text:
Getting Started (FAQs)
Programs and locations
Worldwide events
Campus workshops
Information About Our Trainings
The Barbara Brennan School of Healing and Brennan Institute currently offer three programs:
1. The Professional Studies Diploma Program
2. The Bachelor of Science Degree Program (available only in Florida)
3. The Advanced Studies Diploma Program (available only to graduates)
Supplemental Program:
• Anatomy and Physiology (not available at every location)
All programs require potential students to be 18 years or age and submit proof of high school diploma or GED completion or international equivalent. The Bachelor of Science Degree program is only available at our Florida location.
Tuition and Other Costs
The yearly base tuition for all programs is $7900, with the exception of Japan, which is $8500 per year. Tuition does not include transportation, lodging or food.
Professional Studies Diploma Program:
Anatomy and Physiology 1, offered at $2600, is an adjunct requirement to be completed prior to entering Year 3.
Bachelor of Science Degree:
Anatomy and Physiology I, II, III, IV are requirements of the degree program. A&P 1 is $2600. A&P II, III, and IV are $1500. (A&P 1 is eligible for transfer credit)
Nine General Education Online Courses are also required and are offered at $795 per course. (All courses eligible for transfer credit except Strategies for Success.)For information on various payment plans, see the enrollment agreement for the location you are selecting.
Professional Studies Diploma Program
Professional Studies Year 1
Year 1 focuses on levels 1, 2 and 3 of the Human Energy Field. The spiritual purpose of Year 1 is to transform the relationship with the Self, and in doing so create a foundation for the next three years' work. This transformation is essential to becoming a professional healer. One cannot truly connect, know, or honor another until one connects, knows, and honors the Self. It is a wonderful year of opening to new horizons.
Year 2 deepens the experience of the previous year by holding the spiritual purpose of the 4th level of the Human Energy Field, the relationship to others. The student is changing his/her relationships to other humans, non-humans, and non-physical beings. The work is extensive since it encompasses more lifetimes than this present one. The student's relationship to his/her self expands through many lifetimes. There is a new relationship to this planet, this universe, and additional dimensions or realms. A great deal of personal work is taken on by each student as he or she grapples with blocks to personal expression. Insight, self-responsibility, and compassion grow, along with hands-on experience of the 4th level.
Year 3 focuses on the Hara line, which is the line of intention and the embrace of surrender. The hara line is a major energetic support for the shift in the student's commitment to his/her healer-ship. The spiritual purpose of this year is to deepen each student's awareness and experience to the Divine by studying the spiritual levels of the Human Energy Field—the 5th, 6th, and 7th—thereby setting the stage for the student's change in relationship to the spiritual world—Divine Will, Divine Love, and Divine Mind. It is a profound year, rich in exploration, which brings the student's understanding of self and the Divine into greater and greater communion.
Year 4 focuses on the Hara and the Core Star levels. All the training of the previous years culminates in this year's spiritual purpose, which is to assist in the emergence and expression of the unique essence of each healer. The skills which are mastered require strength, centering, great love, and stamina. It is here that the student finds autonomy through focusing on their intentionality, being in their essence, and allowing that essence to more fully express itself in the world. Each student learns to integrate the work more fully into their daily lives, giving rise to a new relationship to one's life task and core essence. This final year offers itself in celebration as each student honors the completion of their four-year journey into Brennan Healing Science and their commitment to the community of the sacred human heart.
Bachelor of Science Degree Program
To earn a Bachelor of Science degree in Brennan Healing Science, students must complete the following:
• Four-Year Brennan Healing Science Professional Studies Program
• Four Courses in Anatomy and Physiology
• Nine Courses of General Education in the following areas: English, Science/Math, Social/Behavioral Sciences, and Humanities (all offered online)
A fundamental and comprehensive study in anatomy and physiology is an important aspect of learning for the professional healer. This knowledge provides an essential framework for Brennan Healing Science students, as they learn to work with the energy of specific organs and body systems. An understanding of the anatomy and physiology of the physical body, and its interrelatedness to the Human Energy-Consciousness System supports a truly integrative approach to healing.
During the third year of training at the Barbara Brennan School of Healing, students learn hands-on healing techniques and skills for balancing and assisting the healing of specific organs and body systems. This focused work requires a knowledge of the anatomy and physiology of the physical body so that students are able to relate their High Sense Perceptions and healing work to the associated physical structures and their functioning. Anatomy & Physiology for Healers (A&P I) must be completed prior to Year 3 of the academic training.
Anatomy and Physiology I (Anatomy and Physiology for Healers)
The curriculum focuses on the structure and function of the human body. Each system of the body is reviewed in terms of its overall structure and function; the relationship of the Human Energy-Consciousness System and its physical manifestation; hands-on healing techniques; utilization of High Sense Perception in accessing structure and function; and experiential exercises integrating Brennan Healing Science skills, Psych-Spiritual Development skills and the development of High Sense Perception.
Anatomy and Physiology II
The students utilize and expand upon the skills and knowledge they have gained in their study of basic Anatomy and Physiology (A&P I), as well as their general studies in Year 2 of the Brennan Healing Science Academic Program. Moving beyond structure and function, this course assists in developing the student's High Sense Perception and explores the effects of relationships and supporting systems on physical health and illness.
As Year 2 focuses on the theme of relationship, the Anatomy and Physiology II Course extends this learning to explore the facets of relationship in regard to the physical body, including how the physical body 6 in relationship to the energy consciousness system responds and the resultant manifestations of disease or recovery from illness. Adjunctive to the second year of training in Brennan Healing Science, it also enhances the student's ability to integrate the Healing Science skills with the functioning of the physical body, including how beliefs, thoughts, and emotions affect the body systems and physical health.
Classes focus on the dynamic physiologic and energetic processes of being in relationship with others and with the world. Classroom lectures and experiential learning covers character structures and their relationship to the manifestation of disease processes, the physiologic and energetic relationship and interaction between body systems, the science and energy consciousness of psychoneuroimmunology, the effect of the environment on the immune system, the energetic, emotional and physiologic impact of trauma and post-traumatic stress disorders and the energy consciousness and related pathophysiologic aspects of heart disease.
Anatomy and Physiology III
A&P III students continue to learn about the energetic and physical manifestations in the healthy body as well as the changes that result from common illness or pathophysiology. During this course of study, students learn to expand their High Sense Perception from a cellular to a holographic scope that includes the dis-ease history of the body's organs. Health issues specific to men and women are discussed, as well as the specifics of working with clients in various life stages. Year 3 of undergraduate study is supported, emphasizing the Healing Science skills of restructuring and 5th level work, as the students explore more fully the physiologic changes that occur during dis-ease processes and healing.
Anatomy and Physiology IV
A&P IV students focus on the integration of their learning with the application of their skills in preparation for working with clients in a clinical setting as a Brennan Healing Science Practitioner. Through direct supervision, students are guided through comprehensive learning and evaluation in clinical practice sessions, demonstrating the following: personal knowledge of the Healing Science, Psych-Spiritual Development,Professional Practice and Integrative Care skills through thorough client interviewing, intake, history taking and assessment; accurate High Sense Perception; appropriate use of Brennan Healing Science hands-on healing techniques; session closure; and post-treatment recommendation. Classroom7 lecture time focuses on the further development of each student's ability to work deeply within specificity in relationship to the disturbances in the related structure and function of the Human Energy-Consciousness System.
The Advanced Studies program offers professional courses of study in Brennan Integration Work. It provides a powerful journey of transformation—expanding and deepening your facilitation skills as a healer and further opening the way for the full expression of your life's work.
Advanced Studies Year 1
Year One of the Advanced Studies program focuses exclusively on a practitioner's capacity to attend to a client's ongoing personal process. It emphasizes body and energy awareness in a person's emotional and psychological experience. Students are taught how to track and understand individual and group dynamics and to experiment with making process observations and reflections versus giving guidance and advice to their clients.
Year Two of the Advanced Studies program is a continuation and deepening of what students learn in Year One. In Year Two, students are expected to demonstrate a clear understanding of individual process dynamics, and an ability to deepen a client's work, both within a session and over the course of successive sessions. Students participate in group presentations, and specialized segments are presented to incorporate techniques to help clients manage emotional intensity.
For graduates of BBSH and BBSH United Kingdom only.
Download the Florida 2021–22 Advanced Studies Catalog.
Download the Florida 2021–22 Advanced Studies Application.
Download the Florida 2021–22 Advanced Studies Student Confidential.
Download the BBSH United Kingdom 2021–22 Advanced Studies Catalog.
Download the BBSH United Kingdom 2021–22 Advanced Studies Application.
Download the BBSH United Kingdom 2021–22 Advanced Studies Student Confidential.
Download the BBSH United Kingdom 2021–22 Advanced Studies Year 1 Questionnaire.
Location, Dates, and Application Information
Florida: 4-year Professional Studies and Bachelor of Science Program
The 2021–22 Resident Training portion of the programs is held at the Bonaventure Resort & Spa in Weston, Florida, just outside of Fort Lauderdale, 20 minutes (15 miles) from Fort Lauderdale/Hollywood International Airport and 45 minutes from Miami International Airport. Fort Lauderdale Beach is approximately 30 minutes (20 miles) away.
During the Resident Training, the Resort becomes a wonderful, vital community that provides an invaluable support system for the students staying there. Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay on campus at the hotel for Resident Training.
4-Year Brennan Healing Science Program Offerings:
• Professional Studies Diploma
• Bachelors of Science Degree
• Anatomy and Physiology I–IV
Barbara Brennan School of Healing 2021–2022 Resident Training Dates
Each Class Week Is Held Thursday–Sunday
• Class 1: October 14–17, 2021
• Class 2: December 9–12, 2021
• Class 3: February 17–20, 2022
• Class 4: April 28–May 1, 2022
• Class 5: June 16–19, 2022
Saturday Zoom Class Meeting Dates
Anatomy & Physiology I meets two days following each class week.
Anatomy & Physiology II-III meets one day following each class week.
Anatomy & Physiology IV meets one day before each class week.
Our 2021–22 BBSH School Catalog provides more detailed information about our program.
PROFESSIONAL STUDIES DIPLOMA or BACHELOR OF SCIENCE DEGREE
1. Apply for the Florida Professional Studies Diploma or Bachelor of Science Degree Program to be accompanied by the BBSH 2021–22 Student Confidential. In order to apply, both of these forms must be submitted. This addendum also contains the application for the Florida Anatomy & Physiology I–IV courses.
2. For Bachelor of Science Degree only: Download the required General Education Courses Application.
3. Complete both the Application and Student Confidential and name your files—Last Name, Year of study, School (Mollo, Yr-1, FL)
All applicants need to complete both the Application and Confidential as fillable PDF documents and return them to the email address for the school.
United Kingdom: 4-year Professional Studies Program
The 2021–22 Resident Training portion of the program is held at the Jurys Inn in Oxford, UK. Jurys Inn is 45 minutes from Heathrow International Airport and 5 miles from the Oxford railway station. Jurys Inn is just a short drive from the city centre, with its beautiful architecture and countless attractions. Additional logistical information will be provided upon request or enrollment.
During the Resident Training, the Inn becomes a wonderful, vital community that provides an invaluable support system for the students staying there. Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay on campus at the hotel for Resident Training.
BBSH United Kingdom is the designated "hybrid" school for those in similar time zones, as classes will be offered simultaneously in person and online. Students may choose to attend either in person or remotely, or a combination of both.
• Anatomy and Physiology 1 for Healers
BBSH United Kingdom 2021–2022 Resident Training Dates
Each Class Week Is Held Thursday–Sunday (Western European Time Zone)
• Class 1: September 23–26, 2021
• Class 2: November 18–21, 2021
• Class 3: January 13–16, 2022
• Class 4: March 10–13, 2022
• Class 5: May 12–15, 2022
Anatomy & Physiology for Healers meets the two days following each class week.
Our 2021–22 BBSH United Kingdom Catalog  provides more detailed information about our program.
Download the BBSH United Kingdom 2021–22 Professional Studies Application and the BBSH United Kingdom 2021–22 Student Confidential.
All applicants need to complete both the Application and Confidential as fillable PDF documents and return them to the email address for the school. In order to apply, both of these forms must be submitted.
California: Professional Studies Years 1–3 Training
The 2021–22 Resident Training portion of the program is held at the Hilton Garden Inn San Francisco/Oakland Bay Bridge in Emeryville, California.
Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay on campus at the hotel for Resident Training. BBSH California is the designated "hybrid" school for those in similar time zones, as classes will be offered simultaneously in person and online. Students may choose to attend either in person or remotely, or a combination of both.
Emeryville, California 2021–2022 Resident Training Dates
Each Class Week Is Held Thursday–Sunday (US Pacific Time Zone)
• Class 1: September 30–October 3, 2021
• Class 2: December 2–5, 2021
• Class 3: February 3–6, 2022
• Class 4: March 31–April 3, 2022
• Class 5: June 2–5, 2022
Anatomy & Physiology I (for Healers) meets the two days following each class week.
Our 2021–22 BBSH California Catalog  provides more detailed information about our program.
Download the BBSH California 2021–22 Professional Studies Application and the BBSH California 2021–22 Student Confidential.
New York Area: Professional Studies Year 1 Training
The 2021–22 Resident Training portion of the program is held at the Center for Natural Wellness School of Massage Therapy in Albany, New York.
Students are responsible for finding their own lodging. Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay in Albany and, if possible, reasonably close to the School.
Year 1 Brennan Healing Science Program Offerings Only. Students will need to transfer to BBSH Florida, BBSH California, or BBSH United Kingdom to complete the training.
Albany, New York 2021–2022 Resident Training Dates
• Class 3: January 20–23, 2022*
*The January 2022 Resident Training Week will be held remotely via Zoom.
Our 2021–22 BBSH New York Area Catalog  provides more detailed information about our program.
Download the BBSH New York 2021–22 Professional Studies Application and the BBSH New York 2021–22 Student Confidential.
Colorado: Professional Studies Year 1 Training
The 2021–22 Resident Training portion of the program is held at the Boulder Shambhala Center in Boulder, Colorado.
Students are responsible for finding their own lodging. Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay in Boulder and, if possible, reasonably close to the Boulder Shambhala Center.
Year 1 Brennan Healing Science Program Offerings Only. Students will need to transfer to either BBSH Florida, BBSH California, or BBSH United Kingdom to complete the training.
Boulder, Colorado 2021–2022 Resident Training Dates
Our 2021–22 BBSH Colorado Catalog  provides more detailed information about our program.
Download the BBSH Colorado 2021–22 Professional Studies Application and the BBSH Colorado 2021–22 Student Confidential.
France: Professional Studies Year 1 Training
The 2021–22 Resident Training portion of the program is held at Studio Akordance in Paris, France.
Students are responsible for finding their own lodging. Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay in Paris and, if possible, reasonably close to Studio Akordance, located at 13 bis rue Philippe de Girard in Paris.
Paris, France 2021–2022 Resident Training Dates
• Class 1: October 7–10, 2021
Our 2021–22 BBSH France Catalog  provides more detailed information about our program.
Download the BBSH France 2021–22 Professional Studies Application and the BBSH France 2021–22 Student Confidential.
Germany: Professional Studies Year 1 Training
The 2021–22 Resident Training portion of the program is held at the Seminarzentrum Sonnenstrahl in Kißlegg, Germany.
Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay on campus at the hotel for Resident Training.
Kißlegg, Germany 2021–2022 Resident Training Dates
• Class 1: September 2–5, 2021
• Class 2: November 4–7, 2021
• Class 4: April 7–10, 2022
Our 2021–22 BBSH Germany Catalog  provides more detailed information about our program.
Download the BBSH Germany 2021–22 Professional Studies Application and the BBSH Germany 2021–22 Student Confidential.
Japan: Professional Studies Years 1 & 2 Training
The 2022 Resident Training portion of the program is held in Nagoya, Japan.
Students are responsible for finding their own lodging if they choose to attend Classes 3 and 5 in person. Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay in Nagoya during each Resident Training week.
Years 1 and 2 Brennan Healing Science Program Offerings Only for 2022.
Nagoya, Japan 2022 Training Dates
• Class 1: March 17–20, 2022 (via Zoom)
• Class 2: May 5–8, 2022 (via Zoom)
• Class 3: July 14–17, 2022 (in Nagoya)
• Class 4: September 22–25, 2022 (via Zoom)
• Class 5: November 3–6, 2022 (in Nagoya)
Our 2022 BBSH Japan Catalog  provides more detailed information about our program.
Download the BBSH Japan 2022 Professional Studies Application.
All applicants need to complete all forms contained in the Application and return them to the email address for the school.
Australia: Professional Studies Year 1 Training
The 2022 Resident Training portion of the program is held in Sydney, Australia.
Students are responsible for finding their own lodging if they choose to attend Classes 3 and 5 in person. Because of the nature of the intensity and complexity of Resident Training, we strongly recommend that students stay in Sydney during each Resident Training week.
Year 1 Brennan Healing Science Program Offerings Only for 2022.
Sydney, Australia 2022 Training Dates
• Class 3: July 14–17, 2022 (in Sydney)
• Class 5: November 3–6, 2022 (in Sydney)
Florida & United Kingdom: Advanced Studies Program Applications
Enrollment in Advanced Studies is only available for graduates of BBSH and BBSH United Kingdom.
Copyright ©2022 Barbara Brennan School of Healing. All Rights Reserved. Licensed by the Florida Commission for Independent Education - License No. 2897


text:
Home » Budget Industry » Panel: Navy and Coast Guard Operating More in a Maritime 'Grey Zone'
Panel: Navy and Coast Guard Operating More in a Maritime 'Grey Zone'
By: Ben Werner
A US Navy visit, board, search and seizure (VBSS) team, approached a suspected pirate after the Motor Vessel Nordic Apollo reported being under attack and fired upon by pirates in 2011. US Navy Photo
SAN DIEGO, Calif. — Between war and peace is the grey zone – a legal status where the rules of engagement aren't always clear for the Navy and Coast Guard forces increasingly operating there, according to top commanders from the services.
The Navy and Coast Guard are tasked with protecting the trade and sovereign interests of both the U.S. friends and allies. But, without a clearly identified mission and clearly articulated and supporting rules of engagement, it's difficult for ship commanders to determine threat levels and follow an acceptable course of action, said Vice Adm. John Alexander, the commander of U.S. 3rd Fleet. Alexander was part of a panel of admirals and a former ambassador at the WEST 2018 conference discussing grey zone operations.
"It's an asymmetric warfare and the Navy is no stranger to this," Alexander said.
The problem for Navy and Coast Guard ship commanders is separating peaceful fishing fleet or commercial marine traffic from ships operated by an adversary. Ship commanders have a short window of time to determine intent when suddenly facing such questions as who are they facing and what is an appropriate use of the military might at their disposal.
Ships from most navies generally follow the same operational norms as those used by the U.S. Navy. The panel agreed commanders on both sides generally know where the grey zone ends and conflict begins. Some countries are just more apt to operate right up to the edge dividing grey from conflict.
But defining the grey zone itself can be tricky. Not every country has the same idea of where conflict begins, said panelist Nina Hachigian, former U.S. Ambassador to the Association of Southeast Asian Nations.
Alexander said, "What is the grey zone? I kind of view it as non-state actors executing state security objectives and utilizing the ambiguity that they have to make it hard to respond."
China, for example, often operates right at the grey zone's edge, panelist Vice Adm. Fred Midgette, the U.S. Coast Guard's Pacific Area Commander. The nation is building-up the size of its coast guard fleet and claiming territory at sea. The reason is to project its force and impose its national will on international arenas.
Illegal fishing off Gabon in 2011. NOAA Photo
Countering China's influence in the region is very complicated. China's cooperation is a central part of U.S. efforts to restrain North Korea's nuclear program and the nation is a major trade partner for neighboring countries and the U.S., Hachigian said.
Yet China also on occasion acts in a way that doesn't respect international norms, Alexander said. He pointed to China's attempt to spread its international waters, and fisheries, by building islands. Pouring sand on a low-tide elevation doesn't necessarily create a habitable location, he said.
Diplomatically, though, when trying to counter such actions, the U.S. is hampered by not having signed the United Nations Convention on the Law of the Sea, Hachigian said. The U.S. follows the convention, but by not being a signatory, loses some moral standing when confronting other nations who have signed the treaty. The result is different countries will look at the same scenario differently.
"So, we didn't ratify it; we follow the rules. China signed the damned thing; they don't follow the rules," Alexander said.
"So who's more right in this argument?"
Article Keywords: piracy, us coast guard, us navy, West 2018
Categories: Budget Industry, News & Analysis, Piracy, Surface Forces, U.S. Coast Guard, U.S. Navy
About Ben Werner
Ben Werner is a staff writer for USNI News. He has worked as a freelance writer in Busan, South Korea, and as a staff writer covering education and publicly traded companies for The Virginian-Pilot in Norfolk, Va., The State newspaper in Columbia, S.C., Savannah Morning News in Savannah, Ga., and Baltimore Business Journal. He earned a bachelor's degree from the University of Maryland and a master's degree from New York University.
View all posts by Ben Werner →
← Document: New Pentagon Harassment Prevention and Response Policy PACOM CO Harry Harris Tapped to be Ambassador to Australia; U.S. 5th Fleet CO to Pacific Fleet →

redpajama_set_name: RedPajamaCommonCrawl


Morning lovelies! Is it me, or is winter already feeling never ending? Luckily for us, L.L. Bean Signature just released a few pieces from their Spring line, so I'm going to focus on that fact and count down the days until Spring. My absolute favorite piece they released so far was the Crinkle Silk Shirt. It's so 1940s looking! I'd love to wear this with a twirly-skirt, t-strap heels, and a little scarf. Or, pair it with skinny jeans and a black leather jacket for a nighttime going out look. I love those sweet puffy sleeves and vintage looking rounded collar. Also, don't fabric covered buttons seem to dress up any shirt? Love those, too. What would you wear this shirt with?
I love the rounded collar too. I would wear it with a floral skirt, and tights, and a cardigan sweater with a vintage brooch.
Oh, I love the idea of the vintage brooch!!
it seems that the fabric were cozy if I wear that shirt.


Azure, Microsoft's premiere cloud product launched in the year 2010, has contributed a lot in Microsoft's revenue growth. It is also the driving force for the Microsoft's ongoing migration into the cloud market by developing strategic tie-ups with cloud market leaders such as SFDC. According to Gartner's ranking, Azure is the only leading cloud platform in IaaS (Infrastructure-as-a-Service) and gained a significant slot in PaaS(Platform-as-a-Service) space. As per the forecasts of Forbes, Azure's annual revenue would reach $2.3billion.
Virtual Machines: Get full control over the server in the cloud and maintain it as your business requirement.
Cloud Services: Managed virtual machines with web and worker roles.
Service Fabric: Build highly scalable, reliable and powerful applications composed of micro services.
Batch: For running large scale parallel and HPC (High Performance Computing) applications.
Scheduler: create jobs that run reliably on simple or complex schedules to invoke any type of service.
Remote App: Access windows apps from any device and any location that run within Remote App Virtual Machines (VMs).
Web apps: Managed web platforms, get started for free and scale as you go using many tools/languages.
Mobile Apps: Add back end capabilities to mobile apps with native client support on most device platforms.
APIs: Create and surface your app logic as APIs for other services and apps to consume.
Logic Apps: Build/execute business processes by linking with your own custom APIs from the API gallery/marketplace.
API Management: Publish and manage APIs to developers, partners and employees securely and at scale.
Notifications Hub: deliver millions of platforms for push notifications from any backend application anywhere.
Backup: Managed service that handle backups/restore of windows servers machines/backup agents.
Import/Export: For massive data transfer-chip encrypted disks to move data in/out from blob storage.
Site Recovery: coordinate replications and recovery of system center private clouds.
Storsimple: automated policy-driven solution to extend on-premises primary storage for backup and disaster recovery.
SQL Database: Managed relational database services with high availability and selectable performance levels.
Storage Queues: Simple message queue for application decoupling architecture for scale out.
BizTalk Services: Build EDI and Enterprise Application integration (EAI) solutions in the cloud.
Hybrid connections: Connect app in Azure with on-premises resources without a VPN or dedicated line.
Service Bus: Messaging capabilities and to cloud connectivity solutions.
Automation: Run durable PowerShell scripts to automate frequent, long-running, complex azure tasks.
Portal: Web-based experience to provision, control and monitor all azure services.


Manchester United and Real Madrid drew 1-1 after 90 minutes with Anthony Martial and Jesse Lingard combining well to take first blood at the end of the first half of the match. In the second half, around the 69th minute, Victor Lindelof made a howler giving away a penalty which Casemiro converted levelling the score. Marouane Fellaini had a chance to win the match for United, with his shot off target. The match went to a penalty shootout to find the eventual winner with United winning 2-1 with Henrikh Mkhitaryan and Daley Blind scoring United's penalties.
Jose Mourinho made nine changes to his starting XI ahead of the match with Real Madrid in at the Levi's Stadium in Santa Clara, California. Sergio Romero, Timothy Fosu-Mensah, Eric Bailly, Phil Jones, Matteo Darmian, Michael Carrick, Marouane Fellaini, Andreas Pereira, Jesse Lingard, Marcus Rashford and Anthony Martial all start. Juan Mata misses out with an ankle injury sustained in the 2-1 victory over Real Salt Lake earlier in the week. United and Real Madrid both started on the front foot, looking to get the better of their opposition. Both teams had credible chances with Phil Jones and Sergio Romeo stopping Real Madrid from scoring.
United started to take advantage of their opposition around the seven-minute mark with Marcus Rashford and Anthony Martial using their pace to get the better of the Spanish team with the Frenchman getting a good shot on goal which was thwarted by Keylor Navas. Both teams were getting the ball but doing nothing with it. United had pressured the Spanish champions a few times, the last with Marouane Fellaini trying to get something for United by Marcelo took him on, using his head to keep the ball, literally, getting the better of the big Belgian midfielder.
It was starting to become end-to-end football with both teams attacking, in periods of the match, but nothing getting through and the ball ending up back at the other end of the pitch. Both teams were playing well and considering this was the first pre-season match for the Spanish side, they were giving United a good game, which in the heat in California would give them a good work out ahead of the new season. Timothy Fosu-Mensah was playing well against Gareth Bale, so far getting the better of the Welshman for most of his threats on United's right flank. At the half hour mark, the match was stopped for a water break, which was much-needed for some.
After the break things started to take off in the match with chances at either end. Anthony Martial had a chance to break forward, getting into the box and laying off the pass to the other flank. Fosu-Mensah had the ball and tried to pass it into the box, which Madrid regaining possession and thwarting United's attack. Minutes later Jesse Lingard had a chance to break the deadlock, firing just wide of the mark. Madrid had a chance with about two minutes of the half left with Lucas Vasquez offside and being flagged as being so. Jones had him covered though. Luca Modric played the ball into United box, Romero missed the ball and Bailly made the clearance.
Real Madrid won a corner inside the last minute of the half with Toni Kroos taking it, United won possession by two players combining to make the clearance with United trying to break forward but ending up back inside their own half. United took the lead in the seconds before the break with Anthony Martial showing his skill on the left, cutting into the box and passing across the face of the goal with Lingard making the simple tap-in to put United ahead. Real Madrid had the chance to equalise just before the break but it was flagged for offside. So far so good for United, 1-0 in the lead at the break.
At the start of the second half Jose Mourinho made eight changes with David De Gea, Chris Smalling, Victor Lindelof, Daley Blind, Paul Pogba, Ander Herrera, Henrikh Mkhitaryan and Romelu Lukaku all replacing Romero, Fosu-Mensah, Bailly, Jones, Carrick, Pereira, Lingard and Rashford. United started to try and restart the match after all the changes, which seems to make the second half duller with players trying to get into the match. Ander Herrera was taken off seven minutes into the second half with Scott McTominay replacing him, which was a blow for the Spanish midfielder who was looking to get more minutes in this match.
In the 62nd minute of the match Marouane Fellaini, one of three players who started the match headed over the Real Madrid crossbar as United looked for that elusive second goal which would all but confirm the victory for United. In the 69th minute of the match, United defender Victor Lindelof gave away a penalty for taking out Theo Hernandez, who was taken out moments before by Henrikh Mkhitaryan. Casemiro took the penalty and David De Gea could not get to it. 1-1 and everything to take from the game. This could go to penalties yet if United do not find a winner.
Seven minutes from time United could have found the winner they needed through Fellaini, whose shot was not on target, not even at risk of causing any damage to United's opposition. In the dying minutes of the match, the youthful Real Madrid side were shooting from distance and generally trying to find the winning goal after being played back into the match with the penalty. The match was heading to penalties to find a winner. It was 1-1 after 90 minutes. Martial took the first penalty which was off target completely. David De Gea saved Madrid's penalty, 0-0 after one each.
Scott McTominay took United's second penalty, getting his shot on target but Kiko Casilla made the save to thwart the youngster. Oscar Rodriguez took Madrid's second penalty with De Gea making his second save of the shootout. Henrikh Mkhitaryan took United's third penalty, beating Casilla to put United ahead. Real Madrid scored their third penalty making it 1-1. Victor Lindelof took United's fourth penalty, aiming straight for the goalkeeper's legs, poor penalty. Madrid missed their fourth penalty, still 1-1 after four penalties each. Daley Blind took United's fifth penalty, straight down the middle finding the back of the net 2-1 to United. Casemiro missed Madrid fifth and United take the win.


text:
Clinical Science| March 1998
Bayesian Modeling of Muscle Biopsy Contracture Testing for Malignant Hyperthermia Susceptibility
Julian C. P. Loke;
Julian C. P. Loke
David H. MacLennan
(Loke) Lecturer, Department of Anesthesia, Malignant Hyperthermia Investigation Unit.
(MacLennan) University Professor, Banting and Best Department of Medical Research.
Julian C. P. Loke, David H. MacLennan; Bayesian Modeling of Muscle Biopsy Contracture Testing for Malignant Hyperthermia Susceptibility . Anesthesiology 1998; 88:589–600 doi: https://doi.org/10.1097/00000542-199803000-00007
Phenotyping malignant hyperthermia (MH) by contracture testing has a low but quantifiable degree of inaccuracy, measured by its sensitivity and specificity. Quantifying the limitations inherent in diagnostic testing for MH can help resolve issues in clinical practice, such as the interpretation of a negative test and the apparent lack of complete genetic linkage to RYR1.
Bayesian models, mathematical descriptions of the outcome of diagnostic testing, were constructed. The inputs to the model include patient factors, summarized in a single number called pretest probability (PTP), and sensitivity and specificity that specify the accuracy of the entire test process. The outputs of the model include positive predictive value (PPV) and negative predictive value (NPV), which are numeric expressions of diagnostic certainty of positive and negative test results. A special case was constructed for equivocal results.
The PPV, NPV, and efficiency of contracture testing for MH are functions of PTP, sensitivity, and specificity. The NPV is high for all clinical PTP, whereas PPV is clinically useful for moderate to high PTP.
Diagnostic contracture testing for MH is clinically useful because of high NPV and can exclude MH with near certainty. For MH probands, the clinical grading scale for MH may guide PTP estimation, whereas for relatives of probands, PTP is a function of kinship to a known MH-susceptible relative. A sequential testing strategy optimizes diagnostic information by maximizing PTP within a pedigree. Incomplete testing of parents of an MH susceptible child can pose a significant risk of false-negative results for the untested parent. Even with optimal pedigree testing strategies, the PPV drift effect results in a considerable source of phenotypic uncertainty for genetic linkage studies.
biopsy of muscle, contracture, malignant hyperthermia due to anesthesia, proband, caffeine halothane contracture test, pretest probability of disease, laboratory test finding, parent, genetic pedigree
MALIGNANT hyperthermia (MH) is an inherited, autosomal dominant, pharmacogenetic disorder in which susceptible patients can exhibit acute, rapidly progressive life-threatening hypermetabolic reactions when exposed to succinylcholine, potent inhalational anesthetic agents, or both. [1,2]In families with MH, prediction of MH susceptibility (MHS) before surgery is achieved by contracture testing of skeletal muscle biopsies for abnormal threshold sensitivity to caffeine [3]and to halothane. [2,4]
Two protocols exist for contracture testing for diagnosis of MHS. The North American Caffeine-Halothane Contracture Test (CHCT)[5]and the European In Vitro Contracture Test (IVCT)[6]differ only slightly in the testing technique. Both protocols assign a positive (MHS) and a negative (MHN) diagnosis, but the European protocol allows for an equivocal (MHE) classification that results in the same clinical treatment as a positive diagnosis does. [6]For linkage studies, the MHE classification is considered nondiagnostic.
The discovery of linkage of the calcium-release channel gene, RYR1, to human MH, [7,8]the demonstration that a point mutation in RYR1 is tightly linked to the porcine form of MH, [9,10]and that nine point mutations in RYR1 can be linked with human MH [11–19]has increased interest in the molecular genetics of human MH. Although only about 50% of human families with MH have a link to the region on human chromosome 19q13.1 containing RYR1, [20]many apparently unlinked families have only a single recombinant event. [21]
Several large European MH families, with no link to chromosome 19, have been included in a systematic linkage study using a set of polymorphic microsatellite markers covering the entire human genome. Linkage has been observed in single families for chromosome 3q13.1, [22]for chromosome 5p and for chromosome 1q. [23,24]Analysis of the chromosome 1q-linked family led to the discovery of a mutation in the CACNL1A3 gene encoding the alpha-1 subunit of the dihydropyridine receptor [23]and established a second MH locus in which mutations can be linked to MH.
The major difficulty with linkage studies in human MH pedigrees is their reliance on accurate phenotypic data. [21]Like most other clinical diagnostic tests, phenotyping of MHS by contracture testing of a muscle biopsy has a quantifiable inaccuracy, measured by its sensitivity and specificity. The sensitivity of a diagnostic test is defined as the ability of the test to diagnose disease correctly when disease is known to exist. [25–27]Specificity refers to the ability of the test to exclude disease when disease is known to be absent. [25–27]Although false-negative results are rare [28–34]and false-positive results may occur, [30,31,33,35,36]a complete understanding of the nature and implications of these limitations inherent in diagnostic testing for MH is essential for good clinical practice and genetic linkage studies.
The North American Malignant Hyperthermia Registry has compiled figures on sensitivity and specificity of the CHCT. [37,38]The European Malignant Hyperthermia Group (EMHG) has also published data on sensitivity and specificity of the IVCT. [35,39,40]Both groups have used the International Malignant Hyperthermia Clinical Grading Scale (CGS), [41]devised by collaboration of representative MH clinicians from at least six countries, as a case-finding instrument when establishing sensitivity.
A Bayesian model is a mathematical description of how sensitivity and specificity affect the outcome of a clinical diagnostic test. [25–27]The other input to the model is pretest probability (PTP), which is defined as the probability, or clinical suspicion, that a person has disease before testing. The likelihood of disease is modified (conditioned) by the diagnostic test result: It is increased with a positive result and decreased with a negative result. The degree to which PTP is revised by a test result depends on the sensitivity and specificity of that diagnostic test, and it can be calculated. [25–27]The aim of this investigation was to develop a Bayesian model to calculate conditional probabilities starting from the current estimates of sensitivity and specificity of muscle biopsy contracture testing for MH. New values for sensitivity and specificity can be accommodated by simple recalculation.
Our Bayesian model assumes only that sensitivity and specificity are correct. Sensitivity and specificity are difficult to estimate because there is no "gold standard" for MHS. Exposing CHCT-positive patients to triggering anesthetics that provoke life-threatening reactions is not only unethical but may require several such anesthetics before confirming MHS. [2,31,33,36]Similarly, looking for anesthetic reactions in a highly selected group of CHCT-negative patients would give an estimate of sensitivity [28,29,31–33,36,42]but would be subject to spectrum bias, test-retest bias, and selection bias, which are difficult to overcome. Analysis of data that were used to study the agreement between CGS and IVCT from two European test center [43,44]can also yield estimates of sensitivity (1.00) and specificity (0.53–0.66) that differ from the pooled EMHG estimates, suggesting that such biases may truly exist.
The effect of inaccuracies in estimating sensitivity and specificity on the Bayesian model can be examined, and robust conclusions can be drawn. If the values for sensitivity and specificity for contracture testing are accepted as published, then the conclusions from this manuscript must hold.
Although limited analyses of such data have been done, [30,35]our more extensive mathematical model can examine the effect of proband CGS rank and of various pedigree testing strategies. This allows us to propose rational applications of contracture testing data, clinically and in future genetic linkage research, by quantifying the degree of uncertainty in phenotypic diagnosis.
(Table 1) summarizes sensitivity and specificity figures for the North American Malignant Hyperthermia Registry [38]and the EMHG. [40]For the North American Malignant Hyperthermia Registry CHCT, the sensitivity is 0.97 and specificity is 0.78. For the EMHG IVCT, the sensitivity is 0.99, and the specificity is 0.936.
Construction of Bayesian Models
Construction of a 2 x 2 contingency table using current estimates of sensitivities and specificities allowed the calculation of conditional probabilities associated with varying PTPs as the input variable. The positive predictive Value (PPV) is the calculated conditional probability of a true positive (TP), given a positive test result. The negative predictive value (NPV) is the conditional probability of a true negative (TN), given a negative test result. The PPV and NPV are calculated values that depend on fixed sensitivity and specificity and variable PTP. The efficiency of testing is calculated as the proportion of correctly assigned results (TP + TN) over all results, including false-positive (FP) and false-negative (FN) results (Table 2).
In the EMHG "clinical" IVCT, MHE results in the same treatment as MHS: Where a more "specific" IVCT result is required, such as for genetic linkage studies, MHE results are considered nondiagnostic. Accordingly, a 3 x 2 contingency table was constructed to model the "specific" IVCT. Equivocal predictive value is the calculated conditional probability of MH given an MHE result. In this case, efficiency is calculated as the proportion of correctly assigned results (TP + TN) over all results, which now also include equivocal positive (EP) and equivocal negative (EN) results (Table 3). The MHE rate was 0.14 in probands, and 0.05 in control patients. [35,40]
All contingency tables were coded with computer spreadsheet software (Borland's Quattro Pro 5; Microsoft's [Redmond, WA] Excel, v. 7.0) and modeled with PTP values from 0 to 1. Selected values were checked by manual calculation. Results were plotted using Origin 3.73 (MicroCal, Northampton, MA).
(Figure 1) illustrates the effect of PTP on PPV, NPV, and efficiency of diagnostic contracture testing for MH. In all cases, for PTPs between 0 and 0.75, NPV remains near 1.00. A high NPV is required clinically so that the risk of a false-negative result is acceptably low. The PPV is a measure of the degree of certainty that can be associated with a positive test result. It is a function of PTP and specificity. When PPV is low, such as at low PTPs, a positive result is likely to be falsely positive.
In the case of the EMHG, the "specific" interpretation of the IVCT produces a higher PPV and NPV (Figure 1(B)). The graph of equivocal predictive value against PTP is close to the diagonal, confirming that MHE alone is a poor predictor of MH. The MHE classification implies that the likelihood of MH is unchanged by the test and remains at the PTP. The increased proportion of MHE patients who are left undiagnosed contributes to a reduction in efficiency by nearly 0.2 at high PTPs.
Statistical Imprecision in Estimating Sensitivity and Specificity
The PPV is likely to be affected by any imprecision, expressed as the 95% confidence interval, in estimating specificity (Table 1). However, even a major change in specificity from 0.82 to 0.92, within the 95% confidence, has a minor effect on the shape of the PPV curve, which retains an elbow at PTP between 0.125 and 0.25 (Figure 2), whereas NPV and efficiency are relatively unaffected. Conclusions about PPV are likely to be reliable for all PTPs.
In contrast, imprecision in estimating sensitivity has a profound effect on NPV at high PTP. When sensitivity is near 1, the NPV of the test will remain high at all PTPs (Figure 1(B)). However, as little as a 0.01 to 0.03 change in the estimate of sensitivity results in a dramatic change at high PTP from a nearly straight line (Figure 1(B)) to a curve (Figure 2(B)), which is similar to the NPV curve for the CHCT (Figure 1(A)), with little change in PPV and efficiency. Conclusions about NPV at high PTPs should account for the decrease in NPV.
The Bayesian model, used in this analysis, does not depend on the mechanism of the test procedure or the disease and can be applied where there is a discrete outcome (e.g., health and disease). There is no assumption about probability distributions, so the model is still valid if MH diagnostic tests do not have a bimodal frequency distribution [45]and even if strongly positive results occur in healthy persons for any reason unrelated to MH.
An alternative approach, using pre-test odds and likelihood ratios, although more cumbersome, is also possible. It is less suitable, however, because contracture test results are reported as discrete outcomes (MHS and healthy) rather than as ranks of likelihood (e.g., a scale of 1 to 10). Because all current clinical testing protocols report discrete outcomes, Bayesian modeling is appropriate.
Sensitivity and specificity refer to the ability of diagnostic testing to discriminate between healthy persons and patients at risk for life-threatening reactions to anesthesia. There was no attempt in this model to characterize discrimination for less typical reactions, such as isolated masseter muscle rigidity, sudden hyperkalemic cardiac arrest, or events not related to anesthesia.
Our model is valid as long as estimates of sensitivity and specificity are accurate. Values from the North American Malignant Hyperthermia Registry and the EMHG (Table 1) indicate general agreement for sensitivity and specificity. In the event that more accurate estimates of sensitivity and specificity become available in the future, the models can be recalculated.
Any bias during measurement of sensitivity, such as unintentional selection or incomplete case finding would affect NPV at high PTPs. A potential source of bias lies in the selection of patients for study based on diagnostic test results. Strict inclusion and exclusion criteria that do not depend on diagnostic test results should be satisfied to avoid over or underestimates based on unintentional bias.
Clinical history was used to define control and proband groups for estimating sensitivity and specificity. [38,40]The validity of CGS, as applied to probands, relies heavily on laboratory measurements made during the management of an anesthetic reaction. It is considered valid because only those patients tested since current protocols were established can be included for analysis, and only those patients with severe reactions were included in the proband group.
The model can regard MH as a single disorder or as a group of disorders that share the features of a life-threatening anesthetic reaction, identifiable by the CGS and by contracture testing. Acute MH can progress so rapidly that any delay in treatment can result in severe morbidity and death despite valiant measures. [2]Aborting a reaction early with dantrolene treatment is lifesaving and also the standard of care. To determine whether MH might demonstrate a spectrum of severity if left untreated is highly unethical. For practical purposes, human MH is an all-or-none phenomenon.
Estimating Pretest Probability for Probands
Referral of patients for contracture testing occurs after they have survived an anesthetic reaction that suggests MH. After exclusion of differential diagnoses such as sepsis, thyroid storm, and pheochromocytoma, features of the anesthetic reaction may be reviewed and recognized as typical of MH (e.g., generalized rigidity, fever, family history, elevated creatine kinase) or atypical (e.g., lack of metabolic acidosis or absence of myoglobinuria). On this basis, a clinician can assign low, medium, and high PTP status of MH in a proband. This subjective process is a clinical skill. However, a similar process is used in the coding for the CGS. Therefore, we propose that the CGS can also be used as a guide to PTP assessment for probands, provided that the information used to score the CGS is complete and accurate.
The CGS was constructed so that D1 indicates a low likelihood that MH occurred (PTP close to 0), and D6 indicates that MH almost certainly occurred (PTP close to 1). [41]D3 and D4 fall on either side of 50% probability (MG Larach, verbal communication, October 1997) and represent medium PTP. Therefore, the CGS can guide estimation of PTP to within a range that is helpful for calculating PPV and NPV.
Separate conclusions can be drawn for conditions of low, medium and high PTP. Provided that sufficient data were collected to allow accurate CGS grading, patients with CGS D1 or D2 will have low PTP, between 0 and 0.25. An example of an anesthetic event ranking CGS D2 is unexplained sinus tachycardia in the absence of electrolyte abnormalities, muscle breakdown, hypercapnia, acidosis, or fever.
For low PTP patients, a negative test result would effectively rule out MH, since NPV approaches 1.00. The PPV, however, is only 0.50 or lower, so a false-positive result becomes as likely as, or more likely than, a true-positive result. Although a negative result would be useful, there would be no simple way to distinguish true positive results from false-positive results. Deciding whether to test remains a clinical decision that can only be determined in each individual case.
When a patient is referred for consultation after D3, D4, or D5 reactions, there is medium PTP, resulting in PPV in the range of 0.70–0.95, and NPV approaching 1.00. This is the situation in which the risk of observing a false-negative result is low, with an acceptable false-positive risk. Thus test results are useful, and testing is clinically indicated. Such a situation would occur, for instance, in a case of isolated masseter muscle rigidity (CGS D3).
Patients with CGS D6 will have high PTP. An example of a D6 reaction is an anesthetic event with generalized muscle rigidity, muscle breakdown with a creatine kinase level > 20,000 U/l and myoglobinuria, inappropriately elevated end-tidal carbon dioxide, sinus tachycardia, rapid inappropriate increase in body temperature, severe metabolic acidosis, and rapid reversal of respiratory and metabolic acidosis with dantrolene. Based on the CGS, such an episode is "almost certainly MH."
A positive test result in the setting of high PTP produces a high PPV but does not alter clinical management. In addition, in cases of high PTP (> 0.85), NPV decreases to < 0.80 for the CHCT (Figure 1), so the risk that a negative result is false increases to 0.20 or more. Similar behavior can be seen within the 95% confidence interval for sensitivity of the EMHG IVCT at high PTPs (Figure 2(B)). For these patients, a negative test result cannot rule out MH with acceptable certainty, defeating the clinical use of contracture testing. They should be offered contracture testing only to provide useful data about sensitivity.
Testing Strategy Optimizes Pretest Probabilities for Relatives
Based on the assumption that MH is inherited as an autosomal dominant trait, [7,11–18,20,21]PTP is a function of the degree of certainty of MH in the proband and the degree of kinship to the closest related proband. Unless a relative has other clinical features (such as having suffered an anesthetic reaction suggestive of MH, elevated resting creatine kinase level, identical siblings, or consanguinity), PTP is fixed at a ratio of 0.5 for first-degree relatives, 0.25 for second-degree relatives, 0.125 for third-degree relatives, and so on. Any uncertainty in the diagnosis of MH in the proband, as indicated by the PPV for the proband, reduces the PTP for the relatives of that proband proportionately.
A Markov chain, a mathematical method of calculating dependent probabilities, [46]was constructed (described subsequently) to model the effect of different pedigree testing strategies. The calculations in the text below apply to the North American Malignant Hyperthermia Registry CHCT (Figure 3(A and B)), and calculations for the EMHG IVCT are depicted in Figure 3(C and D). The same conclusions were obtained for the two tests. For illustrative purposes, proband PTP is set at 1.
A "haphazard" testing strategy describes the situation in which a patient is tested without having first tested the intermediary relatives, leaving gaps in phenotyping of the pedigree (Figure 3(A and C)). For each patient, PTP must be assigned only on the basis of the degree of kinship to the proband. For first-, second-, and third-degree relatives, PTP is sufficiently high that PPV and NPV are informative. For more distant relatives, however, the PPV decreases to < 0.5 for the CHCT and the IVCT, although the NPV is high. A PPV of 0.5 indicates moderate risk of MH, and it is sufficiently high that triggering drugs should be avoided during anesthesia. However, the high likelihood of observing a false-positive reaction poses a significant problem for genetic linkage studies.
An alternative to the "haphazard" strategy would be to test close relatives of the proband first and then to offer testing to the nearest relatives of a person who tested positive. Our model confirms that such a "sequential" testing strategy can optimize the information that can be gained from contracture testing (Figure 3(B and D)) and that it does so by optimizing PTP.
For first-degree relatives of a proband, PTP is 0.5, producing a PPV of 0.82. First-degree relatives have a PTP of one half of 0.82; i.e., 0.41 (Figure 3(B)). If the initial first-degree relative had not been tested (as in the case of a "haphazard" testing strategy), the PTP for the second-degree relative would be only 0.25, with a PPV of only 0.60 (Figure 3(A)). By comparison, "sequential" testing of this second-degree relative results in a higher PPV of 0.75 (Figure 3(B)). This effect is even more pronounced for more distant relatives.
The sequential testing strategy maximizes PTPs, producing the best-case performance for PPV, whereas a haphazard strategy uses PTPs based solely on degree of kinship, resulting in worst-case performance. These represent the upper and lower limits of diagnostic performance. Diagnostic accuracy for real pedigrees will fall somewhere between these two limits because some relatives are dead, have refused testing, or have yet to be tested.
The Positive Predictive Value Drift Effect
Even if the sequential testing strategy could be used to trace a pedigree to completion, there is an inevitable downward drift of PPV as the relationship to the pro-band becomes weaker (Figure 3(B)) because PTP depends on the PPV of the nearest tested relative. Although PPV drifts to a value that is sufficiently high (about 0.7 for CHCT, and 0.9 for IVCT) to warrant avoidance of MH-triggering drugs, the drift may pose a considerable problem for linkage studies, especially in large pedigrees with many distant relatives.
Positive predictive values drift even assuming an optimal testing strategy, absolute certainty of proband diagnosis, and near-perfect sensitivity, as in the IVCT (Figure 3(D)). The PPV drift effect is exaggerated under suboptimal conditions and should be recognized as an important cause of uncertainty in phenotyping pedigrees for linkage studies.
European Malignant Hyperthermia Group "Specific" IVCT
A Markov chain also can be constructed for the alternative "specific" interpretation of the EMHG IVCT, in which the MHE classification is ignored. In Figure 1(C), the graph of the predictive value of an MHE result (shown as EPV) has a slope close to 1. After an MHE result, the likelihood of disease has not changed significantly from PTP, confirming that MHE is truly nondiagnostic.
The NPV for the "specific" IVCT is similar to the clinical protocols (Figure 1(A and B)), but there is higher PPV than the clinical protocols for all PTP (Figure 1(C)), thereby producing more certain phenotypic information for genetic linkage studies. However, the price paid for this is lower efficiency because a nondiagnostic MHE is likely to be observed, especially at moderate-to-high PTP (Figure 1(C)). If a MHE results, the PTP remains unchanged, just as if testing had not occurred. When using the "specific" IVCT, any MHE patients leave a gap in phenotyping a pedigree, producing dips and drift in PPV (Figure 3(F)).
Testing Strategy for Parents of a Child Suspected to Have Malignant Hyperthermia
There is difficulty in interpreting test results for parents of a child suspected to have MH, [47]particularly when causal genes might originate from both parents (MHS x MHS). We examined a hypothetical family using calculations from Bayesian modeling. In determining whether two different genes from two parents are causal for MH in a family, hypotheses can be stated as, "Only one gene from one parent is causal of MH in this family" or "Two genes from two parents are causal of MH in this family."
The calculations that follow assume autosomal dominant inheritance, [7,11–18,20,21]that one and only one parent is MHS, and that there is no dispute about paternity or maternity. The PTP for a parent is set at 0.5. Even under such conditions, we show that it is not possible to use CHCT or IVCT to distinguish between MHS x MHS and MHS x MHN.
When one parent of an MHS patient has a positive contracture test and the other parent is untested, the probability that the result is a true positive is given by PPV, which is 0.94 for the IVCT and 0.82 for the CHCT (Figure 1). The remaining probability is accounted for entirely by false-positive results (Figure 4(A)). Thus, the probability of a false-positive result is calculated as 1 - PPV, which is 0.06 for the IVCT and 0.18 for the CHCT (Table 4). A false-positive result implies that the tested parent was healthy, so the untested parent must be MHS. The automatic assumption that the untested parent is negative will be wrong with this same probability (0.06 IVCT, 0.18 CHCT). "Incomplete" testing, therefore, poses an unacceptable risk of incorrectly identifying the untested half of the pedigree in 1 in every 6–16 such families (Table 4). Further, if these incompletely tested pedigrees were subjected to genetic analysis, the risk of genotype-phenotype discordance is high as a result of misclassification. [47]
If the second parent is tested (Figure 4(B)), the risk of a false-negative diagnosis for that parent is calculated as (1 - PPV)(1 - sensitivity), which is 0.0006 for the IVCT and 0.0054 for the CHCT (Table 4). Based on this, a complete testing strategy, in which testing is offered to both parents, is far safer clinically than an incomplete strategy (Table 4).
Given the condition that one and only one parent is MHS, the probability that both parents will test positive by chance alone is calculated as sensitivity x (1 - specificity), or 0.063 for IVCT and 0.21 for CHCT (see Table 4). This probability, 1 in every 5–15 such families so tested, is sufficiently high to account for reported cases of apparent MHS x MHS without having to invoke the possibility that both parents are MHS, a spontaneous mutation rate, alternate modes of inheritance, or the existence of alternate genetic loci for MHS. [47]
There is no simple way to determine whether both parents are truly MHS or whether only one parent is MHS and the other has a false-positive diagnosis. This does not pose any significant clinical problem, because in either case, both sides of the family are treated clinically as though they are MHS. This can be modified in the face of other clinical evidence, such as anesthetic reaction in one branch of the pedigree or a biopsy result from an identical sibling. However, subjecting families to genetic linkage studies in which both parents test positive holds little prospect for finding correct linkages.
When one parent of an MHS patient has a negative contracture test result and the result for the other parent is unknown, the certainty of the negative diagnosis is equal to NPV. This value is 0.99 for the IVCT and 0.96 for the CHCT. If this result is a true negative one, then the untested parent must be positive, with the same degree of certainty. This value (0.99 IVCT, 0.96 CHCT) is the PTP for the untested parent. In this case, as in the case for high PTP probands, if testing is performed, PPV is unchanged, and NPV decreases to a dangerously low value.
Given our assumptions, testing the second parent provides little extra clinical information and exposes the parent to an unacceptable risk of a false-negative result. A "rational" testing strategy implies that the partner of a negative parent should not be tested, a conclusion that may appear to be counterintuitive. This conclusion may not apply if the assumptions are violated, such as nonpaternity or nonmaternity, spontaneous MH mutation, or alternate genetic modes of inheritance.
Spectrum Bias
The estimates of sensitivity and specificity used in our Bayesian model were made by examining diagnostic test performance in two populations, one with "severe" MH (D6 probands) and the other with an extremely low prevalence of MHS (control patients). Using such extreme populations, "the sickest of the sick" and the "wellest of the well," may overestimate sensitivity and specificity for populations with intermediate prevalence of MHS. This effect is called "spectrum bias."[26]If MHS is truly unequivocal, then spectrum bias may be minimal. If contracture testing for MHS shows a graded spectrum of responses, [48–50]then sensitivity and specificity will be lower in a population with intermediate prevalence than in the extreme populations.
In the absence of an independent "gold-standard" for MHS, there is no simple way to verify true sensitivity and specificity. Any spectrum bias, however, would result in lower PPV and NPV values, but unless true sensitivity and specificity are known, it is not possible to estimate the magnitude of this effect. Even given the highest possible estimates of sensitivity and specificity, limitations in PPV and NPV are inevitable so long as sensitivity and specificity are not both 1.0. By recognizing these limitations, it is possible to make effective use of diagnostic testing information for clinical and research purposes.
The use of Bayesian modeling based on the estimated sensitivity and specificity of diagnostic contracture testing for MH can allow an understanding of the strengths and limitations of muscle biopsy contracture testing. Bayesian modeling of PTP, PPV, NPV, and efficiency can aid in deciding whom to test, when to test, and how best to interpret the test result, both for clinicians and for researchers.
A clinician relies on the excellent NPV, which accounts for the clinical utility of this test. For any person other than a D6 proband, a negative contracture test effectively rules out MH for them and their descendants. To achieve this, there is an acceptably low false-positive rate, measured by high, but imperfect, PPV. In the absence of a better alternative, contracture testing is a useful clinical tool when properly applied with sequential and complete testing strategies.
For genetic analysis, a much higher PPV is required to be certain that a person who had a positive test result is truly MHS. One approach is to alter the test to achieve higher specificity. This is the EMHG "specific" IVCT interpretation. However, the PTP for a relative is fixed by distance in kinship, especially when there are gaps or MHE diagnoses in the pedigree. Even with a highly specific test, an optimal testing strategy, certain proband identification, and perfect sensitivity, a downward drift in PPV is unavoidable.
A more accurate approach is to accept the limitations of contracture testing and to work within them. Previous linkage models have been used to find association with a positive contracture test result, which has a small, but quantifiable, inherent error in predicting MHS. An alternate linkage model that incorporates the estimated errors in phenotyping contained in this article would be less prone to identifying discordance where discordance does not exist.
The current estimate that only 50% of MH families [20]are linked to chromosome 19q13.1 is almost certainly a large underestimate, once allowance is made for phenotypic uncertainty. The frequent finding of about one discordant individual for each six to eight subjected to the CHCT or IVCT [18,21,51,52]would be expected from the modeling presented here. Where such discordance is observed, it is possible that the linkage exists, but it is obscured by phenotypic uncertainty.
The authors thank Drs. M. Larach, G. Allen, and H. Ording for sharing their data on sensitivity and specificity of the CHCT and IVCT as they developed the model, and for their critical reading of the manuscript. The authors also thank Dr. B. A. Britt for her insight into malignant hyperthermia and Dr. A. Logan for his assistance in clinical epidemiology.
Denborough M, Lovell R: Anaesthetic deaths in a family. Lancet 1960; 2:45.
Britt B: Malignant hyperthermia: A review, Thermoregulation: Pathology Pharmacology and Therapy. Edited by E Schonbaum, P Lomax. New York, Pergamon Press, 1991, pp 179-292.
Kalow W, Britt B, Terreau M: Metabolic error of muscle metabolism after recovery from malignant hyperthermia. Lancet 1970; 2:895-8.
Ellis F, Keaney N, Harriman D, Sumner D, Kyei-Mensah K, Tyrrell J, Hargreaves J, Parkh R, Mulrooney P: Screening for malignant hyperthermia. BMJ 1972; 3:559-61.
Larach M, for The North American Malignant Hyperthermia Registry: Standardization of the caffeine halothane muscle contracture test. Anesth Analg 1989; 69:511-5.
European MH Group: A protocol for the investigation of malignant hyperthermia (MH) susceptibility. Br J Anaesth 1984; 56:1267-9.
MacLennan D, Duff C, Zorzato F, Fujii J, Phillips M, Korneluk R, Frodis W, Britt B, Worton R: Ryanodine receptor gene is a candidate for disposition to malignant hyperthermia. Nature 1990; 343:559-61.
McCarthy T, Healy J, Heffron J, Lehane M, Duefel M, Lehmann-Horn F, Faralli M, Johnson K: Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2. Nature 1990; 343:562-4.
Fujii J, Otsu K, Zorzato F, deLeon S, Khanna V, Weiler J, O'Brien P, MacLennan D: Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 1991; 253:448-51.
Otsu K, Khanna V, Archibald A, MacLennan D: Co-segregation of porcine malignant hyperthermia and a probable causal mutation in the skeletal muscle ryanodine receptor gene in backcross families. Genomics 1991; 11:744-50.
Gillard E, Otsu K, Fujii J, Khanna V, deLeon S, Derdemezi J, Britt B, Duff C, Worton R, MacLennan D: A substitution of cysteine for arginine-614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 1992; 11:751-5.
Gillard E, Otsu K, Fujii J, Duff C, deleon S, Khanna V, Britt B, Worton R, MacLennan D: Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia. Genomics 1992; 13:1247-54.
Quane K, Healy J, Keating K, Manning B, Couch F, Palmucci F, Doriguzzi C, Fagerlund T, Berg K, Ording H, Bendixen D, Mortier W, Linz U, Muller C, McCarthy T: Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 1993; 5:51-5.
Zhang Y, Chen H, Khanna V, deleon S, Phillips M, Schappert K, Britt B, Brownell A, MacLennan D: Identification of a mutation in human ryanodine receptor associated with central core disease. Nat Genet 1993; 5:61-5.
Quane K, Keating K, Healy J, Manning B, Krivosic-Horber R, Krivosic I, Monnier N, Lunardi J, McCarthy T: Mutation screening of the RYR1 gene in malignant hyperthermia: Detection of a novel Tyr to Ser mutation in a pedigree associated with central cores. Genomics 1994; 23:236.
Quane K, Keating K, Manning B, Healy J, Monsieurs K, Heffron J, Lehane M, Heytens L, Krivosic-Horber R, Adnet P, Ellis F, Monnier N, Lunardi J, McCarthy T: Detection of a novel common mutation in the ryanodine receptor gene in malignant hyperthermia: Implications for diagnosis and heterogeneity studies. Hum Mol Genet 1994; 3:471.
Keating KE, Quane KA, Manning BM, Lehane M, Hartung E, Censier K, Urwyler A, Klausnitzer M, Muller CR, Heffron JJ, McCarthy TV: Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees. Human Molecular Genetics 1994; 3:1855-8.
Phillips MS, Khanna VK, De Leon S, Frodis W, Britt BA, MacLennan DH: The substitution of Arg for Gly2433 in the human skeletal muscle ryanodine receptor is associated with malignant hyperthermia. Human Molecular Genetics 1994; 3:2181-6.
Lynch PJ, Krivosic-Horber R, Reyford H, Monnier N, Quane K, Adnet P, Haudecoeur G, Krivosic I, McCarthy T, Lunardi J: Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred. Anesthesiology 1997; 86:620-6.
Ball SP, Johnson KJ: The genetics of malignant hyperthermia. J Med Genet 1993; 30:89-93.
MacLennan DH: Discordance between phenotype and genotype in malignant hyperthermia. Curr Opin Neurol 1995; 8:397-401.
Sudbrak R, Procaccio V, Klausnitzer M, Curran JL, Monsieurs K, van Broeckhoven C, Ellis R, Heyetens L, Hartung EJ, Kozak-Ribbens G, Heilinger D, Weissenbach J, Lehman-Horn F, Mueller CR, Deufel T, Stewart AD, Lunardi J: Mapping of a further malignant hyperthermia susceptibility locus to chromosome 3q13.1. Am J Human Genet 1995; 56:684-91.
Monnier N, Procaccio V, Stieglitz P, Lunardi J: Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Human Genet 1997; 60:1316-25.
Robinson RL, Monnier N, Wolz W, Jung M, Reis A, Nuernberg G, Curran JL, Monsieurs K, Stieglitz P, Heytens L, Fricker R, van Broeckhoven C, Deufel T, Hopkins PM, Lunardi J, Mueller CR: A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. Human Molecular Genetics 1997; 6:953-61.
Dawson-Saunders B, Trapp R: Basic and Clinical Biostatistics. Norwalk, Connecticut, Prentice Hall, 1990.
Sox HJ, Blatt M, Higgins M, Marton K: Medical Decision Making. Newton, MA, Butterworth-Heinemann, 1988.
Weinstein M, Fineberg H: Clinical Decision Analysis. Toronto, Canada, WB Saunders, 1980.
Isaacs H, Badenhorst M: False-negative results with muscle caffeine halothane contracture testing for malignant hyperthermia. Anesthesiology 1993; 79:5-9.
Islander G, Ranklev-Twetman E: Evaluation of anaesthesias in malignant hyperthermia negative patients. Acta Anesthesiol Scand 1995; 39:819-21.
Britt B: The North American protocol for the caffeine halothane contracture test in the diagnosis of malignant hyperthermia, Malignant Hyperthermia-A Genetic Membrane Disease. Edited by S Ohnishi, T Ohnishi. Boca Raton, FL, CRC Press, 1994, pp 171-98.
Halsall PJ, Cain PA, Ellis FR: Retrospective analysis of anaesthetics received by patients before susceptibility to malignant hyperpyrexia was recognized. Br J Anaesth 1979; 51:949-54.
Allen GC, Rosenberg H, Fletcher JE: Safety of general anesthesia in patients previously tested negative for malignant hyperthermia susceptibility. Anesthesiology 1990; 72:619-22.
Larach MG: Should we use muscle biopsy to diagnose malignant hyperthermia susceptibility? Anesthesiology 1993; 79:1-4.
Wedel DJ, Nelson TE: Malignant hyperthermia-diagnostic dilemma: False-negative contracture responses with halothane and caffeine alone. Anesth Analg 1994; 78:787-92.
Ording H: Investigation of malignant hyperthermia susceptibility in Denmark. Dan Med Bull 1996; 43:111-25.
Bendixen D, Skovgaard LT, Ording H: Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test. Acta Anesthesiol Scand 1997; 41:480-4.
Larach MG, Landis JR, Bunn JS, Diaz M: Prediction of malignant hyperthermia susceptibility in low-risk subjects. An epidemiologic investigation of caffeine halothane contracture responses. The North American Malignant Hyperthermia Registry. Anesthesiology 1992; 76:16-27.
Allen GC, Larach MG, Kunselman AR: The sensitivity and specificity of the caffeine halothane contracture test: A report form the North American Malignant Hyperthermia Registry. Anesthesiology 1997 (In press).
Ording H: Diagnosis of susceptibility to malignant hyperthermia in man. Br J Anaesth 1988; 60:287-302.
Ording H, for the European Malignant Hyperthermia Group: In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH group: Results of testing patients surviving fulminant MH and unrelated low-risk subjects. Acta Anesthesiol Scand 1997; 41:955-66.
Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H, Rosenberg H, Waud BE, Wedel DJ: A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771-9.
Hopkins PM, Ellis FR, Halsall PJ, Stewart AD: An analysis of the predictive probability of the in vitro contracture test for determining susceptibility to malignant hyperthermia. Anesth Analg 1997; 84:648-56.
von Richthofen V, Wappler F, Scholz J, Fiege M, Kochling A: Prediction of malignant hyperthermia susceptibility with the clinical grading scale. Anesthesiology 1997; 87:A997.
Fricker R, Knolle E, Kress HG: Clinical grading (CG) in the diagnosis of malignant hyperthermia (MH). Anesthesiology 1997; 87:A1000.
Kalow W, Sharer S, Britt B: Pharmacogenetics of caffeine and caffeine-halothane contractures in biopsies of human skeletal muscle. Pharmacogenetics 1991; 1:126-35.
Peng F, Hall WJ: Bayesian analysis of ROC curves using Markovchain Monte Carlo methods. Med Decis Making 1996; 16:404-11.
Islander G, Bendixen D, Ranklev-Twetman E, Ording H: Results of in vitro contracture testing of both parents of malignant hyperthermia susceptible probands. Acta Anesthesiol Scand 1996; 40:579-84.
Ellis FR, Halsall PJ, Christian AS: Clinical presentation of suspected malignant hyperthermia during anaesthesia in 402 probands. Anaesthesia 1990; 45:838-41.
Urwyler A, Censier K, Kaufmann MA, Drewe J: Genetic effects on the variability of the halothane and caffeine muscle contracture tests. Anesthesiology 1994; 80:1287-95.
Nelson TE, Flewellen EH, Gloyna DF: Spectrum of susceptibility to malignant hyperthermia-diagnostic dilemma. Anesth Analg 1983; 62:545-52.
Deufel T, Sudbrak R, Feist Y, Rubsam B, Du Chesne I, Schafer KL, Roewer N, Grimm T, Lehmann-Horn F, Hartung EJ, Muller CR: Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. Am J Human Genet 1995; 56:1334-42.
Serfas KD, Bose D, Patel L, Wrogemann K, Phillips MS, MacLennan DH, Greenberg CR: Comparison of the segregation of the RYR1 C1840T mutation with segregation of the caffeine/halothane contracture test results for malignant hyperthermia susceptibility in a large Manitoba Mennonite family. Anesthesiology 1996; 84:322-9.
supplementalmaterial
Figure 1. Effect of pretest probability (PTP) on positive predictive value (PPV), negative predictive value (NPV), and efficiency of diagnostic muscle biopsy contracture testing for malignant hyperthermia (MH) susceptibility. Separate graphs are shown for (A) the North American Malignant Hyperthermia Registry (NAMHR) Caffeine-Halothane Contracture Test (CHCT), (B) the European MH Group (EMHG) in vitro contracture test (IVCT), and (C) the alternative "specific" interpretation of the EMHG IVCT in which MHE is considered nondiagnostic. The graph of equivocal predictive value (EPV) shows that MHE alone is not a good diagnostic indicator.
Figure 2. (A) The effect of statistical inaccuracy in estimating specificity over a fractional range of 0.892–0.965, representing the 95% confidence interval for the European MH Group (EMHG) in vitro contracture test (IVCT). Positive predictive value is affected slightly but retains an elbow near the pretest probability (PTP) of 0.125–0.25. (B) Inaccuracy, within the 95% confidence interval for IVCT, in estimating sensitivity has a profound effect on negative predictive value (NPV) at high PTPs. A sharp elbow exists at PTPs near 0.8, with NPV decreasing at high PTPs.
Figure 3. Effect of testing strategy on pretest probability (PTP), positive predictive value (PPV), and negative predictive value (NPV) for the North American Malignant Hyperthermia Registry (NAMHR) caffeine-halothan contracture test (CHCT; sensitivity = 0.97, specificity = 0.78), the European MH Group (EMHG) in vitro contracture test (IVCT; sensitivity = 0.99, specificity = 0.936), and the EMHG "specific" IVCT (true positive = 0.825, false negative = 0; false positive = 0.025, true negative = 0.87). The "haphazard" testing strategy (A, C, E) uses a PTP equal to one half of the PTP from the previous generation, resulting in a dramatic decrease in PPV. In contrast, the "sequential" testing strategy (B, D) optimizes PTP based on the PPV of the previous generation and limits PPV drift to 0.73 for the CHCT, and 0.93 for the IVCT. In panels E and F, the proband PTP was set to 0.4, and a gap in the pedigree was produced when a person tests as malignant hyperthermia equivocal or has not been tested. A lower PTP must be assigned, based on the degree of kinship in this "mixed" testing strategy, producing a further decrease in PPVs. For patients other than the proband, NPV approaches 1.00.
Figure 4. A decision tree can be used to calculate conditional probabilities after a positive test result in one parent, assuming that a child is known to be suspectible to malignant hyperthermia (MHS) and that one and only one parent can be MHS. Probabilities of a branch are indicated by italics below the line. (A) Using the "incomplete" testing strategy, the untested parent is assumed to be negative. The probability that the first parent's result is a true positive (upper branch) is the positive predictive value (PPV; italics). The probability that it is a false positive (lower branch) is calculated as 1 - PPV. Therefore, the probability of error in the automatic assumption that the second parent is negative is calculated as 1 - PPV. (B) With a "complete" testing strategy, the second parent is also tested. If the first parent had a true-positive result (first upper branch), the second parent must be healthy under our assumptions. Therefore, the probability that diagnostic testing is negative is the specificity. The only other possible result is a false-positive one, which will occur with a probability of 1 - specificity. Returning to the root of the tree, if the first parent had a false-positive result, he or she must be, in reality, healthy (first lower branch). Therefore, under our assumptions, the second parent must be MHS, so a positive result for the second parent will occur with a probability of (sensitivity), and a false negative result with a probability of 1 - sensitivity. The chance of observing a false-negative result is calculated by multiplying the probabilities that the first parent will have a false-positive result (1 - PPV) by the probability of a false-negative result in the second parent (1 - sensitivity). Table 4shows important calculations.
Download All Figures
Table 1. Sensitivity and Specificity for Currently Used Diagnostic Protocols for Muscle Biopsy Contracture Testing. (95% Confidence Intervals)
Table 2. Bayesian Model of Contracture Testing for Diagnosis of MH, Using a 2 x 2 Contingency Table, Including an Example Calculation for PPV, NPV, and Efficiency Using Sensitivity = 0.97 and Specificity = 0.78, Which Are Fixed Properties of the NAMHR CHCT
Table 3. Bayesian Model of Alternative Interpretation of IVCT for Diagnosis of MH, Using a 3 x 2 Contingency Table
Table 4. Comparison of "Complete" and "Incomplete" Testing Strategies for the Parents of a Known MHS Patient
Pressure Support versus Spontaneous Ventilation during Anesthetic Emergence—Effect on Postoperative Atelectasis: A Randomized Controlled Trial
Negative Pressure Ventilation and Positive Pressure Ventilation Promote Comparable Levels of Ventilator-induced Diaphragmatic Dysfunction in Rats
Muscle Biopsy and In Vitro Contracture Test in Subjects with Idiopathic HyperCKemia
Comparison of the Segregation of the RYR1 C1840T Mutation with Segregation of the Caffeine/Halothane Contracture Test Results for Malignant Hyperthermia Susceptibility in a Large Manitoba Mennonite Family
Anesthesiology (February 1996)
Assessing and Comparing Anesthesiologists' Performance on Mandated Metrics Using a Bayesian Approach
Involvement of Cyclophilin D and Calcium in Isoflurane-induced Preconditioning
Anesthesiology (December 2015)


Completed in 2018, Carmen House captures the essence of the Ibizan country house effortlessly. Designed by Carles Faus Arquitectura the residence measures over 190m2 and features a series of open rooms, that are bathed in light, and show a clear connection to the landscape beyond. Located in the city of Dénia, in Valencia, Spain, purposed vistas are created throughout the spaces, to direct the view and create considered light throughout the rectilinear home. Designed to work with the sun, and the heat gains, the exterior canopies are designed to shield the interiors, while still being the opening portals to the exterior beyond.
Accessed from a side entry, a series of large openings and internal voids open between smaller and more functional spaces within. Encased in a white lime surface treatment, each of the white walls are treated in an almost organic fashion, to create a series of white massed volumes, punctuated by pockets of light. The particular detail given to the crispness of the forms is to be highly commended. The attention to every detail, the minimal lines in space that make up handrails, integrated storage elements, and considered functional elements; these are what make this a very clever and inviting recluse. Carmen House is a beautiful example of minimal gestures of both small and large proportions.