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Redwood City, CA Enter the Hub: where Account Management, Product Development, Marketing Strategies, HR Communications, Digital Content, and Client Engagement collide. This is Customer Success, and at GuideSpark, this is where it?s at. The name says it all?we?re all about making5/31/2016 Redwood City, CA Save This Job
at GuideSpark (View all jobs) Redwood City, CA Advocacy: You will grow and scale GuideSpark?s Customer Advocacy program, which includes identifying and cultivating customer advocates for internal and external requests for customers to participate in a variety of activities. We5/31/2016 Redwood City, CA Save This Job
Redwood City, CA As the Enterprise Product Marketing leader you will play a critical role in fueling the next stage of GuideSpark?s growth. We are one of the fastest growing companies serving over 600 customers including 20% of the Fortune 500 and more than 10 million5/31/2016 Redwood City, CA Save This Job
Redwood City, CA Role Description: We are looking for the ?Best of the Best? to help take us to the next level. The right candidate knows how to architect, design, and build cutting edge applications using leading edge javascript technologies such as React and Redux with5/31/2016 Redwood City, CA Save This Job
Location: Santa Clara, CA Qualifications: Experiences with system level design methodology, HLS or VP applications Experiences and knowledge of C++ and SystemC Knowledge of OSCI TLM-2.0 standard Experiences in model validation or RTL verification Job Functions: Communicate with5/31/2016 Santa Clara, CA Save This Job
Customer Success Campbell, California Description Position at 24/7 Customer Success: Technical Account Manager As a member of the 247 Team, the Technical Account Manager (TAM) is responsible for the ongoing success of 247 clients and partners who have launched applications5/31/2016 Campbell, CA Save This Job
Data Science and Analytics Campbell, California APPLY Description Position at 24/7 RESPONSIBILITIES Perform data collection for new application including designing data collection prompts. Gather client requirements via client facing meetings Manage transcriptions of the5/31/2016 Campbell, CA Save This Job
Data Science and Analytics Campbell, California APPLY Description Position at 24/7 RESPONSIBILITIES Understand design requirements Implement speech applications Implement tuning recommendations REQUIREMENTS Master's or Bachelor's Degree in relevant major (Computer Science,5/31/2016 Campbell, CA Save This Job
Marketing Campbell, California APPLY Description Position at 24/7 247 is redefining the way that companies interact with consumers. The company?s customer engagement platform assists several hundred million visitors across all channels, and engages in 1.5 billion conversations5/31/2016 Campbell, CA Save This Job
Sales Campbell, California APPLY Description Position at 24/7 247 is redefining the way that companies interact with consumers. The company?s customer engagement platform assists several hundred million visitors across all channels, and engages in 1.5 billion conversations5/31/2016 Campbell, CA Save This Job
Professional Services San Jose, California Apply Description -To learn about our company culture and what our employees have to say about their experience at Halogen, please check out #halogenlife and our company page on Glassdoor. --- Transactional HR practices are rapidly5/31/2016 San Jose, CA Save This Job
Responsibilities: Support engineering team to develop various light emitting diodes (LED) products in a R&D environment. Perform various aspects of LED packaging. Test LED performance. Support the design of different LED component. REQUIRED QUALIFICATIONS: AA in technical5/30/2016 San Jose, CA Save This Job
RESPONSIBILITIES: Providing assistance to engineers in the electrical/electronic aspect of Solid State Lighting product prototyping, hardware troubleshooting, firmware design, software validation, documentation and agency approval. REQUIRED QUALIFICATIONS: Bachelor5/30/2016 San Jose, CA Save This Job
RESPONSIBILITIES: Involvement in Solid State Lighting product development such as: Hardware integration Firmware design Software validation Documentation and certification Must be able to work in all phases of the design process, including prototype, test and5/30/2016 San Jose, CA Save This Job
RESPONSIBILITIES: Reliability qualification and quality control of LED products (components and modules) according to industrial standards for electronic, optical, and mechanical reliability Work with design, manufacturing, and application engineers to qualify LED5/30/2016 San Jose, CA Save This Job
Position: FAE (Santa Clara, California) Job Description 6WIND seeks a Field Application Engineer (FAE) to serve the company?s growing team in North America. Your mission will be to become a key and respected technical resource to the development organizations in major Networking5/30/2016 Santa Clara, CA Save This Job
Field Software Engineer (Santa Clara, California) Job Description 6WIND is looking for an engineer with developer level software experience to join the company?s growing team in North America. This is an essential role within our organization to support and grow our rapidly5/30/2016 Santa Clara, CA Save This Job
About the Position Based in San Mateo, CA and part of Bankrate.com?s network of websites, Caring.com is the leading online destination for people struggling with the day-to-day realities of caring for aging parents, spouses or other loved ones. We provide much needed5/30/2016 San Mateo, CA Save This Job
300 - Development - Mountain View, CA - Full Time POSITION SUMMARY: The Senior Software Engineer will design, develop, manage and deploy web application. ESSENTIAL DUTIES AND RESPONSIBILITIES: Determines operational feasibility by evaluating analysis, problem definition,5/30/2016 Mountain View, CA Save This Job
About the Position Verix, a leading global provider of business analytics solutions for the Life Science industry, is looking for a hands-on marketing manager to lead in the development and execution of field and online marketing activities that seek to expand demand generation5/30/2016 Los Altos, CA Save This Job


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Simple Definition of headache
: an ache or pain in the head
: a difficult or annoying situation or problem
Examples of headache in a sentence
I'm starting to get a headache.
The symptoms include fever and headache.
The city's biggest headache is traffic.
Managing your finances can be a real headache.
Before 12th Century
First Known Use of headache
before 12th century
Rhymes with headache
air brake, awake, backache, beefcake, beefsteak, betake, blacksnake, bull snake, canebrake, caretake, cheesecake, cheesesteak, clambake, club steak, corncrake, cube steak, cupcake, daybreak, disc brake, drum brake, earache, earthquake, fair shake, fast break, firebreak, firedrake, fish cake, flank steak, forsake, friedcake, fruitcake, green snake, grubstake, hand brake, handshake, heartache, heartbreak, hoecake, hotcake, housebreak, intake, jailbreak, keepsake, king snake, lapstrake, mandrake, milk snake, mistake, moonquake, muckrake, namesake, newsbreak, oatcake, oil cake, opaque, outbreak, outtake, Pan-Cake, pancake, partake, pound cake, pump fake, rat snake, remake, retake, rewake, rock brake, seaquake, sea snake, seedcake, sheldrake, shortcake, snowflake, sponge cake, Swiss steak, tea cake, toothache, unmake, uptake, wheat cake, windbreak, wind shake, youthquake
HEADACHE Defined for Kids
Definition of headache for Students
1 : pain in the head
2 : something that annoys or confuses <This traffic is a real headache.>
Medical Dictionary
Learn More about headache
Thesaurus: All synonyms and antonyms for headache Spanish Central: Translation of headache Nglish: Translation of headache for Spanish speakers Britannica English: Translation of headache for Arabic speakers Britannica.com: Encyclopedia article about headache
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subset: commoncrawl


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The Race Expo • July 29th and 30th, 2016
Join thousands of runners and race spectators at The San Francisco Marathon 2016 Race Expo and experience the best in running, health, and nutrition.
Location: Festival Pavilion at Fort Mason, 2 Marina Blvd, San Francisco, California 94123
Time: July 29 from 12PM – 7PM, and July 30 from 9AM – 5PM
Admission: Free to the public
Bib Pick-up: All race participants are required to pick up their bib, timing chip, and race shirt at the Race Expo. If a runner cannot attend the expo, a friend or family member may pick up the packet with a copy of the runner's photo ID and bib number confirmation email.


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Hats off to Robinson, TDOT
Published: Sunday, November 20, 2005 at 3:30 a.m.
Last Modified: Saturday, November 19, 2005 at 11:00 p.m.
Dear Editor: Some weeks ago several streets adjoining Rice Mine Road were resurfaced. Unfortunately many large clumps of solidified asphalt ended up in the gutters at the entrance to my subdivision.
I tried to remove these large pieces of asphalt but didnt have much luck.
I then called Mr. Joe Robinson of TDOT and explained the situation. Mr. Robinson called me the next morning and a crew from TDOT came and took care of the problem.
Our hats are off to Mr. Robinson and the dedicated city employees who work so hard to keep us looking like an All-American City." Thank you.
Dear Editor: Gasoline prices have dropped from their peak after Hurricane Katrina, giving us a reprieve from out-and-out panic, but not from the dread of what the future holds. When will we next be held hostage by the price of oil? It is not a question of if," only of when."
World politics aside, the reality is that oil is a non-renewable resource and it is shameful that we have not already weaned ourselves from our dependence on it. We Americans are historically independent and self-sufficient. We have every right to be angry about our current circumstances. The problem is not a lack of alternative energy sources. There are a number of proven technologies available. The problem is the failure of our elected leaders (strongly influenced by special-interest groups) to make development and implementation of these alternative energy sources a priority for this country.
In fact, the current administration seems perversely committed to dragging us further and further down Oil and Gas Road, apparently unable to read the numerous signs saying Dead End." The promotion of enormous investment in drilling in the Artic National Wildlife Refuge is a waste of time and money that would be more wisely spent on new energy sources. Are we experiencing the results of our vice-presidents secretive meetings on energy policy? If so, its no wonder he took extreme measures to hide the content of those meetings from the American people. This is not the responsible leadership this country needs.
Abigail L. Morgan
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Loss of Lives in Clinical Trials...
Clinical-Style Validation, Regulation, and Quality Control...
Capitol Hill Critics Second-Guess Agencies Using...
Keep the Opportunities, Lose the Opportunists
UCB has acquired a minority stake in Beryllium, a developer of treatments for severe diseases of the immune system or of the central nervous system. Neither the percentage stake, nor the value of that stake or other financial terms, was disclosed by Beryllium in announcing the transaction today.
Beryllium said UCB's minority stake is an outgrowth of a six-year-old collaboration between the companies that already had yielded "significant scientific breakthroughs" in developing undisclosed first-in-class small molecule drugs.
Beryllium CEO Johan Pontin, said in a statement his company's ongoing partnership with UCB was aimed at "helping translate the basic understanding of proteins involved in disease into important druggable targets to develop novel therapeutic modalities."
Added Ismail Kola, evp of UCB's New Medicines unit: "Beryllium's extensive target-centric drug discovery expertise, comprehensive disease pathways knowledge, deep experience in protein characterization and diverse technological capabilities have enabled UCB to progress rapidly on important discovery research projects," We look forward to strengthening our relationship with an agile, committed and reliable partner as Beryllium expands its business."
As part of the agreement between UCB and Beryllium, Neil Weir, UCB New Medicines' senior vice president for discovery research, has taken a seat on Beryllium's board of directors.
The UCB stake in Beryllium follows by a week Beryllium's May 12 disclosure that it finalized its consolidation of restructured assets from Emerald Bio and deCODE Genetics, and expanded its leadership team. Beryllium sold off a reagent business and robotics business, both of which it acquired from deCODE in 2009 when the company filed for bankruptcy. Emerald Bio was a spinout of Iceland-based deCODE, which was acquired in 2012 by Amgen for $415 million.
Beryllium named as its head of Dalia Cohen, Ph.D., a former CSO at Asterand and Rosetta Genomics who led the functional genomics team at Novartis for eight years. The company also named three vice presidents: Daniel Kemp, Ph.D., vp of drug discovery; Arturo Morales, Ph.D., vp of informatics; and Thomas Roddy, Ph.D., vp of drug discovery.
Founded in 2009, Beryllium maintains East Coast operations in Bedford, MA, and West Coast operations in Bainbridge Island, WA. Beryllium plans to expand operations this year, telling Mass High Tech it will add 25 Bedford-based employees to its total staff of about 60, and will triple the size of its 9,000-square-foot Bedford headquarters by October.
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MDMA (commonly known as the empathogen "ecstasy") is classified as a Schedule 1 drug, which is reserved for compounds with no accepted medical use and a high abuse potential. Two researchers from Stanford, however, call for a rigorous scientific exploration of MDMA's effects to identify precisely how the drug works, the data from which could be used to develop therapeutic compounds.Do you agree that ecstasy should be studied for its potential therapeutic benefits?
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text:
King enjoyed second stint as counselor at Manning camp
Published: Thursday, July 17, 2008 at 3:00 p.m.
Last Modified: Thursday, July 17, 2008 at 5:29 p.m.
THIBODAUX High profile NFL and college quarterbacks werent the only athletes putting on a show at the Manning Passing Academys Air It Out session on Saturday.
There were receivers catching the passes making the quarterbacks look good in front of fans in attendance. One of the wide receivers running routes and snagging balls was Tulane senior Brian King.
King was paired up with Georgia All-American quarterback Matt Stafford in the rotation and the two gave the 1,000 onlookers some special moments at John L. Guidry Stadium.
This is my second year (at the camp), and its been a lot of fun. You do a lot of things for and with the campers as well as the counselors, King said at the Manning Passing Academy media session. I have a lot of fun being out here with Peyton, Eli and Archie (Manning) and you meet a lot of people out here and make a lot of connections. That is the one thing I like about it.
Wowing crowds in Thibodaux with his receiving skills isnt anything new for King. As a senior at Slidell High School, King and his teammates put on an offensive show in a 2004 first-round playoff game against Thibodaux High.
Slidell, the 23rd seed, survived an offensive shootout to beat Thibodaux, the 10th seed, 43-33, which eventually propelled Slidell to the 5A semifinals.
King torched Thibodauxs secondary with 10 receptions for 143 yards and a touchdown.
That is a game I have good memories of and we were the underdog. Thibodaux was coming out of a tough district, and it was a great experience coming down here and playing in that atmosphere, King said. It was a real close game and high scoring, just the way we liked it. We ended up losing to Evangel in the semifinals, but I have a lot of great memories of that year.
King ended his senior season with Slidell with 90 receptions for 1,107 yards and 12 touchdowns. He parlayed his talent both on and off the field into a scholarship to Tulane.
In his first two season with the Green Wave, King had 31 receptions, but last season he finished with 30 catches for 446 yards and two touchdowns.
King said with a second year in coach Bob Toledos system, Tulane should improve on its 4-8 record in 2007.
We have a year under our belt, I think it will be a big difference. We know how things are going to run this year and we have a lot of things in place to be successful, King said.
Last season, Tulane rode the legs of running back Matt Forte, who became a second-round draft choice of the Chicago Bears in the 2008 NFL draft. Forte ran through Green Wave opponents for 2,127 yards and 23 touchdowns.
King said Tulanes offense should be effective but not as run-orientated.
I think we will be good. Of course, you are going to miss Forte a 2,000-yard rusher. That is hard to replace, King said. With the players we have coming back, we should be good. I think the overall attitude of the team and coaching staff is a big change. We want to get things done and that is exciting.
With his work concluded at the Manning Passing Academy, King can now focus on his final season in an Green Wave uniform.
However, King said that working in a camp such as the Manning Passing Academy is a satisfying feeling.
They get a lot of fundamentals and a lot of positive feedback, King said. We are out here teaching things they can use back home. (What I like) is the simple fact that I helped someone improved their game.
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Over the last month of the boys basketball season, the Washington Blue Jays have played 12 of their 19 games to date.
In their last two games, both GAC Central road contests against Ft. Zumwalt North and Ft. Zumwalt South, the tank may have been on empty.
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Email this article from PlasticsNews.com
Indiana molder Creative Liquid adding equipment
KENDALLVILLE, IND. (Nov. 29, 1:10 p.m. ET) — An Indiana injection molder is investing $1.4 million in new equipment and adding 12 jobs.
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text:
By Movement Ventures
Open iTunes to buy and download apps.
Featured by Mashable and LifeHacker, LittleBit helps you do one thing consistently until it's a habit. Most people try to change too much at once. They soon get overwhelmed and give up. By choosing one thing and doing a little bit each day, you will find that it's easy to create whatever habit you want! LittleBit was built to help you develop the habits you want, any habit.
--------- How It Works -----------
Choose something you want to do everyday, like:
- Go for a walk
- Study a particular book or language
- Read with the kids
- Floss your teeth
- Do 1 Jumping Jack
LittleBit will remind you to do it.
Everytime when you complete your daily habit, you will gain a "Bit" and capture the moment with a picture.
If you miss a day, one of your "Bits" will be in jeopardy.
If you miss two days in a row you will lose a "Bit" of progress.
Get 21 "Bits" to complete the habit and unlock a photo reel of your successes to share with your friends!
--------- Features -----------
- Focus yourself. Habits are difficult to get started. LittleBit helps by tackling one habit at a time.
- Don't beat yourself up if you miss a day. Success is based on overall consistency, not streaks, like other habit apps.
- Take a picture of your successes each day. Share them with friends.
- Set a custom reminder time.
- Hit the Snooze Button to give yourself another hour.
- Set a custom daily deadline time.
- Keep a library of success in your Habit History.
- Complete 21 Bits on your habit, and unlock your photo reel of awesomeness.
What's New in Version 1.0.2
Fixed a bug where tapping multiple times on a photo would freeze the app.
Photos now display correctly if taken in landscape orientation.
iPhone Screenshots
Customers Also Bought
- Category: Health & Fitness
- Updated: 12 January 2014
- Version: 1.0.2
- Size: 4.2 MB
- Language: English
- Developer: Movement Ventures, LLC
- © 2015 Movement Ventures, LLC
Compatibility: Requires iOS 6.1 or later. Compatible with iPhone, iPad, and iPod touch.


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The Poplars is set in Rumsam, Barnstaple giving guests the perfect balance of the town with its bustling pannier markets and the quiet leafy atmosphere of a more rural setting. A Bed & Breakfast where you can be spoilt and relax is ideal for both leisure or business travellers who will have the chance to unwind in the peaceful setting, enjoy a warm welcome with tea and cake and look forward to a delicious breakfast.
The Edwardian house is set in large mature gardens which enjoy easy access to the Tarka Trail making it an ideal stop over for cyclists and walkers. Guests have direct access to the garden through the breakfast room and are always welcome to take a stroll or to sit and take in the views of the majestic copper beech.
The Poplars is a much loved family home and we look forward to welcoming you to share our little slice of Devon with a comfortable setting, good food and a friendly atmosphere.


text:
Classic Apartment near City Center
Maximální počet hostů5
Počet místností1
Velikost70 m²
Floor No.2
- Vhodné pro rodiny s dětmi
- Internet/WiFi
- Kuchyně
- Pračka / sušička
- Televize
- Parkování k dispozici
- Uzamykatelný pokoj
- Ručníky
|Wohlersweg, 21079 Hamburg, Německo
|Typ nemovitosti
|Ident. objektu
|Acceptance rate
|Response time
|A few hours
|Calendar updated
|2 days ago
Inclusive of bedding and towels. Changes of the bedding 1 x per week, towels as required.
We build 1 to 2 guest couches at accommodation of 3 or 4 persons in the living room. When required a journey cot is available.
The surroundings are located very quietly in a living street with detached houses.
The next bus station is approx. 5 minutes remote, the next railroad station reached one in approx. 10 minutes. There are also numerous purchase possibilities. The suburban train drives every 5 or 10 minutes and needs for the Hamburger for 15 minutes central station.
Wished until approx. 11 o'clock on the departure day check-outly ( provided that following guests are registered.
Check into flexible. Provided that guests still are in the house, being able to pieces of baggage already be kept safe before as well as shower/toilet/being used in a seperaten washhouse outside the apartment.
Hamburg lifts up a tourism flat rate also at a private letting of guest rooms for every guest. This goes by the overnight stay price per guest.
Business travelers are excepted from the regulation.
Overnight stay price per guest tourism appraisal fee per day and guest
10. 01 to 25. 00 euros 0. 50 Euro
25. 01 to 50. 00 euros 1. 00 Euro
The tourism cab has to be paid in cash on the day of the journey.
It would be nice if the guest would have minimal knowledge of German, since the hosts speak any foreign languages.
|Weekly rate for up to 2 guests
|458 €
|Cena za více než 2 ubytované(ých)
|11 € Cena za osobu/noc navíc
|Maximální délka pobytu
|2 weeks
|Příjezd po
|Check-in before
|Odjezd před
|Stornovací podmínky
We rented Helga & Rainer's house in Hamburg... Perfect home, nice people.. Everything is available to meet our needs at home. Thank you for your hospitality.. We hope to see you again soon... Our home in Hamburg...
We felt very comfortable in the apartment, the owners are very kind, the apartment is very nice
This apartment is wonderful .We were very happy to stay here and the location is within walking distance of all amenities in harburg. The apartment itself was very generously proportioned and was beautifully maintained and presented in spotless condition. The family live next door so very easy in case of emergency or any questions . looking forward to our next stay. Angela
Thank you Helga,Rainer and Mirco for a lovely welcome and a nice stay. Was great. Best regards Susann
Die Wohnung ist sauber, komfortabel und komplett ausgestattet, wirklich alles vorhanden. Sehr nette und sympathische Vermieter.
Helga & Rainer sind sehr nette und sehr freundliche Gastgeber, die sich auch unkompliziert und bestens auf uns eingestellt haben. Immer wieder gerne.
Herzensgute Gastgeber, wunderschönes, ruhiges und sauberes Ferienhaus!
Wir kommen zu 100% wieder!
Vielen Dank für 4 schöne Tage Hamburg
- Ověřenou kvalitu ubytování
- Prověření každého hostitele
- Bezpečné platby prostřednictvím SSL šifrování


text:
Play Video
my babys new tattoo
Posted by cedarshaw on Jul. 23, 2007
Elizabeth Rage takes you through the steps to create the Enchantress look f...
On this episode, Master Chalk Artist Chris Carlson takes on an epic Star Tr...
Get you geek on and come check out these hilarious clips!
Posted by cedarshaw on Jul. 23, 2007


text: Back to: Other March 13, 2010 12:09 AM Saturday Boredom Busters Perry Groten reports: The day kicks off with the Painting of the Shamrock at 9th and Phillips at 11:30 this morning. Then the annual Saint Paddy's Day parade will make its way through downtown Sioux Falls starting at 2:00 pm. There will be a special fly over by the Vanguard Squadron. Everything will wrap up this evening when the Falls will go green after dark. The Sportsmen's show is going on today as well. Starting at 10:00 am at the Sioux Falls Convention Center. Tickets are $7 for adults, $2.50 for kids. There will be 200 exhibits. The Coors Bull Riding Classic is also happening at the Expo Building at the Sioux Empire Fairgrounds. Competition kicks off at 7:30 pm. Tickets are $18 for adults and $5 for kids. The Parker Volunteer Fire Department is hosting a fundraiser. Starting at 6:00 pm there will be a diner followed by bingo. It's happening at the Parker Community Building. Donations will help pay for equipment for the department. {{Title}} Remove Change News General Courts Web Only Crime Outdoors Events Center Non-Homepage Boredom Busters Pipeline Positively KELOLAND Technology Hunger Affordable Care Act Shops Flooding Remembering 9/11 Drought JazzFest Spring Storm Honor Flight Spencer Anniversary DoApp Health News Business News Sports Agriculture Markets Livestock Crops Politics HealthBeat Cancer Children's Health Heart Health Wellness & Nutrition General Health Beat Women's Health RX Resources What's Going Around OTC Diabetes Recalls Dental Health Men's Health Politics South Dakota Legislature Budget Congress Taxes General Local Campaign President US Senate New Laws US House Iowa Ballot Issues Local Races Minnesota Gubernatorial Education Funding College Elementary High School Pre K School Supplies Middle School Sports Professional College High School Sports Zone Headlines Summit League Tournament Olympics Business Industry Your Money Matters Development Gas & Energy Legislation Economy/Stocks Employment General Health Care Technology Education Funding Tourism Banking/Finance Housing Transportation Insurance Meetings & Events Retail & Restaurants All Industries On The Move Shops Agriculture Featured Stories Eye on KELOLAND Inside KELOLAND Weather Snow Forecast Records Rain Flooding Drought WX Corner General World News Investigates GEAR UP Sponsored Done {{Title}} [x] Add or, Select from existing Opening existing... Close existing Most popular communities Click to select: Show all200Communities Show only most popular Opening all... {{Title}} ({{ItemsCount}}) 2635 Views


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Garnethill Paperback – September 20, 2007
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Maureen O'Donnell, surely one of the most unlikely crime solvers in recent history, comes from a family so seriously dysfunctional that it deserves a television series of its own. Her mother is an overly dramatic alcoholic who "could scene-steal from an eclipse"; her brother Liam is a bumbling drug dealer; and the black sheep of the family is a sister who went to London and became a Thatcherite. The troubled but gutsy Maureen decides to dump her boyfriend, Douglas--an abusive (and married) psychologist she met while a patient at a sex-abuse clinic. After a night of drinking with a friend who's a social worker, Maureen wakes up to find that Douglas has been tied to a kitchen chair in her flat with his throat slashed. As someone with both a motive and a history of mental illness, Maureen is the most likely suspect--until a second, similar murder occurs that links the crimes to a local psychiatric hospital. Denise Mina, who has a background in health care, law, and criminology, is definitely a writer to watch. --Dick Adler --This text refers to an out of print or unavailable edition of this title.
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Copyright 1999 Reed Business Information, Inc. --This text refers to an out of print or unavailable edition of this title.
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Top Customer Reviews
Comparing Scottish crime writers with Ian Rankin may be a cliché, but what he and Mina both do well is to root their stories in place, bringing alive the corners and cultures of the cities which are their settings. Mina's characters travel across most parts of the city, and she recreates cafés, pubs, streets and tenement closes with an accuracy that Glasgow readers should appreciate and in which they will recognise many minor landmarks far from the tourist trail and the trendy shops and bars. And the humour (the book is tremendously funny in places), banter and psyche are very Glaswegian, dark and ironic. The excellent sense of suspense at the heart of the book is bolstered by engaging - if sometimes disturbed - characters and an intricate recreation of their Glasgow.
Who murdered Douglas and why? There seem to be plenty of people with sufficient motive, but who had the opportunity? This novel deals with the uncomfortable world of victims of sexual abuse and how they relate to a world which has already let them down. Given the setting, it is easy to understand how (and why) Maureen feels compelled to take control of the investigation herself where she can.
This novel won the 1998 John Creasy Memorial Award for best first crime novel. This will be an uncomfortable novel for some to read: Ms Mina has succeeded in creating characters whose experiences and responses to abuse are frighteningly realistic and common.
Highly recommended.
Jennifer Cameron-Smith
In "Granethill", Mina created a real world peopled by a mentally troubled but loveable heroine, Maureen O'Donnell, and her dysfunctional family and friends along with a host of other solid and believable characters. The novel's setting is Granethill, a bleak Glasgow neighborhood where a grisly murder has taken place and where the only person who can solve the case is Maureen.
After a night of heavy drinking with her best friend Leslie, a social worker, Maureen decides to break up with her therapist boyfriend Douglas Brady who she recently discovered is married. Her mind made up, she arrives home extremely drunk and goes straight to bed. The next morning when she is returning from the bathroom, a blood soaked raincoat catches her eye, she looks away from it down the hall to her living room. There is Douglas, tied to one of her kitchen chairs with his throat slashed.
The police, led by Chief Inspector Joe McEwan, first set their sights on Maureen, but later change their focus to her brother Liam, who although a supportive and loving elder brother, just happens to be a drug dealer. It is up to Maureen to solve the case and take the police's attention away from Liam.
Most Recent Customer Reviews
I was disappointed because the book came highly recommended. It was okay, just not compelling.Published 4 months ago by Suellen Fulstone
I loved this book! The plot and pace kept me thoroughly intrigued, and descriptions left vivid images in my mind, especially a few which caused me to pause and reflect, wonderfully... Read morePublished 11 months ago by BShatki
Maureen O'Donnell comes from a dysfunctional family. She is dealing with a history of sexual abuse and trying to find her own way in the world. Read morePublished 12 months ago by L. .G. avid reader
Playing catch-up and thoroughly enjoying it! I am new-ish to Denise Mina's mysteries and they have been great to read so far. Read morePublished 14 months ago by Janet K. Nabring-Stager
Garnethill, Exile and Resolution are the three books in this series and Garnethill is the author's debut novel. Read morePublished 15 months ago by Barbara


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|Fast Break: Nets cut down sluggish Celtics
|04.10.13 at 9:43 pm ET
The Nets ran the Celtics out of their own building, 101-94, but the Bucks bailed them out by losing in overtime to the lowly Magic. The C's own a three-game advantage on Milwaukee with four games to play. Here's what went wrong against the Nets, a tough matchup for the Celtics should they meet in the second round.
Worst first: In the opening quarter, the Nets committed three times as many turnovers (6) as they had assists (2). The Celtics held Brooklyn to 7-of-19 shooting, including an 0-for-3 frame from Williams. And somehow the C's trailed 22-21 after one. The fact that everyone not named Brandon Bass or Paul Pierce combined to shoot 3-of-16 didn't help. The Celtics had a chance to bury Brooklyn early. Instead, the opposite.
Garnett and Green: For different reasons, Kevin Garnett and Jeff Green struggled. Garnett seemed to be playing his way back into shape in his second game since missing two weeks with a foot injury, although he made 4-of-5 shots after finishing 1-for-6 from the floor in the first half. Meanwhile, Green got open looks but had an awful shooting night (4-17 FG). Easy rule of thumb: If scoring options 2 and 3 aren't working, the Celtics are in trouble.
Foul mood: Avery Bradley picked up three fouls in the first half and his fourth 49 seconds into the second, and Williams took full advantage. Actually, he was the reason Bradley got into foul trouble in the first place. The Nets point guard continued his improved play since failing to make the All-Star roster for the first time since 2009, recording a double-double (29 points, 12 assists). Speaking of fouls, the Celtics didn't attempt a free throw for almost 28 minutes (thanks to a heaping helping of jump shots). Somebody check on Tommy Heinsohn.
Super Bass: After averaging fewer than 10 points for the first five months of the season, Bass has scored in double digits in all five games this month. Heck, he practically reached that mark in the first quarter. Illustrating a more versatile offensive arsenal, he threw down a vicious two-handed dunk over Brook Lopez, knocked down an 18-foot jumper and showed off a creative post move on Reggie Evans on consecutive Celtics buckets in the opening frame. In an odd move, Celtics coach Doc Rivers opted not to play Bass for a lengthy second-half stretch while Reggie Evans and Kris Humphries of all people grabbed rebound after rebound.
Living Wilcox: Likewise, the C's nearly had to file a missing persons report on Chris Wilcox, who hasn't been the same since injuries to his thumb and alley-oop partner Rajon Rondo's knee. For the second straight game, Shavlik Randolph was the first big off the bench, and for the second straight game, Wilcox played like his playoff minutes depended on it. After all, he's never participated in the NBA's postseason. Eighty percent of his shots have come within 2 feet of the basket, and Wednesday was no different, but at least he earned those buckets.
Truth handles: While many of the Celtics regulars struggled — and frankly turned in a preseason performance — Pierce (23 points) plodded his way through another stellar effort. After citing the "chippiness" between the two teams, Pierce probably had this game circled on his calendar. He scored 13 points on four shots in the third quarter alone. While the lead continued to slip away from the C's as the game wore on, Pierce at least gave them a fighter's chance, even if he was the only one fighting.
To Doc Rivers, the key to playoff success will be outmaneuvering his opponent. Given the fact that he's going to be facing either the Knicks or Pacers in the first round, he's going to need as many options as possible.
Thus, with Paul Pierce and Jeff Green finding their rhythm heading into the playoffs, this gives Rivers and his staff another bullet in the holster.
"I like the ability to have that lineup and other lineups instead of just having this 'small lineup' with Jeff at the 4," Rivers said. "We want to have three lineups ' Jeff at the 2, Jeff at the 3, Jeff at the 4. Or if you want to call Paul the 2, I don't care who you call the 2. I just think it gives us more versatility.
Wednesday against the Nets, Rivers featured the lineup (Pierce, Green, Kevin Garnett, Brandon Bass and Avery Bradley) that's likely going to start the playoffs, of course barring another in an seemingly unending avalanche of injuries.
"This lineup is good," Rivers said. "It's important because it gives us a third lineup, because there's one lineup we can't go to, and that's the very big lineup, like two 7-footers. We're not going to be able to do that. We need to have as much versatility as possible going into the playoffs to play multiple styles."
Before Wednesday at the Garden, the Celtics and Nets hadn't met since Boston's cakewalk on Christmas Day when the Celtics beat the Nets, 93-76. A game later, Avery Johnson was fired and PJ Carlesimo was promoted to head coach. The Nets are 31-18 since. Read the rest of this entry »
|Why the buddy system is 'huge' for Doc Rivers
|at 12:37 pm ET
WALTHAM — Doc Rivers isn't just one of the most personable coaches among fans and media, he's one of the most likable among his fellow NBA head coaches.
And that – as it turns out – has its rewards.
As the playoffs near, Rivers has been tapping into that network of coaches for some inside intel. But Rivers isn't looking for advance scouting tips on his opponents; he's looking for what other coaches see in the Celtics.
Rivers was asked Tuesday at practice what he thought of teams like Cleveland and Washington defending Paul Pierce and Jeff Green with smaller, quicker guards.
"That won't last," Rivers predicted. "I think teams will go back and forth on it. And they did even in the game the other night [vs. Washington]. They started out small, went big and then went back to small. I think teams are trying to figure out which way they would guard them."
Why is that? All Rivers had to do was ask longtime friend and former Atlanta teammate Randy Wittman, now the coach of the Wizards.
"It's nice when you play, honestly, a team that's not in the playoffs and talk to the coach after the game. I asked what their reasoning [is] for choosing one or the other. It's been interesting the comments I've gotten back."
What kind of information?
"Good information," Rivers smiled. "They've always helped, and they're open for the most part," Rivers said of his postgame chats with the coaches. "They're not going to tell you their secrets but they're going to tell you some of their thoughts so they're helpful."
It's not just Wittman, either. On the current four-game homestand that ends against Brooklyn, the Celtics have played Detroit [Lawrence Frank], Cleveland [Byron Scott] and Washington [Wittman]. All three teams will be home in two weeks when the playoffs begin. And all three have head coaches with direct ties to Rivers.
"That's huge because otherwise, I wouldn't ask, to be honest," Rivers said. "So, if you have a relationship with a coach, it helps. And there's also a lot of coaches not coaching right now that you talk to a lot. You even ask them, 'Who would you guard or how would you attack?' It's good getting somebody outside of us because they see us entirely different than we see ourselves."
|Irish Coffee: Paul Pierce, Kevin Garnett trade rumors return
|at 12:26 pm ET
With the trade deadline long gone and the Celtics positioning themselves for another playoff run, just when you thought it was safe to table the discussion of trading veterans Paul Pierce and Kevin Garnett, Yahoo! Sports NBA writer Marc J. Spears reminds everyone that their departure is a very real possibility in the near future.
These two names were certainly hot before the trade deadline. A lot of people were wondering if Garnett might go to the Clippers or Paul might get moved. If something's going to happen with either one of them or both of them, the summer is a better time for that, because you're not in a rush. There's no real big deadline. You can think about it. Even draft night is a possibility.
Keep in mind, Pierce has one more year left on his deal. Pierce is still a valuable player, still a dynamic player. Keep an eye on a team like the Clippers. Not so much even for Garnett, but for Pierce, because if the Clippers stumble in the first or second round, I think that small forward position is something that they could use. They need maybe that No. 3 scorer or even that No. 2 scorer to kind of get them over the hump and be in the elite. He's from L.A., so I don't think Danny Ainge is going to send him to Minnesota. He's going to send him somewhere that he would be happy with, and I'm sure Paul probably thinks he he could get an extension with a team like the Clippers.
But the problem with trading Garnett is — no matter where it is, even if it was Miami — he could potentially retire. He's not a guy who wants a change, and he's a guy who's big on commitment. It would have to be a place where you'd have to have some stars that could convince him, but, to me, I think Pierce is probably the more likely guy if either of the two are to get moved in the offseason.
While speculation resumes about their future, Pierce and Garnett focus on preparing for the playoffs. The two spoke at length about developing consistency in a year full of inconsistencies. Here are the highlights.
|Paul Pierce doesn't see Brittney Griner making NBA
|04.09.13 at 2:59 pm ET
While Mavericks owner Mark Cuban claimed he might select Baylor women's basketball sensation Brittney Griner in the second round of this June's NBA draft and Heat wing Shane Battier suggested a woman will make the league in his lifetime, Celtics captain Paul Pierce doesn't foresee either scenario playing out anytime soon.
"I think it will be a little difficult, just because of the physicality of the sport," said Pierce, who has watched the many highlights of Griner. "The men are much faster, much stronger and much more athletic. Will it happen one day? I don't know. They have a women's league, where they are the best women in the world. Honestly, I can't tell you if I can see a woman right now playing in the NBA. Not in the next couple of years. No."
The 6-foot-8 senior set NCAA women's career records for dunks and blocks, won the national title as a junior and claimed her second straight Naismith Women's College Player of the Year trophy this season.
"If she is the best on the board, I will take her," Cuban told reporters before a game last week.
Added Battier: "There's no doubt that in our lifetime, there will be a woman NBA player."
As usual, Celtics coach Doc Rivers did a better dancing around the issue than anyone.
"If I find a green man walking down the street and I think he can rebound, I'm going to draft him," he told reporters prior to Friday's loss to the Cavaliers. "So, I don't think anyone cares. Obviously, it would make a huge story and it would be really cool. I just don't know the answer. I don't watch it enough to know, but it would be great."
Perhaps Pierce and Griner should play a game of 1-on-1 to settle this NBA debate once and for all.
|Doc Rivers compares gay NBA player coming out to Jackie Robinson, and other practice notes
|at 1:53 pm ET
WALTHAM — Sometimes movies imitate real life. And sometimes, it's the other way around.
With news last week that Dallas Mavericks owner Mark Cuban would welcome an openly gay player on his team and the coming out announcement by Magic Johnson's son, the subject has been a topic of discussion.
Doc Rivers was asked before Tuesday's practice about the potential impact on the NBA if a player came out as openly gay. Rivers drew a comparison to Jackie Robinson breaking the color barrier in baseball and major professional sports in 1947.
"There'll be a lot of talk about it and then I think it will go away," Rivers said. "It's [interesting]. As a team, I took the team to see '42' [on Monday]. There was a lot of talk and then all of a sudden, everybody starts playing. And I think the same thing will happen. So, that's the way I look at it."
Rivers also said there was much about the movie that reminded him of the 'Ubuntu' concept he brought in during the 2008 championship season.
"It was really good. It was fantastic," Rivers said. "It was a great team message. It's funny, you think race, but, really, it was more of a team message, when players on the Brooklyn Dodgers accepted Jackie. And a lot of it was because he was their teammate. Actually, one of the guys said that, he said, 'What do you expect? I'm your teammate.' And I just thought that was really a cool honor."
Rivers was asked if his players knew the historical impact and the story behind Robinson's MLB debut and breaking the color barrier.
"Yeah, I think a lot of players know the history," Rivers said. "Some may not have, I don't know that. But I always go by — I thought guys were at their full attention throughout the movie, and engaged, which I thought was really cool."
Other practice notes:
"Obviously, we have to take care of our position," Rivers said. "But, for Kevin, rest is always important, and Paul as well. But, other than that, we've thought about (resting them), we've talked about it."
"Yeah, that's a sad, sad thing," Rivers laughed. "I'm so disappointed in Terry. I mean, getting lost going out to have a drink with me — I can see that. But getting lost going to the ballpark, my gosh. And he lives two blocks away, and he was walking! I didn't know you could get lost walking. But, I guess you can."
|Kevin Garnett: 'I know what I have in there – I know who's willing to fight'
|04.08.13 at 12:02 am ET
Kevin Garnett knew coach Doc Rivers and trainer Ed Lacerte would be watching his every move Sunday night.
Playing for the first time since inflammation and bone spurs in the left foot caused him to sit out eight games, Garnett paced himself and scored 12 points and grabbed six rebounds in 24 minutes as the Celtics beat the Washington Wizards, 107-96, at TD Garden.
"I felt okay," Garnett said of playing for the first time since March 22 in Dallas. "I felt strong enough to play. I felt decent in my minutes and I picked and choosed when I was aggressive. I did the things I typically do. That was it. I told Ed that if I felt like I couldn't go that I wouldn't push myself but Doc has a lot of trust in what I'm doing. We were on the same page so so far so good.'
Rivers said the situation, as it turned out, was ideal for Garnett's return – that is, 24 minutes in a low pressure environment.
'I thought he was really good, really good," Rivers said. "And I thought his rhythm was good early. I was surprised how well he was running; I noticed that [Saturday] in practice. We did all fast-break stuff and I was just doing it for him, just so he could blow his lungs out, and I was surprised how well he was running. So that was good. And I don't know what we played him ' 24 minutes ' that's, I mean, you couldn't script that. That was perfect. Actually I wanted 20, but 25 was what I didn't want to go.'
Garnett was 6-of-9 from the field and was able to defend well, posting a plus-8 while on the court. While Paul Pierce was busy pointing out how important Garnett's presence is to Boston's postseason hopes, Garnett was focused instead on the way the rest of his team is playing.
'It doesn't matter what line-up goes or who's on the floor as long as we're playing the right way," Garnett said. "That's all my concern is. Just making sure that we're sharing the ball, playing as a team, giving up for each other, playing defensively, being one voice, one sound ' those are the things that are most important.' Read the rest of this entry »
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The Pentek WPX100BB20P Poly String Wound Big Blue Sediment Filter Cartridge is a 20" fibrillated polypropylene wound water filter used for whole house filtration. The advanced string wound design of the Pentek WPX100BB20P allows it to capture sediment, dirt, rust, limescale, silt, sand, and other particulates down to the 100 micron level. The WPX100BB20P is best used when the minimization of extractables and/or fiber migration is needed.
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Chinese Orange Pheasant
By Hank Shaw on March 3, 2016 | 12 Responses
OK, I'll admit it: I like Sad Panda's orange chicken. The combination of crispy, sweet, spicy and tart is more or less crack cocaine to humans, and I am not immune. Here's my version of that recipe, done with pheasant, grouse, quail, turkey or partridge.
Posted in Asian, Featured, Pheasant, Grouse, Quail, Quick and Easy, Recipe, Wild Game | Tagged asian recipes, chicken recipes, Chinese recipes, chukar, easy recipes, grouse, partridges, pheasant, quail | 12 Responses
Pan Roasted Partridge with a Winter Salad
By Hank Shaw on November 30, 2015 | Leave a response
Pan roasted partridges cooked simply and served with a my all-time favorite winter salad: radicchio, Belgian endive and bitter greens like dandelions. This is a bright, happy dinner to make on a cold winter night.
Posted in Featured, Pheasant, Grouse, Quail, Recipe, Wild Game, Winter Recipes | Tagged easy recipes, grouse, partridges, pheasant, salads, Wild Game, woodcock | Leave a response
Pheasant Noodle Soup
By Hank Shaw on November 23, 2015 | 8 Responses
Pheasant soup. Pheasant noodle soup, to be exact. Why it's taken me so long to post up this classic I have no idea. But it's comfort food at it's best: Easy to make, satisfying, and you'll get leftovers.
Posted in American Recipes, Featured, Pheasant, Grouse, Quail, Recipe, Wild Game | Tagged classic recipes, grouse, partridges, pheasant, soups, Wild Game | 8 Responses
Chaos Theory and Roast Partridge
By Hank Shaw on October 26, 2015 | 5 Responses
Roast partridge, grouse or quail is a wonderful idea, but in practice the bird often comes out dry. Pan roasting is a far better way to roast game birds. This is by far the best way to cook upland birds, or small, skinny ducks like teal.
Posted in Cooking Basics, Featured, How-To (DIY stuff), Pheasant, Grouse, Quail, Recipe, Wild Game | Tagged Cooking Basics, easy recipes, grouse, partridges, quail, Wild Game | 5 Responses
Pheasant Green Curry
By Hank Shaw on February 19, 2015 | 8 Responses
As much as I like Indian curries, I like Thai curries even more. This is a bright, spicy Thai green curry done with pheasant breasts. It's actually a lot easier to make than it looks.
Posted in Asian, Featured, Pheasant, Grouse, Quail, Recipe, Wild Game | Tagged asian recipes, curry, partridges, pheasant, quail, rabbits and hares, stews, Wild Game | 8 Responses
Pheasant Confit
By Hank Shaw on December 19, 2013 | 13 Responses
Most of us know about duck confit — where you salt duck legs, then slow cook them in duck fat until they are meltingly tender, then you crisp them up in a hot oven? Yeah, that's confit. There's a reason it's all over restaurant menus, but check it: This process works great with pheasant and other upland game birds, too!
Posted in Charcuterie, Featured, French, Pheasant, Grouse, Quail, Recipe, Wild Game | Tagged classic recipes, French Recipes, grouse, partridges, pheasant, preserved foods, quail, turkey recipes | 13 Responses
Spanish Partridge, Pheasant or Quail Escabeche
By Hank Shaw on November 1, 2013 | 5 Responses
An old Spanish recipe for partridges, you sear the birds then simmer them in a vinegary sauce and store in jars in a cool place, like a fridge. I like to take a couple partridges out and eat them at room temperature, while watching football…
Posted in Appetizers and Snacks, Featured, Pheasant, Grouse, Quail, Recipe, Spanish, Wild Game | Tagged classic recipes, partridges, pheasant, quail, spanish recipes, Wild Game | 5 Responses
Grilled Partridges with Tomato Salad
By Hank Shaw on September 20, 2013 | 3 Responses
As we say farewell to the hot weather of summer — and for many, our tomato patches — here is a fantastically simple way to enjoy a small bird such as a partridge, chukar, quail or game hen.
Posted in Featured, Pheasant, Grouse, Quail, Quick and Easy, Recipe, Summer Recipes, Wild Game | Tagged chukar, easy recipes, gluten free, grilling, partridges, quail, tomatoes | 3 Responses


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2005 Infiniti QX56 4WD 4dr SUV (5.6L 8cyl 5A)
Great car. I really like the style. Great handling for the size. Needs better quality for interior. Overall great car!!
style and drive
better interior quality
2005 Infiniti QX56 Rwd 4dr SUV (5.6L 8cyl 5A)
Beautiful car with powerful engine. The leather interior cannot measure up to Lexus's although the design is far better.
The exterior body and design is the best in its class
the quality of interior leather
This car has a great drive train but rides rough, rattles and the wheels vibrate like crazy. The dealership says it was design so tight that you will feel more of the road. If the road is not a good road then you will feel it in the steering wheel. I'm trying to get them to satisfy me but not getting anywhere. This car needs work.
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Suppose that under the conventional randomized clinical trial setting, a new therapy is compared with a standard treatment. In this article, we propose a systematic, 2-stage estimation procedure for the subject-level treatment differences for future patient's disease management and treatment selections. To construct this procedure, we first utilize a parametric or semiparametric method to estimate individual-level treatment differences, and use these estimates to create an index scoring system for grouping patients. We then consistently estimate the average treatment difference for each subgroup of subjects via a nonparametric function estimation method. Furthermore, pointwise and simultaneous interval estimates are constructed to make inferences about such subgroup-specific treatment differences. The new proposal is illustrated with the data from a clinical trial for evaluating the efficacy and toxicity of a 3-drug combination versus a standard 2-drug combination for treating HIV-1–infected patients.
One of the major components for modern evidence-based medicine is to utilize the patient's "baseline" information for personalized disease management and treatment selection. For instance, in a recent study, it was demonstrated that the benefit of giving toxic chemotherapy prior to hormone therapy with tamoxifen for postmenopausal women with lymph node–negative breast cancer varies depending on the estrogen receptor (ER) status of the tumor. Those with ER-negative tumors benefited substantially from chemotherapy, while those with ER-positive tumors did not benefit as compared to receiving tamoxifen alone (Goldhirsch and others, 2002). In another example with an observational study, Sabine (2005) suggested that the efficacy and toxicity profiles for the highly active antiretroviral therapy vary markedly across different subgroups of HIV-infected patients and recommended certain subject-specific treatment strategies. These individualized decision rules can be extremely useful in practice. However, there are numerous examples that the results from the so-called subgroup analyses, which were not properly planned or executed subgroup analyses, could not be validated (Rothwell, 2005, Pfeffer and Jarcho, 2006, Wang and others, 2007).
In this paper, we consider the case that a new therapy was compared with a control under the standard randomized comparative clinical trial setting. Generally, the main goal of a randomized clinical trial is to make inferences about an "overall" treatment difference with respect to efficacy and toxicity. On the other hand, a "positive" trial does not imply that all future patients would benefit from the new treatment. Moreover, a "negative" study does not mean that all patients should be treated by the standard therapy. In fact, based on the extensive collection of the study patient's baseline information from a clinical trial, it would be valuable to utilize such information to make inferences about the individual-level treatment efficacy.
In practice, a commonly employed first step to perform subgroup analyses is to examine whether there are statistically significant interactions between the treatment assignment indicator and various baseline covariates via, for example, parametric regression models (Byar, 1985). This ad hoc "fishing expedition" approach may not accurately or efficiently identify proper subgroups of patients who would benefit from the new treatment. Recently, Song and Pepe (2004) proposed a novel procedure to identify a critical value for a "single" covariate, which may guide us to split the future population into 2 groups. Patients in one group would be treated by the new therapy and those in the other group would take the control. Although such a approach is interesting with respect to an overall utility for the entire population, it does not provide a treatment choice scheme at a subject-specific level. Moreover, if the treatment difference is not monotonically associated with this single covariate, such a procedure may not be appropriate. To examine the treatment difference at a subject-level with a single covariate (Bonetti and Gelber, 2000, Bonetti and Gelber, 2005) grouped the patients with their covariate values and utilized a moving average procedure to make inferences about the profile of the treatment differences over the covariate. Recently, in her unpublished thesis, Park (2004) proposed a procedure to identify patients who may or may not benefit from the new treatment based on generalized linear models and the Cox proportional hazards models. The validity of her procedure heavily relies on the model assumptions.
In this paper, we consider the case that each patient has "multiple" baseline covariates and propose a systematic, 2-stage method to identify patients who would benefit from the new treatment. Specifically, for the first stage, we use a parametric or semiparametric model to estimate the subject-specific mean response for each treatment group. We then utilize the resulting difference of these 2 estimates as an index scoring system to group patients. That is, subjects in each subgroup would have the same parametric index score. For the second stage, we calibrate the estimated treatment differences with a consistent, nonparametric function estimation procedure and provide valid "pointwise" and "simultaneous" inferences about the true average treatment difference for each group of patients by controlling the desirable confidence level locally and globally. The new proposal is illustrated with a data set from a clinical trial for evaluating a 3-drug combination versus a standard 2-drug combination for treating HIV-infected patients. For cost-benefit decision makings, we also provide the underlying mean treatment response for each treatment group over the index score and the estimated relative frequency for the parametric score.
Suppose that study subjects in a population of interest are randomly assigned to either a standard treatment denoted by G = 0 or an experimental treatment denoted by G = 1. Let U denote a vector of baseline covariates, Y denote the response variable, and Y(k) denote the potential outcome of an individual if he/she were assigned to treatment group G = k. Without loss of generality, we assume that a larger value of Y is beneficial. Now, suppose that for subjects with U = u, we are interested in estimating the treatment difference
Our data consist of n random vectors {(Yi,Ui,Gi),i = 1,…,n}, where we assume that {(Yi,Ui):Gi = k} are nk = ∑i = 1nI(Gi = k) independent and identically distributed random vectors, for k = 0,1. Furthermore, the ratio n1/n goes to a constant in the open interval (0,1) as n→∞. To estimate (u), one may consider a nonparametric function procedure. In practice, however, when u is not univariate, generally it is difficult, if not impossible, to estimate (U) well nonparametrically.
To reduce the complexity of the high-dimensional problem, conventionally one utilizes a parametric or semiparametric procedure to estimate (u). Here, we consider the following generalized linear "working" model to approximate the mean function of Y(k):
where Z, a p×1 vector, is a function of U with first column being 1, gk is a known, strictly increasing smooth link function, and βk is an unknown vector of regression coefficients. Note that in (2.1), we only model the mean function of Y. To estimate the parameter vector βk in (2.1) without distribution assumptions about the response, one may use a solution to the following estimating equation:
Using the arguments given in Tian and others (2007), one can show that converges to a deterministic vector even when Model (2.1) is incorrectly specified. This stability property is crucial for developing our new procedure. It follows that for a given u, a parametric estimator for (u) is
Note that when Model (2.1) is correctly specified, is the true parameter for Model (2.1) and is a consistent estimator of (u).
Let U0 be the baseline covariate vector for a future subject from the study population. If this subject is treated by treatment k, the response is Y(k)0,k = 0,1. For U0 = u0, we may use to decide which treatment this specific subject should be treated with. The adequacy of such a decision heavily depends on the appropriateness of Model (2.1). On the other hand, may be used as an index scoring system for grouping future subjects with potentially similar treatment differences. That is, we divide the future population into many strata based on the score such that patients in the same subset have the same parametric score value v. To employ such scoring system in clinical practice, one could create strata by segmenting all possible values of into small intervals.
Now, for any given v, consider subjects in the subset Ωv. We propose to consistently estimate the average treatment difference for this subgroup,
based on a local likelihood approach (Tibshirani and Hastie, 1987, Fan and Gijbels, 1996), where μk(v) = E(Y(k)0|U0Ωv),k = 0,1, and the expectation is taken with respect to the data and (Y(k)0,U0). Specifically, we obtain the root to the local weighted estimating equation, where
where h is the smoothing parameter chosen such that h = Op(n − ν) with 1/5 < ν < 1/2, Kh(x) = K(x/h)/h, K(x) is a symmetric kernel function with a finite support, and ψ(·) is a suitably chosen, nondecreasing function. Here, g(x) = x if the response Y is continuous and g(x) = exp(x)/{1 + exp(x)} if Y is binary. Transforming the score via an appropriately chosen function, ψ(·) could potentially improve the performance of the kernel estimation (Wand and others, 1991, Park and others, 1997). The μk(v) can then be estimated by This estimator corresponds to the local linear least square estimator for continuous Y and local linear logistic likelihood estimator for binary Y. Subsequently, we estimate as
In Section A of the Supplementary Material available at Biostatistics online, we show that is uniformly consistent for , for v = [ρl,ρr], where is an interval properly contained in the support of .
To construct confidence interval for , the average treatment difference among the stratum Ωv, we show in Section B of the Supplementary Material available at Biostatistics online that for large n, the distribution of can be approximated by the conditional distribution of a mean-zero normal variable
given the data, where is a random sample from the standard normal variable and is independent of the data, is obtained by replacing in with , for k = 0,1, where for any function g, g(·) denotes its derivative. Note that is a solution to the counterpart of estimating equation (2.2), which is perturbed with the same set of in (2.4). Also, note that are the only random quantities in (2.4), whose distribution can be approximated easily by simulating repeatedly. A (1 − α) pointwise confidence interval estimates for can be constructed via this large-sample approximation, which is . Here, is the standard error estimate of and d is the upper (1 − α/2) percentile of the standard normal.
To select subgroups that may benefit from the new treatment, one may aim to identify regions of v such that is above or below a certain threshold value. However, as for any subgroup analysis, it is crucial to control for the global error rate. For the present case, we may control for the overall error rate by constructing a simultaneous confidence band for . Specifically, to make inference about the treatment differences over a range of v, one may construct a simultaneous confidence band for A conventional way to obtain such a confidence band is based on a sup-type statistic
Although does not converge weakly as a process in v, we show in Section C of the Supplementary Material available at Biostatistics online that a standardized version of converges in distribution to a proper random variable. In practice, for large n, one can approximate the distribution of by , the sup of the absolute value of divided by , with (2.4) perturbed by the same set of perturbation variables for all v. It follows that the 100(1 − α)% simultaneous confidence interval for is
where the cutoff point γ is chosen such that pr
The simultaneous interval estimators for can be used to suggest treatment options for patient subgroups. For example, if there is little concern regarding the cost of the new treatment relative to the standard treatment, then one may suggest the new treatment to subgroups in On the other hand, if the new treatment is expensive or has serious adverse risk, only patients with where c0 is a preselected cutoff value representing adequate benefit. Making decisions based on the simultaneous confidence intervals ensures that there is no inflated type I error associated with testing whether exceeds or is above a certain threshold value for a range of v. This is particularly important if is a nonmonotone function crossing zero more than once.
As for any nonparametric functional estimation problem, the choice of the smoothing parameter h for is crucial for making inferences about . We may choose a single smooth parameter for 2 nonparametric function estimates, and . Since each study subject is assigned to a single-treatment group, therefore, we cannot use the standard cross-validation method with the integrated mean square error criterion to choose h for . A reasonable, feasible alternative to choose an "optimal" smooth parameter is minimizing an average squared distance between the observed "cumulative" treatment difference, and their predicted counterparts in the validation samples under the -fold cross-validation setting. Noting that
we propose to use empirical estimates of E(Yi|Gi = 1,Ui ≤ u) − E(Yi|Gi = 0,Ui ≤ u) as the observed cumulative treatment difference and the empirical counterpart of as the predicted cumulative treatment difference based on the proposed procedure. Here and in the sequel, for any 2 vectors U = (U1,…,Uq)T and u = (u1,…,uq)T, U ≤ u denotes {Uj ≤ uj,j = 1,…,q}. Specifically, we randomly split the data into disjoint subsets of about equal sizes, denoted by {ι,ι = 1,…,}. For each ι, we use all observations not in ι to obtain estimators for the parametric index score and with a given h. Let the resulting estimators be denoted by and , respectively. We then use the observations from ι to calculate the empirical integrated cumulative square error
where I(·) is the indicator function and is an empirical weight function such as the empirical distribution function. Last, we sum (2.8) over ι = 1,…,, and then choose h by minimizing this sum. It is important to note that since the bandwidth is selected by minimizing a quantity which is composed of cumulative predicted errors, the order of such optimal bandwidth is expected to be n − 1/3 (Bowman and others, 1998). Thus, the selected bandwidth satisfies the condition required for the resulting functional estimator with the data-dependent smooth parameter to have the above desirable large-sample properties.
We use a data set from a clinical trial conducted by the AIDS Clinical Trials Group (ACTG) to illustrate the new proposal. Here, we present 2 cases, the first one is for a continuous response and the second case is for a binary end point. This study, ACTG 320, is one of early studies for examining the clinical added value from a protease inhibitor with 2 nucleoside analogues for treating human immunodeficiency virus type 1 infection (Hammer and others, 1997). A total of 1156 patients were randomized to 2 treatment groups. Here, treatment 0 is the 2-drug combination, zidovudine and lamivudine, and treatment 1 is the 3-drug combination consisting of the above 2 and indinavir. The study was terminated at the second formal interim analysis due to substantial overall improvements from the 3-drug combination over the standard 2-drug combination with respect to various study end points. However, even with this potent new treatment, some patients may not respond to the therapy but instead suffer from nontrivial toxicity. Therefore, for future patients' disease management, it is important to predict patient's treatment responses based on certain "baseline" markers.
For the first example of the illustration, we let the response Y be the patient's change of CD4 count at week 24 from the baseline level, an important end point for evaluating HIV treatments. In our analysis, we only considered subjects who had baseline covariate and CD424 values (n0 = 429, n1 = 427), where CD4k denote the CD4 count at week k. Here, the vector u of baseline covariates consists of CD40, log10RNA0, and age. To accommodate the potential nonlinear relationship between CD40 and the response, we let z in Model (2.1) be the vector (1,CD40,logCD40,log10RNA0,Age)T. Furthermore, we let g0(·) and g1(·) be the identity function. The estimated regression coefficients for fitted models via the estimating equations (2.2) are summarized in Table 1(a). It appears that the 2 resulting fitted regression functions are rather different, indicating that there are potential interactions between the baseline covariates and the treatment response. It is interesting to note that for the 2-drug combination group, only age is marginally significant. On the other hand, the baseline CD4 and RNA are highly associated with the response for the 3-drug combination group. Moreover, note that younger patients with higher log10RNA0 tend to have high scores. For example, among the 44 patients with age below 40, log10RNA0 more than 5, and CD40 between 100 and 150, the average score is 95. On the other hand, among the 46 patients with age above 40, CD40 above 150, and log10RNA0 below 5, the average score is only 25.
Estimated regression coefficients and their standard error estimates for the 2 treatment groups with the data from ACTG 320
For the second step, we used this continuous score index to group future patients and predict the true treatment difference for patients with with Here, since the estimated score has a left skewed distribution, we let ψ(v) = log( − log[Φ{(v − 70)/25}]) be the transformation for choosing the smooth parameter h. The kernel function K(·) is the Epanechnikov kernel, and the smoothing parameter h was obtained through a 10-fold cross-validation as a minimizer for the criterion (2.8). Furthermore, in (2.8), the weight function , where . The resulting bandwidth h = 0.93 for the transformed score. Here, the confidence intervals for were constructed for the transformed score ψ(v)[ − 1.73,1.12]. This corresponds to v[30,94], which is where is the pth percentile of the observed . In Figure 1(c), we present the estimate , the solid curve. This curve, in some region, seems markedly different from the 45-degree line. For example, subjects with score 60 have an estimated average treatment difference of 45, indicating that the parametric risk estimates need to be calibrated.
(a): The estimated density function of the parametric score with respect to week 24 CD4 changes; (b): Estimated group averages of week 24 CD4 changes over the score for 2- and 3-drug combination groups; (c): Estimated treatment differences (thick curve), ...
To make further inferences about we approximated the distribution of the estimator via the aforementioned perturbation-resampling method (2.4) with 500 independent realized normal samples of . In Figure 1(c), we present the resulting 0.95 pointwise intervals (bounded by the dotted curves) and its simultaneous band (gray area). For risk-cost-benefit decision makings, we also present the estimates the underlying mean changes at week 24 for both treatment groups in Figure 1(b). We present the relative frequency of patients in the study population based on the index score in Figure 1(a). Since most patients have estimated scores between 50 and 90, the estimation of the true treatment differences tends to be more precise in this region.
The average treatment response from the 3-drug combination group is uniformly higher than its counterpart from the 2-drug combination. However, the treatment differences do not change much when index score values are low but for score values higher than 50, the treatment differences appear to increase significantly. The confidence interval estimates displayed in Figure 1(c) play important roles for treatment selections, especially with additional information regarding the toxicity profiles over the index score.
For the second example, we considered the patient's response being a binary variable, which is one if the week 24 RNA is below 500 copies per milliliter (the criterion for the RNA response used for ACTG 320). Since the linear effects of CD40 are almost 0 for both groups, we only included logCD40 for this analysis. It follows that z = (1,logCD40,log10 R N A 0, A g e )′ and g0(x) = g1(x) = exp(x)/{1 + exp(x)} for Model (2.1). Here, n0 = 408 and n1 = 416. In Table 1(b), we present the estimates for the regression parameters and their estimated standard errors. It appears that older patients with higher baseline CD4 tend to have higher score. The score appears to increase initially with log10RNA0 and drop after log10RNA0 exceeds 4.0. For the present case, the estimated score is between − 1 and 1, we applied a transformation ψ(x) = log{(x + 1)/(1 − x)} for choosing smooth parameter. The optimal bandwidth corresponding to the transformed score is 0.49 using the 10-fold cross-validation procedure as the one for the continuous response case. The confidence intervals for were constructed over ψ(v)[0.72,1.76] which corresponds to v[0.34,0.71]. In Figure 2(c), we present the estimated treatment differences (solid curve) over the index score. For this end point, the 3-drug combination is substantially and uniformly better than the 2-drug combination as shown in Figure 2(b). For instance, for patients with a score of 0.35, the probability of having RNA suppressed below the limit of quantification is 46% if treated with the 3-drug therapy and only 8% if treated with the 2-drug alternatives. For this subgroup, the true treatment difference was estimated as 0.38 with 95% pointwise confidence interval [0.32,0.43] and 95% simultaneous confidence interval [0.30,0.46].
(a): The estimated density function of the parametric score with respect to week 24 HIV-RNA; (b): Estimated averages of week 24 RNA over the score for 2- and 3-drug combination groups; (c): Estimated treatment differences (thick curve), 3-drug combo minus ...
To assess the performance of the proposed procedure under practical settings, we conducted numerical studies to examine the finite-sample performance of our proposed point and interval estimators. Based on the results of the studies, we find that the new proposed estimation procedure has negligible bias and the coverage levels are very close to the nominal counterparts. For example, in one of our simulation studies, we simulated data with continuous CD4 response by mimicking the HIV study. Specifically, we generated CD424 from a log-normal model with a 3×1 covariate vector, U = (log10RNA0,Age,logCD40)T. First, for each subject, we generated U from a multivariate normal with mean and covariance matrix obtained from the observed HIV data. Then, for each given value of U, we generated CD424 from
where α1 = (0.13,0.0086, − 0.45)T, α0 = ( − 0.041,0.0033, − 0.24)T, σ1 = 0.69, and σ0 = 0.73. These parameters are also obtained from fitting the above model to the observed data.
We considered a moderate sample size of n0 = n1 = 500 and relatively large-sample size of n0 = n1 = 5000. Since the estimated score has a left skewed distribution, we let ψ(v) = log( − log[Φ{(v − 76)/33}]) be the transformation for choosing the smooth parameter h. For computational ease, the bandwidth for constructing the nonparametric estimate was fixed at h = 0.95 for nk = 500 and 0.39 for nk = 5000. Here, these h's were chosen as the averages of the bandwidths selected based on (2.8) from 10 simulated data sets. For both settings, the nonparametric estimator has negligible bias, the estimated standard errors are close to their empirical counterparts, and the empirical coverage levels of the 95% confidence intervals are close to the nominal level. In Figure 3, we summarize the results of our findings performance for the point and interval estimation procedures for when nk = 500 in (a) and 5000 in (b). The proposed procedures have negligible bias and the estimated standard errors are close to the empirical standard errors. When the sample size is relatively small, the estimated standard errors are slightly lower than the empirical standard errors and the coverage levels are slightly lower than the nominal level when the score is near the upper boundary points. However, both the standard error estimates and the coverage levels improve when we increase the sample sizes to nk = 5000. For example, when v = 80, the coverage level for is 97.7% when nk = 500 and 95.4% when nk = 5000. When v = 115, the coverage level for is 92.3% when nk = 500 increase to 94.5% when nk = 5000. The simultaneous confidence intervals have a coverage level of 95.9% when nk = 500 and 97.1% when nk = 5000.
Summary of the simulation results for (a) n0 = n1 = 500 and (b) n0 = n1 = 5000. Left panel: the empirical average of the estimated treatment difference (solid black curve) versus the true treatment difference (solid gray curve). Shown also are the 45o ...
Under the parametric models given in the first stage, the estimated score consistently estimates the true conditional treatment difference (u) = E(Y(1) − Y(0)|U = u). Consequently, the calibrated estimator is also a consistent estimator of (u). The nonparametric estimator may be less efficient than its parametric counterpart. When the parametric models fail to hold, inferences about the treatment differences based on alone may be invalid. On the other hand, is always a consistent estimator of the average treatment effect for the subgroup with regardless the adequacy of the first-stage working models in (2.1). Nevertheless, how well approximates (U) does affect the effectiveness of the proposed procedure in selecting treatment options. When is a poor approximation to (u), grouping patients based on may not be optimal in terms of treatment selection and including additional covariates for constructing may yield a more informative scoring system. More flexible parametric models those considered in Royston and Sauerbrei (2004) can be used to improve the fitting in the first stage. Another important issue is the selection of predictive covariates for constructing . This initial step could be carried out with careful exploratory analyses. When there are large number of candidate predictors, appropriate subset selection procedures such as the LASSO (Tibshirani, 1996) may be used. On the other hand, it is important to note that under correct specification of (2.1) with {g1,g0} being nonidendity functions, covariates predictive of the treatment difference (U) are not only those significantly "interact" with the treatment assignment but also those relate to the outcome in either treatment groups. When the models are misspecified, interactions may not be well defined and ensuring the validity of the inferences about treatment difference under such settings becomes even more crucial.
In practice, it is often not feasible to completely recover information on (u) when the dimension of U is not small and the effects of U on Y are complex. An interesting and important question is how to evaluate the parametric index scoring system, which can "efficiently" group patients for the first stage of our proposal. Unlike the standard risk prediction problem, there is no obvious metric such as the receiver operating characteristic curve to evaluate the performance of the index system globally or locally. On the other hand, one may assess the effectiveness of in grouping patients by examining how well approximates (u). To examine whether is an adequate approximation to (u), one may construct cumulative residual processes based on (2.7) similar to those used in (2.8). One may expect due to the same reason, it is also important to compare different scoring systems. Intuitively, a scoring system is good if the corresponding has big variation for U0 in the target population and thus can better differentiate different patients subgroups.
In practice, one may also be concerned about the efficiency in estimating . It is possible to improve efficiency by augmenting the proposed estimators similar to those proposed in Zhang and others (2008). Specifically, using the fact that the treatment assignment G is independent of U, one may augment the proposed estimator with estimating functions of the form
where p1 = P(G = 1) and ζ is a prespecified multivariate function of U. Let denote the covariance of and and denote the variance–covariance matrix of . Then the augmented estimator could be more efficient than , especially if is significantly correlated with .
One may use the same approach presented in this article to estimate individual-specific treatment differences from an observational study. Such estimates, however, may not have the causal interpretation for the treatment intervention. The treatment difference may also be quantified using other measures for the contrast between 2 treatment groups, for example, the relative risk or odds ratio for binary response variable. Furthermore, using the same idea presented in this article, one may develop subject-level inference procedures for the treatment differences with a censored event time end point. For example, one may fit a proportional hazards working model for the 2 treatment groups and obtain the conditional hazard ratio as the scoring index. Subsequently, we may obtain risk differences within each subgroup based on conditional Kaplan–Meier estimates. When the variability or sample size of one treatment group is substantially larger than the other, one may allow the bandwidth h to depend on the treatment group. For such cases, optimal {h0,h1} can be chosen to minimize the integrated cumulative squared error in (2.8) with respect to both bandwidths. We provide theoretical justifications for the proposed procedures under this more general case in the Supplementary Material available at Biostatistics online.
U.S. National Institutes of Health (R01 GM079330, R01 HL089778, R01 AI052817, U54 LM008748-06).
Supplementary material is available at http://biostatistics.oxfordjournals.org.
The authors are grateful to the editors and the reviewers for their insightful comments on the article. Conflict of Interest: None declared.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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