a nested case-control approach, we identified CCS diagnosed and/or treated for a primary malignancy before age 18 years (1986-2015). CCS who developed an SMN (cases) were matched, by primary cancer and year of diagnosis, with CCS who did not develop an SMN (controls) over the same period (1:5 ratio). Potential predictors for SMN development (chemotherapy, radiation, and MIPOGG output) were applied retrospectively using clinical data pertaining to the first malignancy. Conditional logistic regression models estimated hazard ratios and 95% CIs associated with each covariate, alone and in combination, for SMN development. RESULTS: Of 13,367 children with a primary cancer, 317 (2.4%) developed an SMN and were matched to 1,569 controls. A MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio 1.53; 95% CI, 1.06 to 2.19) in a multivariable model that included primary cancer therapy exposures. MIPOGG was predictive of SMN development, showing value in nonhematologic malignancies and in CCS not exposed to radiation. CONCLUSION: MIPOGG has additional value for SMN prediction beyond treatment exposures and may be beneficial in decision making for enhanced individualized SMN surveillance strategies for CCS.

Response biomarkers in neonatal intervention studies.

BackgroundUp to 90% of all drugs used in neonatal intensive care units (NICUs) have not been clinically tested for safety and efficacy. To promote drug development for neonates, the pharmaceutical industry is moving toward rigorous testing, necessitating the need to development, and validating biomarkers in neonates to predict their response. The objective of this review is to evaluate the quality of the response biomarker reporting in neonatal clinical trials.MethodsA validated literature search strategy was applied. Prospective neonatal intervention studies reporting response biomarkers published in 2014 were included. The data were extracted independently and in duplicate using a data-extraction form.ResultsFollowing the full-text review, 167 published prospective neonatal trials were included; 35% (59/167) reported the use of response biomarkers. In these 59 trials, we identified 275 biomarkers used to measure the response (pharmacodynamics and safety) reported as primary or secondary outcomes. Heart rate and oxygen saturation were the most commonly reported. Measurement and instrumentation data were often not provided.ConclusionWe identified a huge variability in the selection, measurement, and reporting of neonatal response biomarkers in prospective intervention studies. Reporting initiatives are needed to reduce research waste and improve the reproducibility of biomarker use in neonatal intervention studies.

Skin and adhesive issues with continuous glucose monitors: a sticky situation.

The purpose of this article is to describe challenges associated with successful use of continuous glucose monitoring (CGM) by young children with type 1 diabetes (T1D) and to detail the techniques and products used to improve the duration of sensor wear. The DirecNet Study Group conducted 2 studies in 169 children with T1D between the ages of 1 and 9 years who were instructed to wear a CGM device daily. Problems related to skin irritation and sensor adhesiveness in these young children presented challenges to daily use of the CGM. Study coordinators instituted a variety of techniques using commercially available products to attempt to overcome these problems. Three primary factors that contributed to reduced CGM use were identified: the limited body surface area in smaller children, ambient temperature and humidity, as well as the type and duration of physical activity. Using supplemental products to minimize the impact of these factors resulted in improved adherence and reduced skin irritation. Achieving satisfactory adhesion of the CGM sensor and transmitter may involve finding the right supplemental product or combination of products through trial and error. Optimizing adhesion and minimizing skin irritation can significantly improve duration of use and tolerability of CGM devices by young children.

Prevention of nocturnal hypoglycemia using predictive alarm algorithms and insulin pump suspension.

OBJECTIVE: The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes. RESEARCH DESIGN AND METHODS: Forty subjects with type 1 diabetes (age range 12-39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care). RESULTS: The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events. CONCLUSIONS: Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur.

Preventing hypoglycemia using predictive alarm algorithms and insulin pump suspension.

BACKGROUND: Nocturnal hypoglycemia is a significant problem. From 50% to 75% of hypoglycemia seizures occur at night. Despite the development of real-time glucose sensors (real-time continuous glucose monitor [CGM]) with hypoglycemic alarms, many patients sleep through these alarms. The goal of this pilot study was to assess the feasibility using a real-time CGM to discontinue insulin pump therapy when hypoglycemia was predicted. METHODS: Twenty-two subjects with type 1 diabetes had two daytime admissions to a clinical research center. On the first admission their basal insulin was increased until their blood glucose level was <60 mg/dL. On the second admission hypoglycemic prediction algorithms were tested to determine if hypoglycemia was prevented by a 90-min pump shutoff and to determine if the pump shutoff resulted in rebound hyperglycemia. RESULTS: Using a statistical prediction algorithm with an 80 mg/dL threshold and a 30-min projection horizon, hypoglycemia was prevented 60% of the time. Using a linear prediction algorithm with an 80 mg/dL threshold and a 45-min prediction horizon, hypoglycemia was prevented 80% of the time. There was no rebound hyperglycemia following pump suspension. CONCLUSIONS: Further development of algorithms is needed to prevent all episodes of hypoglycemia from occurring.

Educating families on real time continuous glucose monitoring: the DirecNet navigator pilot study experience.

PURPOSE: The purpose of this article is to describe the process of educating families and children with type 1 diabetes on real time continuous glucose monitoring (RT-CGM) and to note the similarities and differences of training patients using continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). METHODS: A total of 30 CSII participants and 27 MDI participants were educated using the Navigator RT-CGM in a clinical trial. Time spent with families for visits and calls was tracked and compared between patient groups. The Diabetes Research in Children Network (DirecNet) educators were surveyed to assess the most crucial, time intensive, and difficult educational concepts related to CGM. RESULTS: Of the 27 MDI families, an average of 9.6 hours was spent on protocol-prescribed visits and calls (not measured in CSII) and 2 hours on participant-initiated contacts over 3 months. MDI families required an average of 5.4 more phone contacts over 3 months than CSII families. According to the DirecNet educators, lag time and calibrations were the most crucial teaching concepts for successful RT-CGM use. The most time was spent on teaching technical aspects, troubleshooting, and insulin dosing. The most unanticipated difficulties were skin problems including irritation and the sensor not adhering well. CONCLUSION: Educators who teach RT-CGM should emphasize lag time and calibration techniques, technical device training, and sensor insertion. Follow-up focus should include insulin dosing adjustments and skin issues. The time and effort required to introduce RT-CGM provided an opportunity for the diabetes educators to reemphasize good diabetes care practices and promote self-awareness and autonomy to patients and families.

Low-fat vs. high-fat bedtime snacks in children and adolescents with type 1 diabetes.

OBJECTIVE: The purpose of this study was to determine whether, in a group of children with type 1 diabetes using insulin pump, a prebedtime snack with a relatively high fat content provides greater protection from nocturnal hypoglycemia than a snack containing the same amount of carbohydrate and protein but a lower fat content. RESEARCH DESIGN AND METHODS: Ten subjects, aged 6 to <18 yr, in a trial evaluating the Abbott Navigator glucose sensor, agreed to this ancillary study. On 12 or more separate nights, each subject was randomized by a Web site to a carbohydrate-low-fat (30 g CHO, 2.5 g protein, and 1.3 g fat; 138 kcal) snack or a carbohydrate-high-fat (30 g CHO, 2 g protein, and 20 g fat; 320 kcal) snack. Subjects used their usual evening snack algorithm to determine the size (in 15-g carbohydrate increments) and insulin dosage. RESULTS: Average glucose on 128 valid study nights before snack was similar in both groups. The proportion of nights with hypoglycemia (a sensor or meter glucose value or=200 mg/dL and at least 50 mg/dL above baseline, 35% high fat vs. 30% low fat). CONCLUSIONS: There were no statistical differences between the high- and low-fat snacks on the frequency of hyperglycemia or hypoglycemia. This study highlights the feasibility of web-based research in patients' home environment.

Real-time continuous glucose monitoring.

PURPOSE OF REVIEW: To summarize the current literature on real-time continuous glucose monitors, focusing on devices that have been approved or are pending approval. RECENT FINDINGS: Real-time continuous glucose sensors are new tools to assist in diabetes management. Several devices are currently being sold and additional monitors are expected to be available shortly. These sensors measure interstitial glucose - a distinct physiologic space when compared with the blood glucose. The ability to recognize trends in blood glucose levels provides a new paradigm for making insulin dose decisions and treating hypo- and hyperglycemia. SUMMARY: Real-time continuous glucose monitoring systems are currently less accurate than home glucose meters, but provide information every 1-5 min throughout the day and night with alarms for hyper- and hypoglycemia, providing information on glucose trends and nocturnal glycemic excursions. Current real-time sensors are behavior modification tools. Thus, improvements in diabetes control depend on the willingness of patients to modify their diabetes management based on information provided by these devices.